Review Article Genome Stability Pathways in Head and Neck...

Hindawi Publishing CorporationInternational Journal of GenomicsVolume 2013 Article ID 464720 19 pageshttpdxdoiorg1011552013464720

Review ArticleGenome Stability Pathways in Head and Neck Cancers

Glenn Jenkins12 Kenneth J OrsquoByrne23 Benedict Panizza13 and Derek J Richard2

1 University of Queensland Brisbane QLD Australia2 Cancer and Ageing Research Program Institute of Health and Biomedical Innovation at the Translational Research InstituteQueensland University of Technology Brisbane QLD Australia

3 Princess Alexandra Hospital Brisbane QLD Australia

Correspondence should be addressed to Glenn Jenkins jenkinsglenngmailcom

Received 7 June 2013 Revised 19 September 2013 Accepted 20 September 2013

Academic Editor Margarita Hadzopoulou-Cladaras

Copyright copy 2013 Glenn Jenkins et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Genomic instability underlies the transformation of host cells towardmalignancy promotes development of invasion andmetastasisand shapes the response of established cancer to treatment In this review we discuss recent advances in our understandingof genomic stability in squamous cell carcinoma of the head and neck (HNSCC) with an emphasis on DNA repair pathwaysHNSCC is characterized by distinct profiles in genome stability between similarly staged cancers that are reflected in risk treatmentresponse and outcomes Defective DNA repair generates chromosomal derangement that can cause subsequent alterations in geneexpression and is a hallmark of progression toward carcinoma Variable functionality of an increasing spectrum of repair genepolymorphisms is associated with increased cancer risk while aetiological factors such as human papillomavirus tobacco andalcohol induce significantly different behaviour in induced malignancy underpinned by differences in genomic stability Targetedinhibition of signalling receptors has proven to be a clinically-validated therapy and protein expression of other DNA repair andsignalling molecules associated with cancer behaviour could potentially provide a more refined clinical model for prognosis andtreatment prediction Development and expansion of current genomic stability models is furthering our understanding of HNSCCpathophysiology and uncovering new promising treatment strategies

1 Introduction

Carcinogenesis and evolution of the cancer genome aredriven by genomic instability We review here advances inour understanding of the pathways that preserve genomeintegrity that have improved insight into cancer behaviourprediction prognosis and personalised therapy Traditionalanticancer therapy has exploited the inherent genomic insta-bility of malignancy however this mutagenic pressure alsopromotes the emergence of treatment resistance invasionand metastasis (Figure 1) Squamous cell carcinoma of thehead and neck (HNSCC) is the sixth most-common cancerin the developedworld [1 2] and represents a therapeutically-challenging behaviourally-heterogenous category of diseaseGenomic instability is a defining characteristic of HNSCC[3] Subregional differences in patterns in risk treatmentresponse and prognosis in HNSCC are underpinned by aeti-ological factors that affect genomic stability in different ways

In HNSCC the principal subsites of the upper aerodigestivetract are oral cavity (including tongue floor of mouth andbuccal surface) nasopharynx oropharynx (including tonsiland base of tongue) and larynx An important emergentepidemiological change in HNSCC has been the increasingprevalent of human papillomavirus- (HPV-) associated can-cer

Chemotherapy regimens in HNSCC are based on plat-inum compounds prototypically cisplatin with or without5-fluorouracil [4] with greatest effect when given concur-rently with radiotherapy [5 6] The absolute 5-year sur-vival benefit conferred by concurrent cisplatin5-fluorouracilchemotherapy is a modest 45 [5 7] and is associated withsignificantly increased treatmentmorbidity andmortality [8]Newer chemotherapeutic agents include taxols and epider-mal growth factor receptor- (EGFR-) inhibitors [9] Additionof docetaxel a mitotic spindle stabilizer to PF inductionchemotherapy has been shown to confer an additional

2 International Journal of Genomics

Viral oncoprotein-induced cell cycle

dysregulationTobacco alcohol and other

exogenous carcinogens Ionising radiation

Nonselective cytotoxic chemotherapy

Ionising radiation

Functional genomic stability pathway

polymorphism

Germline DNA repair-deficient syndrome Predisposing

factors

Causative agents

Therapeutic cytotoxic agents

Figure 1 Common genomic stressors in carcinogenesis and therapy

survival benefit [10] although heterogeneity between trialtreatment arms and high loss-to-followup make absolutebenefit difficult to interpret EGFR inhibitor therapy hasemerged as an effective adjuvant in HNSCC and is discussedin detail below

Chromosomalmutation is one of themost readily observ-able features of cancer and has been known to underpinmalignancy for over a hundred years [11] The mechanismbehind most common chromosomal lesions is genomicinstability which is influenced by the interdependent triad ofaccumulating DNA damage defective DNA damage repairand replication stress In HNSCC DNA damage is increasedby exposure to carcinogens (tobacco alcohol and variousregionally specific botanicals) Ineffective repair by a numberof germline variations in the DNA repair pathways longrecognised in congenital repair syndromes such as Fanconianemia have been increasingly implicated as factors inHNSCC particularly in phenotypically silent individualswith single-nucleotide polymorphisms (SNPs) of DNA repairgenes The DNA damage response is a highly conservedpathway that is activated on the basis of a ldquothresholdrdquoof DNA damage events and functions to inhibit cell cycleprogression via checkpoint signalling for either repair orapoptosis as well as directly in the repair of the lesions Thesepathways are known to be constitutively active in dysplasticlesions [12ndash14] This genetically unstable environment drivesmutagenic stress with selective pressure for inactivation ofgrowth restrictingapoptotic processes [13 15] Replicationstress drives the accumulation of DNA lesions in HNSCCand is promoted by genetic loss of cell-cycle checkpointcontrol through mutation and epigenetic loss via oncoviralcoinfection with high-risk human papillomavirus (HPV)

Head and neck squamous-cell carcinoma has a malepredominance and is associated with tobacco alcohol anduse of a number of alkaloid-rich regional stimulants (suchas betel nut) A subset of HNSCC is strongly associated withldquohigh-riskrdquo HPV subtypes 16 and 18 infection [16] that are

present in up to 60ndash80 of nonoral HNSCC and 30 oforal cavity SCC in a Western population [17ndash20] This groupof disease that affects younger patients is proportionallyassociatedwith number of sexual partners and has a distinctlyimproved prognosis and different treatment profile fromHPV-unrelated oropharyngeal HNSCC [21ndash27] as well as adistinct pattern of chromosomal mutation [28 29] Prog-nostic significance in oral cavity SCC is less clear (reviewedin [19]) The association of HPV with oral squamous-cellcarcinoma was observed 30 years ago [30] however theepidemiological changes became more evident over the fol-lowing decades as decreased tobacco use and increased HPVprevalence highlighted this subgroup [16] Viral oncoproteinsE6 and E7 have been implicated as the causative agentsin HPV-associated HNSCC E6-induced ubiquitin-mediatedproteosomal degradation of tumour suppressor p53 causescell-cycle dysregulation and increased replication stress [31ndash33] Oncoprotein E7 binds to and disrupts pRb-mediateddegradation of transcription activator E2F which promotesgenes responsible for cell-cycle progression [34ndash36] Tumoursuppressor protein p16 a CDK4A inhibitor is characteristi-cally elevated in E7-induced pRb suppression to the extentthat p16 levels are typically used as a surrogate marker forHPV-related SCC [37ndash39] E7 has also been shown to induceaberrant centrosome number and mitotic spindle formation[40 41] These proteins function to allow viral replicationin the normally postmitotic upper differentiated epitheliallayers [42] Whole-exome sequencing has shown that HPV-related HNSCC is associated with less instability with a 2-fold lowermutation rate [43] Interestingly while suppressionof the upstream DNA damage response ataxia-telangectasiamutated protein (ATM) and ataxia-telangectasia and Rad3-related protein (ATR) is deleterious forHPVepisome stability[44] cell line studies have shown that the radiosensitivity ofHPV-16 related SCC is attributable in part to a repair defectwith accumulation of unrepaired DNA double strand breaksand resultant cell-cycle arrest [45] This study was conducted

International Journal of Genomics 3

using a limited number of cell lines rather than fresh tissuehowever the relative contribution of HR and NHEJ in HPV-related SCC has yet to be explored

While p16 is characteristically elevated inHPV-associatedoropharyngeal cancer up to 56ndash63 of OSCC and 59 ofpremalignant leukoplakia lesions show specific downregu-lation of p16 as expected of the tumour-suppressor role ithas [46ndash49] HPV-associated oral cavity SCC shows a lowerincidence of p16 positivity (65 high risk HPV cf 44 low-riskHPV negative cancers) [50] as does hypopharyngealcancer (11 high-risk HPV cf 0 low-riskHPV negativecancers) [51] CDK2NA (encoding p16) is commonly inhib-ited via promoter hypermethylation and this is associatedwith a worse prognosis [52 53]

2 Chromosomal Mutations in HNSCC

One of the most morphologically apparent features of neo-plasia is chromosomal mutations and rearrangements andthese have been well described in HNSCC Flow cytometricanalysis of both dysplastic and malignant lesions showsthe expected derangement of chromosomal ploidy Clini-cally precancerous lesions show rates of 46 diploidy 37tetraploidy and 17 aneuploidy while malignant lesionsshow 10 diploidy and 90 aneuploidy [54] In addition todeletions and duplications (copy number variation CNV) acritical component of carcinogenesis is allelic loss or loss-of-heterozygosity (LOH)

The first chromosomal aberrations in premalignantlesions are losses of 3p 9p 5p and 17p [55ndash57] ImportantlyCDKN2A encoding p16 is localised to the most commonlyaffected 9p21-22 locus [58 59] which shows LOH in 46ndash71of premalignant lesions and 72 of carcinoma [59 60] and isstrongly associated with progression to cancer andmetastasis[60 61] Lydiatt et al have suggested that this deletion isoverrepresented in HNSCC cell lines [62] although thisstudy found much lower rates of primary tumour deletionsWhile germline p16mutations have been described in familialHNSCC syndromes these are rare [63 64]

Allelic loss of 3p is present in 74ndash81 HNSCC [56 6566] with PCR and hybrid clone studies suggesting threediscrete areas at 3p13-p14 3p212-p213 and 3p25 [65 67] arepositively associated with tobacco-related disease and nodalstatus [68] The FHIT gene encoding a common epithelialtumour suppressor is found at locus 3p142 Expression ofFHIT is suppressed in 65 of HNSCC and is associatedwith worse overall survival [69] Locus 3p2131 contains anumber of tumour-suppressor genes (LIMD1 LTF CDC25ASCOTIN RASSF1a and CACNA2D2) of which alterations toLTF and RASSF1A were associated with significantly worseoutcome in oral cavity disease in an Indian cohort [70]3p25 contains the gene locus for hOGG1 and von Hippel-Lindau tumour suppressor gene hOGG1 is an importantcomponent of the base excision DNA repair pathway andshows LOH in 55ndash61 of HNSCC and is underexpressedin 49 [71 72] As discussed below this mechanism isimportant in the repair of ionizing radiation and commonoxidative and tobacco-related DNA lesions [73] Unrepairedtobacco-induced benzo[a]pyrene lesions commonly result in

GT transversion mutations [74 75] Repair of the oxidativelesion 8-oxoG also relies on this pathway which can resultin a stable GC to 8oxoGA missense substitution whenencountered by the DNA polymerase [76] Together thesesubstitutions comprise 54 of themost common inactivatingp53 point mutations in HNSCC [77] This mutation patternwhich has also been strongly linked to smoking-inducedlung cancer [78] is correlated with smoking exposure-relatedHNSCC [43]

Chromosomal aberrations associated with late diseaseand metastasis are less well characterised It has been foundthat metastatic deposits mostly retain clonality with theirprimary cancers [79] Gains of 3q 11q13 7q112 and 1q21-q22and losses of 8p 11p14 10p12 10q and 14q were reported inassociation with metastasis by Bockmuhl et al [79 80] whoalso found a high rate of 45 deletions in the 8p23 regioncorrelated with poor prognosis [81] This region correspondsto putative tumour suppressor gene CUB and SUSHU mul-tiple domain protein 1 (CSMD1) which is associated with ahigh risk although higher-resolution deletion mapping hasshown inconsistent targeting of this gene [82] Many morechromosomalmutations have been described in later diseases[61 83ndash89] These rearrangements occur at common fragilesites late-replicating regions which can preferentially stallreplication forks under conditions of replication stress [90]Inappropriate recovery of these forks can cause double-strandDNA breaks or inversions [91] and ineffective repair canlead to translocations and deletions [92 93] For more detailon other chromosomal rearrangements see [94 95] for acomprehensive review

3 The DNA Damage Response

Highly conserved across all domains of life is a robust DNAdamage recognition and repair system Genomic materialboth DNA and RNA is under constant degradation fromintrinsic and extrinsic factors These include oxidative stressultraviolet radiation ionising radiation and other chemicalalterations such as alkylation [96 97] Cells under activedivision such as deregulated tumour cells are particu-larly sensitive This differential sensitivity is exploited bychemotherapy and external-beam radiation There are manydifferent types of DNA lesions which are broadly dealt withvia interacting pathways (Figure 2)

(1) mismatch repair (MMR)(2) nucleotide excision repair (NER)(3) base excision repair (BER)(4) single-strand break repair (SSB-R)lowast(5) double-strand break repair (DSB-R)

Single-strand break repair is not usually considered adistinct repair pathway and is integrated into BER NERand DSB-R The most severe form of DNA damage is thedouble-strand break [98] Base excision repair and nucleotideexcision repair pathways involve single-strand break interme-diates which unrepaired become double-strand breaks whenencountered by a replication fork [12] Double-strand break


Me

UvCUvC

Replication errors Alkylating agentsDNA damaging

drugsfailed repair

MMR BER NER SSB-R HRNHEJ

Base mismatch

8-oxoG lesion

Bulky adduct SSB DSB

UV radiationRepair

pathway intermediate

Figure 2 Examples of DNA lesions and repair pathway choice

repair occurs via two pathways nonhomologous end-joining(NHEJ) and homologous recombination (HR) The primarypathway in nonreplicating mammalian cells is NHEJ [12]

ATM is an upstream phosphatidylinositol 3 kinase-likekinase (PIKK) that is recruited to double-strand break sitesand coordinates repair Limited studies in ATM have showna strong increased cancer risk with a specific SNP in anEast Asian population [99] Promoter hypermethylation ofATM has been linked with early age of onset and poorprognosis in one mixed subsite study [100] however thishas not been reproduced in a large oral cavity cancer series[101]Themutationmost common in the ataxia-telangectasiaphenotype does not seem to be a significant contributor tothe development of HNSCC [102]

4 Mismatch Repair Pathway

Microsatellite instability is a distinct measurable form ofgenomic damage that is linked to the mismatch repairpathway principally involving mut-S homologin 2 (MSH2)and mut-L Homologin 1 (MLH1) The archetypical germlinedefect in this pathway is the hereditary nonpolyposis colorec-tal carcinoma syndrome [103] however the involvement ofMSI in HNSCC has been less clearly elucidated Early studiesshowed that direct mutation or deletion of hMLH1hMSH2

was uncommon [104 105] and reported frequency of MSI inHNSCC has ranged from 7 to 100 varying with markerchoice tumour site and patient demographic [104ndash109] MSIhas been found to be more prevalent in younger patients[104] andHa et al have shown that it becomesmore frequentas dysplastic lesions progress to malignancy (14 and 55resp) [110]

The dominant moderator of mismatch repair in HNSCCis promoter hypermethylation rather than direct mutation[111] MLH1 promoter hypermethylation has been found in76 of one OSCC series associated with early disease where38 of tumours exhibited protein underexpression [112]There is however wide variation in the reported prevalence ofpromotermethylation from 8 to 69 [113ndash115] and normaltissue demonstrates promoter methylation of up to 45 [115]Most studies show no correlation with tobacco exposurehowever there may be an association with metachronousprimary cancers [114] A more recent study of MLH1 MSH2andMGMT in mobile tongue SCC showed increased expres-sion of the mismatch repair proteins (551 MSH2 3673MLH1) which was associated paradoxically with less muscleinvasion less perineural invasion but lower overall survivalhigher rates of lymphatic metastasis and more aggressivemorphology implying that this may be a reactive rather thancausative finding [116]


5 Base Excision Repair Pathway

hOGG1 and NEIL1 and 2 are DNA glycosylases that areinvolved in the first step of damage recognitionThey demon-strate significant functional cross-over with each other [117]and show affinity for lesions from 5-fluorouracil (5-FU) UVdamage and 8-oxoguanine (a highly mutagenic by-productof ROS) The hOGG1 locus commonly undergoes LOH asdiscussed above with up to 49 of HNSCC demonstratingunderexpression [72 118] Interestingly there is some evi-dence that this defect is present systemically and may be dueto a germline rather than sporadic mutation [119] althoughhaplotype studies have been inconclusive as shown aboveAPEX1 a processing enzyme immediately downstream ofhOGG1 has been shown to be overexpressed in HNSCC ina Pakistani population and is associated with nodal positivityand later stage [120] NEIL12 form a redundant BER systemsubstituting AP endonuclease (APEX12) for polynucleotidekinase (PNK) [121] and the g4102971CC polymorphism hasbeen linked to increased risk of HNSCC [122]

XRCC1 as discussed above under SNPs has been exten-sively investigated for its role in HSNCC It functions inDNA single-strand break repair downstream of APEX1PNKto scaffold and coordinate nucleotide synthesis [123] Earlystudies of mRNA expression in head and neck cell linesimplied that XRCC1 was not a significant contributor tocancer radiosensitivity [124] however a more recent proteinexpression series in primary laryngeal cancer looking atoutcomes following definitive radiotherapy has contradictedthis [125] Overexpression of XRCC1 in a more recent serieshas been linked to poor outcome in chemoradiation-treatedHNSCC but not other modalities [126] and other studieshave reported a predominant pattern of underexpression inan Indian population [118]

Poly- (ADP-Ribose) polymerase (PARP) 1 and 2 areDNA repair proteins that have direct affinity to many DNAlesions and once bound autocatalyze the generation of aPAR polymer which induces chromatin decondensation andrecruits many other repair molecules including ATM [127]Although it has no direct repair role it is required for efficientbase excision repair nucleotide excision repair HR andalternative-NHEJ [127ndash131] with the most well-understoodrole of single-strand break binding to facilitate polymerisa-tion and ligation Of particular importance in malignancyPARP-1 is required for safe traversal of damaged DNA by thereplication machinery and subsequent HR-mediated repair[128] which is significantly exacerbated under replicationstress Importantly PARP inhibition has been found to besynthetically lethal in BRCA- (HR-) deficient breast cancer[132 133] As discussed above EGFR-inhibition induces anHR and NHEJ deficiency in addition to antiproliferativeeffectsThere is evidence that combined therapy can replicatean HR ldquoblockrdquo in a similar fashion [134] that may be linked toNbs1 suppression [135 136] Indeed cosuppression of manyproteins involved in HR induces in vitro PARP susceptibility[137] Blocking upstream signalling by PI3K also induces HRdefects andPARP-sensitive synthetic lethality in breast cancercell lines [138] There is also limited data in HNSCC demon-strating a link between PARP1 overexpression and cisplatin

resistance [139] suggesting a possible role for chemoresistanttumours

6 Nucleotide Excision Repair Pathway

The nucleotide excision pathway (NER) corrects ldquobulkyrdquoDNA adducts and lesions such as UV photoproducts plat-inum lesions and tobacco-linked lesions [140] Germlinedefects in this pathway are responsible for the xerodermapigmentosum phenotype for which many key proteins areeponymous There are two principal monitoring pathwaysglobal genomic NER and transcription-coupled NER

Global genomic NER is initiated by direct recognitionof DNA lesions irrespective of transcription [141 142] andpolymorphism of several key proteins have been implicatedin HNSCC as shown above Transcription-coupled NERdiffers in that detection and recruitment of repairmolecules isinitiated by stalled RNApolymerase II (RNAP II) with repairmediated by UVSSA-USP7 and BRCA1 [143 144] The lackof a clear association with a cancer syndrome in vitro or denovo cancers make the transcription-coupled pathway a lesspromising factor in cancer genome stability [145 146]

ERCC1-XPF has been extensively studied in lung cancerbreast cancer and HNSCC High ERCC1 expression inHNSCC has been associated with cisplatin resistance andpoor survival in a betel chewing endemic area [147] Twolarger retrospective trials showed prognostic benefit of lowERCC1 expression in HNSCC (HR 042 CI

95 020ndash090 119875003 and HR 012 119875 0043) [148 149] In vivo ERCC1 hasbeen associated with enhanced cisplatin resistance [150] andis involved in alternative NHEJ [151] Metastasis has also beenassociated with increased expression of XPF [152]

SNPs in all eight major NER genes have been implicatedin increasing background risk of oral leukoplakia [153] andaltered PBL expression of ERCC1 ERCC5 ERCC6CSB [154]and ERCC4 [155] have been found to be higher in patientswith oral cancer Similarly to peripheral blood lymphocyteassays done in hOGG1 (discussed above) there is limited evi-dence that there may be a systemic NER deficient phenotypein a small cohort of patients with HNSCC [156] Some SNPshave been implicated as protective or hazardous in singleSNP studies (refer Table 1) while multiple (5ndash7) risk NERgenotypes have been associated with a 24-fold increasedrelative risk of second primary HNSCC [157]

7 Nonhomologous End Joining Pathway

The Ku heterodimer is comprised of Ku70 and Ku80 func-tions as a sensor binding to free dsDNA ends an end-processing 51015840-dRPAP lyase and a recruiter of DNA-PKcs[158] and telomere protection [159] Ku80 overexpression hasbeen linked to poor prognosis local failure and recurrencefollowing radiation [160] While this study did not includetongue cancer specimens the predictive value was greatestin HPV negative cancers (RR 9 119875 lt 001) In contrast twosimilarly-sized mixed studies found Ku70 mRNA levels andprotein overexpression improved recurrence-free survival inlocally advanced HNSCC [161] and tonsillar cancer [162]


Table 1

Reference Subsite Population Study size Gene SNP Odds ratio (P value)

Sliwinski et al [240] Laryngeal Polish 641 (288 cases 353controls)

Rad51 G135CXRCC3 C722T

292 (lt00001)403 (lt00001)

Romanowicz-Makowska et al[241]

Laryngeal Polish 506 (253 cases 253controls)

Rad51 G135CXRCC2 G31479AXRCC2 C41657T

NS [343 (0073)]NS [381 (0061)]NS [214 (0061)]

Werbrouck et al[242] All Belgium 169 cases 352

controls

XRCC3 C722TRad51 G-3429C

Lig4 C26TKu70 C1310G

Ku80 c2110-2408GgtA

196 (002)043 (005)043 (001)

NSNS

Cui et al [243] North American443 cases (includingoesophageal) 912controls

XPG c1104 047 (lt005)

dos Reis et al [244] Oral cavity Brazil 300 (150 cases 150controls)

XRCC1 Arg194TrpArg399Gln

XRCC3Thr241Met

NSNS

Pawlowska et al[245] Laryngeal Polish 506 (256 cases 256

controls) hOGG1 Ser326Cys 296 (0012)

Kietthubthew et al[246]

Oral cavity Thai (betel quid endemic) 106 cases 164controls

XRCC1 Arg194Trpexon 6 NS

XRCC3Thr241Met 33 (001)XRCC3 rs3212057 60 (lt001)

Gresner et al [247] All Polish 81 cases 111 controls Rad51rs5030789 AA 033 (lt005)

Rad51rs1801321 TT 01 (lt005)

Zhang et al [248] All North American 706 cases 1196controls hOGG1 Ser326Cys NS

Elahi et al [249] All North American 169 cases 338controls

hOGG1 Ser326CysCys326Cys

16 (lt005)41 (lt005)

Majumder et al[225] All Indian 180 cases 150

controls XRCC1 c194 c399 NS

Mahjabeen et al[120] Not specified Pakistani 300 cases 300

controls

APEX113TltGGSer129ArgVal131Gly

497lowast (00001)1174lowast (00001)512lowast (00001)

Ramachandran et al[250] Oral cavity Indian 110 cases 110

controls

XRCC1 c194c280c399

XPD c751

309 (lt00001)NS

237 (lt00001)210 (0003)

Tae et al [251] All Korean 147 cases 168controls

XRCC1 R194WR280H R399G

261 (lt005)NS

Kumar et al [118] Not specified North Indian 75 cases 75 controlsXRCC1 Arg399GlnXPD Lys 751GlnhOGG1 Ser326Cys

NS

Kumar et al [228] Not specified North Indian 278 cases 278controls

XRCC1 Arg194TrpArg280HisArg399Gln

XPD Lys751Gln

072 (003)NS

064 (0003)175 (0002)

Kowalski et al [252] All Polish 92 cases 124 controls XRCC1 Arg194TrpArg399Gln NS


Table 1 Continued


Yen et al [253] Oral cavity Taiwan 103 cases 98 controls

XRCC1 Arg194TrpXRCC2 (51015840 locus)XRCC3Thr241MetXRCC4 T139G

NS

ldquopseudo-haplotyperdquomultiple concurrent

SNPs

2ndash245 (003)3ndash503 (0013)4ndash101 (0036)

Tseng et al [254] Oral cavity Taiwan 318 cases 318controls(1)

XRCC4 c247G1394T

rs28360317rs1805377

204 (lt005)NSNSNS

Chiu et al [255] Oral cavity Taiwan 318 cases 318controls(1)

XRCC4 G1394Trs28360071rs28360217rs1805377

NS155 (lt005)

NSNS

Chiu et al [256] Oral cavity Taiwan 292 cases 290controls

ERCC6c399 (AA)

c399 (GG GA)c399 (Any A)

c1097c1413

182 (lt005)NS

143 (lt005)NSNS

Hsu et al [257] Oral cavity Taiwan 600 cases 600controls(1)

Ku80 G-1401TC-319TIntron19

1603 (lt005)(2)NSNS

Bau et al [258] Oral cavity Taiwan 318 cases 318controls(1)

Ku70 T991CG-57CA-31GIntron 3

215 (lt005)NSNSNS

Bau et al [99] Oral cavity Taiwan 620 cases 620controls

ATMrs189037rs600931rs652311rs228589rs227092rs227060

161 (lt005)NSNSNSNSNS

Flores-Obando et al[259]

Meta-analysis Multiple

XPA A23GXPD C22541AAXPD A35931CXPD Asp312AsnXPD C23047GXPD C23051GXPC PAT

XPC Lys939GlnXPC Ala499ValXPF T2063A

ERCC1 C8092AXRCC1 exon 6 TTXRCC1 exon 10XRCC1 exon 9

XRCC3Thr241Met

NS074 (lt005)

NS114 (005)

NSNSNSNS

156 (lt005)NSNS

169 (lt005)NSNSNS

Zhai et al [122] All North America 872 cases 1044controls

NEIL1 g46434077NEIL1 g46438282NEIL2 g4102971CC

NSNS

130 (lt005)lowastCrude odds ratio(1) Same groupcohort(2) Only in Areca-nut exposed subgroup


however these did not stratify for p16 status and had unusualtreatment regimens In support of these findings are in vitrostudies showing that Ku70 loss improved radioresistancein late G2S possibly by allowing the more error-free HR[163]

8 Homologous Recombination Pathway

The Fanconi anemia pathway encompasses eleven proteinsinvolved in the HR-mediated repair of interstrand crosslink(ICL) lesions [164] Fanconi anemia homozygous patientshave a much greater rate of head amp neck solid tumours[165] and underexpression of many Fanconi proteins iscommon in primary HNSCC [166] particularly in youngpatients [167] although the underlyingmechanism is unclearTobacco exposure has been shown to selectively suppressFANCD2 expression in a respiratory epithelial cell line [168]Promoter hypermethylation of FANCF has been found in15 of HNSCC [169] while 42 of OSCC show FANCCmethylation in both malignant and premalignant lesionsin an Indian population [170] In contrast another seriesdemonstrated 31 PHMof FANCB and found other Fanconigenes to be rarely methylated [171] While cisplatin com-monly induces interstrand crosslinks specific upregulationof the Fanconi pathway has not been implicated in cisplatin-resistant HNSCC cell lines [172]

Hyperphosphorylation of replication protein A (RPA) asingle-strand DNA binding protein that is integral to HRhas been implicated as a mechanism for cisplatin resistancein HNSCC cell lines [173] RPA signalling activity is heavilymodulated by phosphorylation status and this posttrans-lational resistance mechanism promotes inappropriate cell-cycle progression

BRCA1 and 2 are essential for efficient HR and germlinemutation is causally linked to breast and ovarian cancers [174175] Low BRCA expression has been correlated with bettercisplatin response and survival in lung cancer [176] BRCA-deficient breast cancers have shown survival benefits withsynthetically lethal PARP inhibition in Phase II trials [177]An interesting pattern in tongue SCC pathogenesis showsBRCA1 overexpression in leukoplakia followed by subsequentunderexpression in carcinoma [178] Sporadic mutation ofBRCA2 is rare [179] as is promoter hypermethylation [169]

9 The Epidermal Growth Factor Receptor inDNA Repair

Epidermal growth factor receptor (EGFR) is a transmem-brane signalling protein belonging to the receptor tyrosinekinase family which has significant implications in HNSCCEGFR is physiologically activated via ligand binding (trans-forming growth factor-120572 TGF-120572) and active EGFRpromotescell proliferation and enhances radioprotective mechanismsthrough the mitogen-activated protein kinase (MAPK) path-way and the extracellular signal-regulated kinases (ERK12)[180 181] The strongest effect of EGFR activation on DNArepair is via upregulation of the phosphoinositol-3 kinase(PI3K)AKT signalling pathway (Figure 3) PI3K mutations

are common in HNSCC and linked with higher genomicinstability [182] PI3K promotes transcription of the nonho-mologous end-joining complex DNA-PK [183 184] mediatesNbs1 binding for DNA damage detection [185] and promoteseffective DNA double strand break repair [186] while AKT1promotes transcription of the DNA-PKcs subunit [187] andnegatively regulates BRCA1Rad51 nuclear transport [188]Particularly relevant to DNA repair inhibition of the EGFRreceptor induces a NHEJ and HR defect Erlotinib has beenshown to decrease BRCA1-dependentHRby twofold in breastcancer cell lines [189] and attenuate radiation-induced Rad51expression (a key HR protein) [190] Gefitinib delays Nbs1recruitment to DNA double strand break sites in lung cancercell lines and significantly reduces DNA double strand breakrepair [136] Downstream inhibition of PI3K has also beenshown to induce a BRCA12 deficiency in breast cancer celllines [138] The functionality of the BRCAHR pathway isof particular importance for the utility of PARP inhibitors(discussed below)

Constitutively-active inhibitor-sensitive EGFR mutantsare an important mechanism in 10 of nonsmall cell lungcancer (NSCLC) cases conferring a significant survival bene-fit when cancer cells dependent on this proliferative signal aredeprived via EGFR-inhibition [191 192] Such kinase domainmutations are rare however in HNSCC with mutation ratesof 7ndash16 in Asian and 0ndash4 in Japanese and Caucasian pop-ulations and are not present in HPV-positive tumours [193ndash197] This suggests that they do not have a significant rolein oncogenesis and may instead reflect underlying instabilityIn striking contrast an EGFR inhibitor-resistant truncationmutant EGFRvIII has been found in up to 42 of HNSCC[198]This mutant has a deletion of exons 2 to 7 involving theextracellular binding domain rather than the kinase domain[199] This results in a protein that is constitutively activehas altered kinase dynamics that favour PI3K signalling andthat promotes ligand-independent invasion and migration[200 201]

Oncogenic mutations in other components of this path-way are less common PI3KCA somatic mutations have beendescribed in 0ndash11 of HNSCC tumour samples and areoverrepresented in cell lines [202ndash204] while PTEN andAkt1mutations are rare [205]

Overexpression of EGFR is very common in HNSCCwith protein immunohistochemical studies showing highexpression in 43ndash68 of HNSCC [197 206ndash208] and Arecaquid-associated OSCC demonstrating a lower rate of 23[209] High EGFR protein levels are strongly linked to poorcause-specific survival [207 208] nodal stage and dedifferen-tiation [197] and emergence of stem-cell like characteristics[210] Altered EGFR copy numbers have been found in 24of HNSCC cases in one study (17 increased 7 decreased)and both are linked to a reduced cause-specific survival anddisease-free survival [211] EGFR amplifications have beendemonstrated in 24 (10 deletions) of laryngeal cancersalthough survival significance was only demonstrated whencombined with chromosome 7 copy-number status [212]There does not appear to be any difference between HPV-associated and HPV-negative cancers with regard to EGFRexpression [50]


Ligand binding domain (ie EGF TGF-120572)

Tyrosine kinasedomain

SOSPI3-KP

RAS

RAFAKT

mTOR

MEK

ERK

Cell proliferationAngiogenesisAntiapoptosisDNA repair modulationDNA-PKcs

Ku70 Ku80

P

EGFR

Nbs1

BRCA1Rad51

Nuclear transport

DNA damage binding

Figure 3 Downstream effects of EGFR on DNA repair proteins

Cetuximab an IgG1 monoclonal antibody against thereceptor domain of EGFR has been shown to add an8 absolute 2-year survival advantage as a monotherapyadjunct to radiotherapy in HNSCC [213] and has becomeincorporated into the standard management of late-stageHNSCC [214] The tyrosine kinase inhibitor gefitinib hasalso been shown to sensitize HNSCC cells to cisplatin viadestabilization of Rad51 [215] however Phase III trials haveshown no advantage as monotherapy in recurrent HNSCCcompared with methotrexate [216] Cancers with high EGFRexpression demonstrate additional benefit from hyperfrac-tionated radiotherapy regimens [217]

Radioprotection in EGFR-competent cells is improvedvia enhanced immediate DNA repair protection fromdamage-induced apoptosis and enhanced proliferation of theEGFR-competent subpopulation during repopulation [218]providing a selective advantage Cetuximab resistance hasbeen linked to EGFR translocation from the cytoplasm to thenucleus and endogenous ligand production [219] Transportdysregulation and HER2-dependent transactivation has alsobeen found to contribute to resistance in lung cancer celllines [220] Emergent resistance is also very common incolorectal cancer where it has been found to be mediated byendogenous upregulation of K-Ras [221]

10 Single Nucleotide Polymorphisms inDNA Repair Pathways

While some areas of genomic DNA are highly conserved thedynamic variability of large domains encompassing codingand noncoding areas is becoming increasingly importantto our understanding of individual disease risks The mostcommon examples are single nucleotide polymorphisms(SNPs) of which 31 million have been identified encom-passing most proteins involved in DNA repair [222] Thetwo principal types of SNPs are synchronous (or ldquosilentrdquo)

and nonsynchronous where a base substitution results in acorresponding protein substitutionThe protein product maybe a ldquofunctional variantrdquo or has some degree of impairedfunction Analogous to hereditary DNA repair syndromesmuch attention has been paid to SNP prevalence and theeffect on HNSCC risk Listed below are a subset of SNPstudies specific for DNA repair proteins involved in thepathways discussed above

In addition to the above studies a series in a Pakistanipopulation found a remarkably high prevalence of novelhOGG1 polymorphism is association with HNSCC althoughthis has not been subsequently validated [223] Interestinglyboth this and a Japanese study found a statistically significantlink between hOGG1 Ser326Cys status and tobacco use[224] complicating statistical analysis Likewise HPV-16positivitymay alter the significance of XRCC1 polymorphismin HNSCC risk possibly explaining the inconsistent resultsbetween study populations [225 226] although these find-ings are in contrast to cervical SCC and HPV-16 status whereno relationship has been found [227] Complex gene-geneinteractions between XRCC1 and XPD haplotypes have alsobeen described [228]

Carles et al [229] examined nine nucleotide excisionrepair gene SNPs with regard to response to definitiveradiotherapy This study found XPA (51015840UTR) XPFERCC1C259C and XPGERCC5 G1104CT46C SNPs resulted ina significantly worse overall survival following treatmentin a cohort of 104 patients over 10 years In a Brazilianpopulation ERCC1 T19007Cwas not found to affect responseto treatment or overall survival in a modest cohort [230]

11 Discussion

Genomic instability underpins the development of dysplasiamalignancy invasion and metastasis in cancers Many ofour cancer therapeutic drugs exploit these genetic stability


pathways by adding extra pressure onto already primedcancerous cells The formation of these cancers is also clearlylinked to genetic instability with the high risk factors suchas HPV tobacco areca nut betel quid and alcohol havingdirect mutagenic effects on the cellular genomeThere is alsoan emerging spectrumofDNAdeficient high risk phenotypesthat are improving our understanding of background geneticrisk These aetiological differences in oncogenesis translateinto distinctly different disease profiles Profiling of theDNA repair pathways in established cancer may allow thedevelopment of robust biomarker-based cancer phenotypingfor both improved prognosis and personalized therapeuticselection The success of the PARP-1 inhibitor olaparib inBRCA1-deficient breast cancer and the early translationalwork in HNSCC underpin the importance of future targetedtherapy in exploiting synthetic lethality in DNA repair

The inherited DNA repair deficient syndromes pro-vide the prototype for insight into DNA repair in cancerhighlighting the importance of the double-strand repairpathways and in particular homologous recombinationAtaxia telangiectasia presents with a significant increasedall-cause cancer risk [231] consistent with its critical repairrole and inherited HR protein BRCA1 and BRCA2 mutantsstrongly predispose toward breast cancer prostate and coloncancer [175] Homologous recombination is the preferredrepair pathway in cells undergoing active replication andis constitutively active in cancer Defective HR is respon-sible for many chromosomal rearrangements [91 232] andemerging evidence shows a robust redundant pathway thatis more complex than previously thought Complementingour knowledge of this pathway is ongoing discovery of HR-essential proteins such as hSSB12 [233 234] RNF8 [235]and Exo1 [236] which coordinate the more well-understoodcore repair complexes such as Rad51 andMRN [237] Furtherexploration of the oncogenic role of these core proteins isneeded

Head andneck cancer is a diverse category of disease withoutcomes influenced largely by primary site and p16 statusExisting studies onmorewell-knownDNA repair biomarkersare often difficult to interpret due to conflation of anatomicalsubsites or limited p16 control Focused well-powered studiescontrolled for anatomical subsite are likely to be of greaterclinical benefit Similarly the abundance of the literatureon genetic polymorphism and cancer risk is tempered byconflicting reproducibility conflation of anatomical sitesand population differences Localisation of SNP studies isimportant given the significantly unique risk factor profilesin East Asian and Chinese populations however it makesgeneralisation of these highly prognostic studies to Westernpopulations difficult

Current gaps in the literature of cancer genomic insta-bility include the nature of interpathway and intrapathwayredundancy Major protein complexes can be less efficientlyreplaced by alternate multipurpose proteins to otherwiseallow DNA repair [235 238] an important mechanism tounderstand in designing synthetically lethal repair blockadeSNPs of backup 8oxoG pathways such as PNKNEIL1 havebeen linked to HNSCC risk [122] and contributes to poorsurvival in non-HNSCC cancer [239] however the role of

this pathway in relation to hOGG1 deficiencies has yet to bedetermined in HNSCC

Improved understanding of the nature of genomic insta-bility in head and neck cancer has helped clarify the inter-play between mutagenic stresses and DNA repair efficiencyFuture characterization of signature instability patterns willguide further therapeutic development targeted at the criticalfoundation underlying malignancy

References

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[2] A Jemal F Bray M M Center J Ferlay E Ward and DForman ldquoGlobal cancer statisticsrdquo CA A Cancer Journal forClinicians vol 61 no 2 pp 69ndash90 2011

[3] TMaeda A JikkoHHiranuma andH Fuchihata ldquoAnalysis ofgenomic instability in squamous cell carcinoma of the head andneck using the random amplified polymorphic DNA methodrdquoCancer Letters vol 138 no 1-2 pp 183ndash188 1999

[4] M Merlano V Vitale R Rosso et al ldquoTreatment of advancedsquamous-cell carcinoma of the head and neck with alternatingchemotherapy and radiotherapyrdquo The New England Journal ofMedicine vol 327 no 16 pp 1115ndash1121 1992

[5] J-P Pignon A L Maıtre E Maillard and J Bourhis ldquoMeta-analysis of chemotherapy in head and neck cancer (MACH-NC) an update on 93 randomised trials and 17346 patientsrdquoRadiotherapy and Oncology vol 92 no 1 pp 4ndash14 2009

[6] S Furness A-M Glenny H V Worthington et al ldquoInterven-tions for the treatment of oral cavity and oropharyngeal cancerchemotherapyrdquo Cochrane Database of Systematic Reviews vol4 Article ID CD006386 2011

[7] J P Pignon J Bourhis C Domenge and L DesigneldquoChemotherapy added to locoregional treatment for head andneck squamous-cell carcinoma three meta-analyses of updatedindividual datardquo The Lancet vol 355 no 9208 pp 949ndash9552000

[8] R M Logan ldquoAdvances in understanding of toxicities oftreatment for head and neck cancerrdquoOral Oncology vol 45 no10 pp 844ndash848 2009

[9] D Murdoch ldquoStandard and novel cytotoxic and molecular-targeted therapies for HNSCC an evidence-based reviewrdquoCurrent Opinion in Oncology vol 19 no 3 pp 216ndash221 2007

[10] M R Posner D M Hershock C R Blajman et al ldquoCisplatinand fluorouracil alone or with docetaxel in head and neckcancerrdquo The New England Journal of Medicine vol 357 no 17pp 1705ndash1715 2007

[11] T Boveri ldquoConcerning the origin of malignant tumours byTheodor Boveri Translated and annotated by Henry HarrisrdquoJournal of Cell Science vol 121 supplement 1 pp 1ndash84 2008

[12] R Hakem ldquoDNA-damage repair the good the bad and theuglyrdquoThe EMBO Journal vol 27 no 4 pp 589ndash605 2008

[13] V G Gorgoulis L-V F Vassiliou P Karakaidos et al ldquoActi-vation of the DNA damage checkpoint and genomic instabilityin human precancerous lesionsrdquo Nature vol 434 no 7035 pp907ndash913 2005

[14] R A DiTullio Jr T A Mochan M Venere et al ldquo53BP1functions in a ATM-dependent checkpoint pathway that is


constitutively activated in human cancerrdquo Nature Cell Biologyvol 4 no 12 pp 998ndash1002 2002

[15] J Bartek J Bartkova and J Lukas ldquoDNA damage signallingguards against activated oncogenes and tumour progressionrdquoOncogene vol 26 no 56 pp 7773ndash7779 2007

[16] E M Sturgis and P M Cinciripini ldquoTrends in head and neckcancer incidence in relation to smoking prevalence an emerg-ing epidemic of human papillomavirus-associated cancersrdquoCancer vol 110 no 7 pp 1429ndash1435 2007

[17] M Hoffmann T Kahn C G Mahnke T Goeroegh B MLippert and J AWerner ldquoPrevalence of human papillomavirusin squamous cell carcinoma of the head and neck determinedby polymerase chain reaction and Southern blot hybridizationproposal for optimized diagnostic requirementsrdquo Acta Oto-Laryngologica vol 118 no 1 pp 138ndash144 1998

[18] N Termine V Panzarella S Falaschini et al ldquoHPV in oralsquamous cell carcinoma vs head and neck squamous cellcarcinoma biopsies a meta-analysis (1988ndash2007)rdquo Annals ofOncology vol 19 no 10 pp 1681ndash1690 2008

[19] K Kansy O Thiele and K Freier ldquoThe role of human papil-lomavirus in oral squamous cell carcinoma myth and realityrdquoOral and Maxillofacial Surgery 2012

[20] S Marur G DrsquoSouza W H Westra and A A ForastiereldquoHPV-associated head and neck cancer a virus-related cancerepidemicrdquoThe Lancet Oncology vol 11 no 8 pp 781ndash789 2010

[21] F Dayyani C J Etzel M Liu C-H Ho S M Lippman and AS Tsao ldquoMeta-analysis of the impact of human papillomavirus(HPV) on cancer risk and overall survival in head and necksquamous cell carcinomas (HNSCC)rdquoHead andNeckOncologyvol 2 no 1 article 15 2010

[22] K K Ang J Harris R Wheeler et al ldquoHuman papillomavirusand survival of patients with oropharyngeal cancerrdquo The NewEngland Journal of Medicine vol 363 no 1 pp 24ndash35 2010

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[24] G DrsquoSouza Y Agrawal J Halpern S Bodison and M LGillison ldquoOral sexual behaviors associated with prevalent oralhuman papillomavirus infectionrdquo Journal of Infectious Diseasesvol 199 no 9 pp 1263ndash1269 2009

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[31] M Scheffner J M Huibregtse R D Vierstra and PM HowleyldquoThe HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53rdquo Cell vol 75 no 3pp 495ndash505 1993

[32] M Thomas D Pim and L Banks ldquoThe role of the E6-p53interaction in the molecular pathogenesis of HPVrdquo Oncogenevol 18 no 53 pp 7690ndash7700 1999

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[34] O Stevaux and N J Dyson ldquoA revised picture of the E2Ftranscriptional network and RB functionrdquo Current Opinion inCell Biology vol 14 no 6 pp 684ndash691 2002

[35] JWHarbour andDCDean ldquoTheRbE2Fpathway expandingroles and emerging paradigmsrdquoGenes andDevelopment vol 14no 19 pp 2393ndash2409 2000

[36] X Liu A Clements K Zhao and RMarmorstein ldquoStructure ofthe human Papillomavirus E7 oncoprotein and its mechanismfor inactivation of the retinoblastoma tumor suppressorrdquo Jour-nal of Biological Chemistry vol 281 no 1 pp 578ndash586 2006

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[38] D Lindquist M Romanitan L Hammarstedt et al ldquoHumanpapillomavirus is a favourable prognostic factor in tonsillarcancer and its oncogenic role is supported by the expression ofE6 and E7rdquoMolecular Oncology vol 1 no 3 pp 350ndash355 2007

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[42] S Duensing and K Munger ldquoMechanisms of genomic insta-bility in human cancer insights from studies with humanpapillomavirus oncoproteinsrdquo International Journal of Cancervol 109 no 2 pp 157ndash162 2004

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[44] T G Edwards M J Helmus K Koeller J K Bashkin andC Fisher ldquoHuman papillomavirus episome stability is reducedby aphidicolin and controlled by DNA damage response path-waysrdquo Journal of Virology vol 87 no 7 pp 3979ndash3989 2013


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[46] T Yakushiji K Uzawa T Shibahara H Noma andH TanzawaldquoOver-expression of DNA methyltransferases and CDKN2Agene methylation status in squamous cell carcinoma of the oralcavityrdquo International Journal of Oncology vol 22 no 6 pp 1201ndash1207 2003

[47] A L Reed J Califano P Cairns et al ldquoHigh frequency ofp16 (CDKN2MTS-1INK4A) inactivation in head and necksquamous cell carcinomardquo Cancer Research vol 56 no 16 pp3630ndash3633 1996

[48] C-H Tsai C-C Yang L S-S Chou and M-Y Chou ldquoThecorrelation between alteration of p16 gene and clinical status inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 30 no 9 pp 527ndash531 2001

[49] P Pande M Mathur N K Shukla and R Ralhan ldquopRB andp16 protein alterations in human oral tumorigenesisrdquo OralOncology vol 34 no 5 pp 396ndash403 1998

[50] A Duray G Descamps C Decaestecker et al ldquoHuman papil-lomavirus DNA strongly correlates with a poorer prognosis inoral cavity carcinomardquo Laryngoscope vol 122 no 7 pp 1558ndash1565 2012

[51] P Ernoux-Neufcoeur M Arafa C Decaestecker et al ldquoCom-bined analysis of HPV DNA p16 p21 and p53 to predictprognosis in patients with stage IV hypopharyngeal carcinomardquoJournal of Cancer Research and Clinical Oncology vol 137 no 1pp 173ndash181 2011

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[59] P van der Riet H Nawroz R H Hruban et al ldquoFrequentloss of chromosome 9p21-22 early in head and neck cancerprogressionrdquoCancer Research vol 54 no 5 pp 1156ndash1158 1994

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[62] W M Lydiatt V V V S Murty B J Davidson et al ldquoHomozy-gous deletions and loss of expression of the CDKN2 gene occurfrequently in head and neck squamous cell carcinoma cell linesbut infrequently in primary tumorsrdquo Genes Chromosomes andCancer vol 13 no 2 pp 94ndash98 1995

[63] K K Yu A M Zanation J R Moss and W G YarbroughldquoFamilial head and neck cancer molecular analysis of a newclinical entityrdquo Laryngoscope vol 112 no 9 pp 1587ndash1593 2002

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[66] R P Hogg S Honorio A Martinez et al ldquoFrequent 3pallele loss and epigenetic inactivation of the RASSF1A tumoursuppressor gene from region 3p213 in head and neck squamouscell carcinomardquo European Journal of Cancer vol 38 no 12 pp1585ndash1592 2002

[67] N Uzawa M A Yoshida S Hosoe M Oshimura T Ama-gasa and T Ikeuchi ldquoFunctional evidence for involvement ofmultiple putative tumor suppressor genes on the short arm ofchromosome 3 in human oral squamous cell carcinogenesisrdquoCancer Genetics and Cytogenetics vol 107 no 2 pp 125ndash1311998

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[70] S Ghosh A Ghosh G P Maiti et al ldquoAlterations of 3p2131tumor suppressor genes in head and neck squamous cellcarcinoma correlation with progression and prognosisrdquo Inter-national Journal of Cancer vol 123 no 11 pp 2594ndash2604 2008

[71] H Blons J P Radicella O Laccourreye et al ldquoFrequent allelicloss at chromosome 3p distinct from genetic alterations of the8-oxoguanineDNA glycosylase 1 gene in head and neck cancerrdquoMolecular Carcinogenesis vol 26 no 4 pp 254ndash260 1999

[72] C-Y Fan K L Liu H Y Huang et al ldquoFrequent allelicimbalance and loss of protein expression of theDNArepair genehOGG1 in head and neck squamous cell carcinomardquo LaboratoryInvestigation vol 81 no 10 pp 1429ndash1438 2001

[73] S S David V L OrsquoShea and S Kundu ldquoBase-excision repair ofoxidative DNA damagerdquoNature vol 447 no 7147 pp 941ndash9502007

[74] E Eisenstadt A J Warren J Porter D Atkins and JH Miller ldquoCarcinogenic epoxides of benzo[a]pyrene andcyclopenta[cd]pyrene induce base substitutions via specifictransversionsrdquo Proceedings of the National Academy of Sciencesof theUnited States of America vol 79 no 6 pp 1945ndash1949 1982

[75] C Bernelot-Moens B W Glickman and A J E GordonldquoInduction of specific frameshift and base substitution events


by benzo[a]pyrene diol expoxide in excision-repair-deficientEscherichia colirdquoCarcinogenesis vol 11 no 5 pp 781ndash785 1990

[76] S Shibutani M Takeshita and A P Grollman ldquoInsertionof specific bases during DNA synthesis past the oxidation-damaged base 8-oxodGrdquoNature vol 349 no 6308 pp 431ndash4341991

[77] H Blons and P Laurent-Puig ldquoTP53 and head and neckneoplasmsrdquo Human Mutation vol 21 no 3 pp 252ndash257 2003

[78] J-H Yoon L E Smith Z Feng M-S Tang C-S Lee andG P Pfeifer ldquoMethylated CpG dinucleotides are the prefer-ential targets for G-to-T transversion mutations induced bybenzo[a]pyrene diol epoxide in mammalian cells similaritieswith the p53 mutation spectrum in smoking-associated lungcancersrdquo Cancer Research vol 61 no 19 pp 7110ndash7117 2001

[79] U Bockmuhl S Petersen S Schmidt et al ldquoPatterns of chro-mosomal alterations in metastasizing and nonmetastasizingprimary head and neck carcinomasrdquo Cancer Research vol 57no 23 pp 5213ndash5216 1997

[80] U Bockmuhl K Schluns S Schmidt S Matthias and IPetersen ldquoChromosomal alterations during metastasis for-mation of head and neck squamous cell carcinomardquo GenesChromosomes and Cancer vol 33 no 1 pp 29ndash35 2002

[81] U Bockmuhl C S Ishwad R E Ferrell and S M GollinldquoAssociation of 8p23 deletions with poor survival in head andneck cancerrdquoOtolaryngologymdashHead and Neck Surgery vol 124no 4 pp 451ndash455 2001

[82] C Toomes A Jackson K Maguire et al ldquoThe presence ofmultiple regions of homozygous deletion at the CSMDI locusin oral squamous cell carcinoma question the role of CSMDIin head and neck carcinogenesisrdquo Genes Chromosomes andCancer vol 37 no 2 pp 132ndash140 2003

[83] V A Papadimitrakopoulou Y Oh A El-Naggar J Izzo GClayman and L Mao ldquoPresence of multiple incontiguousdeleted regions at the long arm of chromosome 18 in head andneck cancerrdquoClinical Cancer Research vol 4 no 3 pp 539ndash5441998

[84] H Nawroz P van der Riet R H Hruban W Koch JM Ruppert and D Sidransky ldquoAllelotype of head and necksquamous cell carcinomardquo Cancer Research vol 54 no 5 pp1152ndash1155 1994

[85] D L van Dyke M J Worsham M S Benninger et al ldquoRecur-rent cytogenetic abnormalities in squamous cell carcinomas ofthe head and neck regionrdquo Genes Chromosomes and Cancervol 9 no 3 pp 192ndash206 1994

[86] F Mertens B Johansson M Hoglund and F MitelmanldquoChromosomal imbalance maps of malignant solid tumors acytogenetic survey of 3185 neoplasmsrdquo Cancer Research vol 57no 13 pp 2765ndash2780 1997

[87] M A Pershouse A K El-Naggar K Hurr H Lin W K AYung and P A Steck ldquoDeletion mapping of chromosome 4 inhead and neck squamous cell carcinomardquoOncogene vol 14 no3 pp 369ndash373 1997

[88] G H Yoo H-J Xu J A Brennan et al ldquoInfrequent inactivationof the retinoblastoma gene despite frequent loss of chromo-some 13q in head and neck squamous cell carcinomardquo CancerResearch vol 54 no 17 pp 4603ndash4606 1994

[89] M Feenstra M Veltkamp J Van Kuik et al ldquoHLA class 1expression and chromosomal deletions at 6p and 15q in headand neck squamous cell carcinomasrdquo Tissue Antigens vol 54no 3 pp 235ndash245 1999

[90] M F Arlt S G Durkin R L Ragland and TW Glover ldquoCom-mon fragile sites as targets for chromosome rearrangementsrdquoDNA Repair vol 5 no 9-10 pp 1126ndash1135 2006

[91] K Mizuno I Miyabe S Schalbetter A M Carr and J MMurray ldquoRecombination-restarted replication makes invertedchromosome fusions at inverted repeatsrdquo Nature vol 493 no7431 pp 246ndash249 2013

[92] M R Lieber ldquoNHEJ and its backup pathways in chromosomaltranslocationsrdquoNature Structural andMolecular Biology vol 17no 4 pp 393ndash395 2010

[93] D O Ferguson and F W Alt ldquoDNA double strand break repairand chromosomal translocation lessons from animal modelsrdquoOncogene vol 20 no 40 pp 5572ndash5579 2001

[94] C Scully J K Field and H Tanzawa ldquoGenetic aberrations inoral or head and neck squamous cell carcinoma 2 chromoso-mal aberrationsrdquoOral Oncology vol 36 no 4 pp 311ndash327 2000

[95] H S Patmore L Cawkwell N D Stafford and J GreenmanldquoUnraveling the chromosomal aberrations of head and necksquamous cell carcinoma a reviewrdquo Annals of Surgical Oncol-ogy vol 12 no 10 pp 831ndash842 2005

[96] T Lindahl and D E Barnes ldquoRepair of endogenous DNAdamagerdquo Cold Spring Harbor Symposia on Quantitative Biologyvol 65 pp 127ndash133 2000

[97] M M Vilenchik and A G Knudson ldquoEndogenous DNAdouble-strand breaks production fidelity of repair and induc-tion of cancerrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 100 no 22 pp 12871ndash128762003

[98] T Rich R L Allen and A HWyllie ldquoDefying death after DNAdamagerdquo Nature vol 407 no 6805 pp 777ndash783 2000

[99] D-T Bau C-H Chang M-H Tsai et al ldquoAssociation betweenDNA repair gene ATM polymorphisms and oral cancer suscep-tibilityrdquo Laryngoscope vol 120 no 12 pp 2417ndash2422 2010

[100] L Ai Q N Vo C Zuo et al ldquoAtaxia-telangiectasia-mutated(ATM) gene in head and neck squamous cell carcinomapromoter hypermethylation with clinical correlation in 100casesrdquo Cancer Epidemiology Biomarkers and Prevention vol 13no 1 pp 150ndash156 2004

[101] M A Rigi-Ladiz D M Kordi-Tamandani and A Torka-manzehi ldquoAnalysis of hypermethylation and expression profilesof APC and ATM genes in patients with oral squamous cellcarcinomardquo Clinical Epigenetics vol 3 no 1 article 6 2011

[102] S Spyridonidou C Yapijakis E Nkenke et al ldquoA common9 bp deletion in the ataxia-telangiectasia-mutated gene is notassociated with oral cancerrdquo Anticancer Research vol 29 no 8pp 3191ndash3193 2009

[103] H T Lynch and T Smyrk ldquoHereditary nonpolyposis colorectal(Lynch syndrome) an updated reviewrdquo Cancer vol 78 no 6pp 1149ndash1167 1996

[104] Y Wang J Irish C MacMillan et al ldquoHigh frequency ofmicrosatellite instability in young patients with head-and-necksquamous-cell carcinoma lack of involvement of the mismatchrepair genes hMLH1 and hMSH2rdquo International Journal ofCancer vol 93 no 3 pp 353ndash360 2001

[105] S PiccininDGasparotto T Vukosavljevic et al ldquoMicrosatelliteinstability in squamous cell carcinomas of the head and neckrelated to field cancerization phenomenardquo British Journal ofCancer vol 78 no 9 pp 1147ndash1151 1998

[106] H Blons A Cabelguenne F Carnot et al ldquoMicrosatellite analy-sis and response to chemotherapy in head-and-neck squamous-cell carcinomardquo International Journal of Cancer vol 84 no 4pp 410ndash415 1999


[107] I I Arzimanoglou F Gilbert and H R K Barber ldquoMicrosatel-lite instability in human solid tumorsrdquo Cancer vol 82 no 10pp 1808ndash1820 1998

[108] A K El-Naggar K Hurr V Huff G L Clayman M A Lunaand J G Batsakis ldquoMicrosatellite instability in preinvasive andinvasive head and neck squamous carcinomardquo The AmericanJournal of Pathology vol 148 no 6 pp 2067ndash2072 1996

[109] C S Ishwad R E Ferrell K M Rossie et al ldquoMicrosatelliteinstability in oral cancerrdquo International Journal of Cancer vol64 no 5 pp 332ndash335 1995

[110] P KHa T A PilkingtonWHWestra J Sciubba D Sidranskyand J A Califano ldquoProgression of microsatellite instabilityfrom premalignant lesions to tumors of the head and neckrdquoInternational Journal of Cancer vol 102 no 6 pp 615ndash617 2002

[111] C Zuo H Zhang H J Spencer et al ldquoIncreased microsatelliteinstability and epigenetic inactivation of the hMLH1 gene inhead and neck squamous cell carcinomardquo OtolaryngologymdashHead and Neck Surgery vol 141 no 4 pp 484ndash490 2009

[112] I Gonzalez-Ramırez V Ramırez-Amador M E Irigoyen-Camacho et al ldquohMLH1 promotermethylation is an early eventin oral cancerrdquo Oral Oncology vol 47 no 1 pp 22ndash26 2011

[113] M Viswanathan N Tsuchida and G Shanmugam ldquoPromoterhypermethylation profile of tumor-associated genes p16 p15hMLH1 MGMT and E-cadherin in oral squamous cell carci-nomardquo International Journal of Cancer vol 105 no 1 pp 41ndash462003

[114] R Czerninski S Krichevsky Y Ashhab D Gazit V Pateland D Ben-Yehuda ldquoPromoter hypermethylation of mismatchrepair genes hMLH1 and hMSH2 in oral squamous cell carci-nomardquo Oral Diseases vol 15 no 3 pp 206ndash213 2009

[115] K Steinmann A Sandner U Schagdarsurengin R HDammann and R H Dammann ldquoFrequent promoter hyper-methylation of tumor-related genes in head and neck squamouscell carcinomardquo Oncology Reports vol 22 no 6 pp 1519ndash15262009

[116] S Theocharis J Klijanienko C Giaginis et al ldquoExpressionof DNA repair proteins MSH2 MLH1 and MGMT in mobiletongue squamous cell carcinoma associations with clinico-pathological parameters and patientsrsquo survivalrdquo Journal of OralPathology and Medicine vol 40 no 3 pp 218ndash226 2011

[117] H Dou S Mitra and T K Hazra ldquoRepair of oxidized basesin DNA bubble structures by human DNA glycosylases NEIL1and NEIL2rdquo Journal of Biological Chemistry vol 278 no 50 pp49679ndash49684 2003

[118] A KumarM C Pant H S Singh and S Khandelwal ldquoReducedexpression of DNA repair genes (XRCC1 XPD and OGG1) insquamous cell carcinoma of head and neck in North IndiardquoTumor Biology vol 33 no 1 pp 111ndash119 2012

[119] T Paz-Elizur R Ben-Yosef D Elinger et al ldquoReduced repair ofthe oxidative 8-oxoguanine DNA damage and risk of head andneck cancerrdquo Cancer Research vol 66 no 24 pp 11683ndash116892006

[120] I Mahjabeen R M Baig M Sabir and M A Kayani ldquoGeneticand expressional variations of APEX1 are associated withincreased risk of head and neck cancerrdquo Mutagenesis vol 28no 2 pp 213ndash218 2013

[121] A Das L Wiederhold J B Leppard et al ldquoNEIL2-initiatedAPE-independent repair of oxidized bases in DNA evidencefor a repair complex in human cellsrdquo DNA Repair vol 5 no12 pp 1439ndash1448 2006

[122] X Zhai H Zhao Z Liu et al ldquoFunctional variants of the NEIL1and NEIL2 genes and risk and progression of squamous cell

carcinoma of the oral cavity and oropharynxrdquo Clinical CancerResearch vol 14 no 13 pp 4345ndash4352 2008

[123] K W Caldecott ldquoXRCC1 and DNA strand break repairrdquo DNARepair vol 2 no 9 pp 955ndash969 2003

[124] E J Dunphy M A Beckett L H Thompson and R RWeichselbaum ldquoExpression of the polymorphic human DNArepair gene XRCC1 does not correlate with radiosensitivity inthe cells of human head and neck tumor cell linesrdquo RadiationResearch vol 130 no 2 pp 166ndash170 1992

[125] P Nix J Greenman N Stafford and L Cawkwell ldquoExpressionof XRCC1 and ERCC1 proteins in radioresistant and radiosen-sitive laryngeal cancerrdquo Cancer Therapy vol 2 pp 47ndash53 2004

[126] M-K Ang M R Patel X-Y Yin et al ldquoHigh XRCC1 proteinexpression is associated with poorer survival in patients withhead and neck squamous cell carcinomardquo Clinical CancerResearch vol 17 no 20 pp 6542ndash6552 2011

[127] F G Sousa R Matuo D Soares et al ldquoPARPs and the DNAdamage responserdquo Carcinogenesis vol 33 no 8 pp 1433ndash14402012

[128] K Sugimura S-I Takebayashi H Taguchi S Takeda andK Okumura ldquoPARP-1 ensures regulation of replication forkprogression by homologous recombination on damaged DNArdquoJournal of Cell Biology vol 183 no 7 pp 1203ndash1212 2008

[129] N Schultz E Lopez N Saleh-Gohari and T HelledayldquoPoly(ADP-ribose) polymerase (PARP-1) has a controlling rolein homologous recombinationrdquo Nucleic Acids Research vol 31no 17 pp 4959ndash4964 2003

[130] M de Vos V Schreiber and F Dantzer ldquoThe diverse roles andclinical relevance of PARPs inDNAdamage repair current stateof the artrdquoBiochemical Pharmacology vol 84 no 2 pp 137ndash1462012

[131] V Schreiber J-C Ame P Dolle et al ldquoPoly(ADP-ribose)polymerase-2 (PARP-2) is required for efficient base excisionDNA repair in association with PARP-1 and XRCC1rdquo Journalof Biological Chemistry vol 277 no 25 pp 23028ndash23036 2002

[132] H E Bryant N Schultz H DThomas et al ldquoSpecific killing ofBRCA2-deficient tumours with inhibitors of poly(ADP-ribose)polymeraserdquo Nature vol 434 no 7035 pp 913ndash917 2005

[133] P C Fong D S Boss T A Yap et al ldquoInhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriersrdquoThe New England Journal of Medicine vol 361 no 2 pp 123ndash134 2009

[134] S Nowsheen J A Bonner A F LoBuglio et al ldquoCetuximabaugments cytotoxicity with poly (ADP-Ribose) polymeraseinhibition in head and neck cancerrdquo PLoS ONE vol 6 no 8Article ID e24148 2011

[135] W M Abuzeid K Khan X Jiang X Cao B W OrsquoMalley Jrand D Li ldquoR013 disruption of DNA damage signaling a noveltherapy for HNSCCrdquo OtolaryngologymdashHead and Neck Surgeryvol 137 no 2 supplement pp P152ndashP153 2007

[136] T Tanaka A Munshi C Brooks J Liu M L Hobbs and R EMeyn ldquoGefitinib radiosensitizes non-small cell lung cancer cellsby suppressing cellular DNA repair capacityrdquo Clinical CancerResearch vol 14 no 4 pp 1266ndash1273 2008

[137] N McCabe N C Turner C J Lord et al ldquoDeficiency inthe repair of DNA damage by homologous recombination andsensitivity to poly(ADP-ribose) polymerase inhibitionrdquo CancerResearch vol 66 no 16 pp 8109ndash8115 2006

[138] Y H Ibrahim C Garcıa-Garcıa V Serra et al ldquoPI3K inhibitionimpairs BRCA12 expression and sensitizes BRCA-proficienttriple-negative breast cancer to PARP inhibitionrdquo Cancer Dis-covery vol 2 no 11 pp 1036ndash1047 2012


[139] T Yamashita S Miyamoto B OrsquoMalley and D Li ldquoThe role ofPARP 1 for cisplatin-based chemoresistancerdquo OtolaryngologymdashHead and Neck Surgery vol 143 no 2 supplement p P54 2010

[140] L-E Wang E M Sturgis S A Eicher M R Spitz W KHong and QWei ldquoMutagen sensitivity to Benzo(a)pyrene diolepoxide and the risk of squamous cell carcinoma of the headand neckrdquo Clinical Cancer Research vol 4 no 7 pp 1773ndash17781998

[141] M Robu R G Shah N Petitclerc J BrindrsquoAmour FKandan-Kulangara andGM Shah ldquoRole of poly(ADP-ribose)polymerase-1 in the removal of UV-induced DNA lesions bynucleotide excision repairrdquo Proceedings of the National Academyof Sciences of the United States of America vol 110 no 5 pp1658ndash1663 2013

[142] S C Shuck E A Short and J J Turchi ldquoEukaryotic nucleotideexcision repair fromunderstandingmechanisms to influencingbiologyrdquo Cell Research vol 18 no 1 pp 64ndash72 2008

[143] J E Cleaver ldquoPhotosensitivity syndrome brings to light a newtranscription-coupled DNA repair cofactorrdquo Nature Geneticsvol 44 no 5 pp 477ndash478 2012

[144] L Wei L Lan A Yasui et al ldquoBRCA1 contributes totranscription-coupled repair of DNA damage through polyu-biquitination and degradation of Cockayne syndrome B pro-teinrdquo Cancer Science vol 102 no 10 pp 1840ndash1847 2011

[145] Y Kamenisch and M Berneburg ldquoProgeroid syndromes andUV-induced oxidative DNA damagerdquo Journal of InvestigativeDermatology Symposium Proceedings vol 14 no 1 pp 8ndash142009

[146] S W P Wijnhoven H J M Kool C T M Van Oostrom et alldquoThe relationship between benzo[a]pyrene-induce mutagenesisand carcinogenesis in repair-deficient Cockayne syndromegroup B micerdquo Cancer Research vol 60 no 20 pp 5681ndash56872000

[147] T-J Chiu C-H Chen C-Y Chien S-H Li H-T Tsai andY-J Chen ldquoHigh ERCC1 expression predicts cisplatin-basedchemotherapy resistance and poor outcome in unresectablesquamous cell carcinoma of head and neck in a betel-chewingareardquo Journal of Translational Medicine vol 9 article 31 2011

[148] A Handra-Luca J Hernandez G Mountzios et al ldquoExci-sion repair cross complementation group 1 immunohisto-chemical expression predicts objective response and cancer-specific survival in patients treated by cisplatin-based inductionchemotherapy for locally advanced head and neck squamouscell carcinomardquo Clinical Cancer Research vol 13 no 13 pp3855ndash3859 2007

[149] H J Jun M J Ahn H S Kim et al ldquoERCC1 expression as apredictive marker of squamous cell carcinoma of the head andneck treated with cisplatin-based concurrent chemoradiationrdquoBritish Journal of Cancer vol 99 no 1 pp 167ndash172 2008

[150] L L Tsai C Yu J-F Lo et al ldquoEnhanced cisplatin resistancein oral-cancer stem-like cells is correlated with upregulationof excision-repair cross-complementation group 1rdquo Journal ofDental Sciences vol 7 no 2 pp 111ndash117 2012

[151] A Ahmad A R Robinson A Duensing et al ldquoERCC1-XPF endonuclease facilitates DNA double-strand break repairrdquoMolecular and Cellular Biology vol 28 no 16 pp 5082ndash50922008

[152] B Koberle C Ditz I Kausch B Wollenberg R L Ferrisand A E Albers ldquoMetastases of squamous cell carcinomaof the head and neck show increased levels of nucleotideexcision repair protein XPF in vivo that correlate with increased

chemoresistance ex vivordquo International Journal of Oncology vol36 no 5 pp 1277ndash1284 2010

[153] Y Wang M R Spitz J J Lee M Huang S M Lippmanand X Wu ldquoNucleotide excision repair pathway genes and oralpremalignant lesionsrdquo Clinical Cancer Research vol 13 no 12pp 3753ndash3758 2007

[154] L Cheng E M Sturgis S A Eicher M R Spitz and Q WeildquoExpression of nucleotide excision repair genes and dhe risk forsquamous cell carcinoma of the head and neckrdquoCancer vol 94no 2 pp 393ndash397 2002

[155] H Yu Z Liu Y J Huang M Yin L E Wang and QWei ldquoAssociation between single nucleotide polymorphisms inERCC4 and risk of squamous cell carcinoma of the head andneckrdquo PLoS ONE vol 7 no 7 Article ID e41853 2012

[156] T Sliwinski L Markiewicz P Rusin et al ldquoImpaired nucleotideexcision repair pathway as a possible factor in pathogenesis ofhead and neck cancerrdquo Mutation ResearchmdashFundamental andMolecular Mechanisms of Mutagenesis vol 716 no 1-2 pp 51ndash58 2011

[157] M E Zafereo E Sturgis Q Wei G Li Z Liu and LWang ldquoNucleotide excision repair and risk of second primarycancerrdquoOtolaryngologymdashHead and Neck Surgery vol 141 no 3supplement 1 pp P55ndashP56 2009

[158] S A Roberts N Strande M D Burkhalter et al ldquoKu is a 51015840-dRPAP lyase that excises nucleotide damage near broken endsrdquoNature vol 464 no 7292 pp 1214ndash1217 2010

[159] S M Indiviglio and A A Bertuch ldquoKursquos essential role inkeeping telomeres intactrdquo Proceedings of the National Academyof Sciences of the United States of America vol 106 no 30 pp12217ndash12218 2009

[160] B J Moeller J S Yordy M D Williams et al ldquoDNA repairbiomarker profiling of head and neck cancer Ku80 expressionpredicts locoregional failure and death following radiotherapyrdquoClinical Cancer Research vol 17 no 7 pp 2035ndash2043 2011

[161] MA PavonM Parreno X Leon et al ldquoKu70 predicts responseand primary tumor recurrence after therapy in locally advancedhead and neck cancerrdquo International Journal of Cancer vol 123no 5 pp 1068ndash1079 2008

[162] S Friesland L Kanter-Lewensohn R Tell E Munck-WiklandR Lewensohn and A Nilsson ldquoExpression of Ku86 confersfavorable outcome of tonsillar carcinoma treated with radio-therapyrdquo Head and Neck vol 25 no 4 pp 313ndash321 2003

[163] E Sonoda H Hochegger A Saberi Y Taniguchi and STakeda ldquoDifferential usage of non-homologous end-joiningand homologous recombination in double strand break repairrdquoDNA Repair vol 5 no 9-10 pp 1021ndash1029 2006

[164] A D DrsquoAndrea and M Grompe ldquoThe fanconi anaemiaBRCApathwayrdquo Nature Reviews Cancer vol 3 no 1 pp 23ndash34 2003

[165] P S RosenbergMHGreene andB PAlter ldquoCancer incidencein persons with Fanconi anemiardquo Blood vol 101 no 3 pp 822ndash826 2003

[166] V B Wreesmann C Estilo D W Eisele B Singh and S JWang ldquoDownregulation of Fanconi anemia genes in sporadichead and neck squamous cell carcinomardquo Journal for Oto-Rhino-Laryngology and Its Related Specialties vol 69 no 4 pp218ndash225 2007

[167] S Tremblay P P dos Reis G Bradley et al ldquoYoung patientswith oral squamous cell carcinoma study of the involvement ofGSTP1 and deregulation of the Fanconi anemia genesrdquoArchivesof OtolaryngologymdashHead and Neck Surgery vol 132 no 9 pp958ndash966 2006


[168] L E Hays D M Zodrow J E Yates et al ldquoCigarette smokeinduces genetic instability in airway epithelial cells by suppress-ing FANCD2 expressionrdquo British Journal of Cancer vol 98 no10 pp 1653ndash1661 2008

[169] C J Marsit M Liu H H Nelson M Posner M Suzukiand K T Kelsey ldquoInactivation of the Fanconi anemiaBRCApathway in lung and oral cancers implications for treatmentand survivalrdquo Oncogene vol 23 no 4 pp 1000ndash1004 2004

[170] A Ghosh S Ghosh G P Maiti et al ldquoAssociation of FANCCand PTCH1 with the development of early dysplastic lesionsof the head and neckrdquo Annals of Surgical Oncology vol 19supplement 3 pp S528ndashS538 2012

[171] I M Smith S K Mithani W K Mydlarz S S Chang andJ A Califano ldquoInactivation of the tumor suppressor genescausing the hereditary syndromes predisposing to head andneck cancer via promoter hypermethylation in sporadic headand neck cancersrdquo Journal for Oto-Rhino-Laryngology and ItsRelated Specialties vol 72 no 1 pp 44ndash50 2010

[172] E R Snyder J L Ricker Z Chen and C V Waes ldquoVariationin cisplatinum sensitivity is not associated with Fanconi Ane-miaBRCA pathway inactivation in head and neck squamouscell carcinoma cell linesrdquo Cancer Letters vol 245 no 1-2 pp75ndash80 2007

[173] K CManthey J G Glanzer D D Dimitrova andG G OakleyldquoHyperphosphorylation of replication protein A in cisplatin-resistant and -sensitive head and neck squamous cell carcinomacell linesrdquo Head and Neck vol 32 no 5 pp 636ndash645 2010

[174] D Thompson D F Easton and The Breast Cancer LinkageConsortium ldquoCancer incidence in BRCA1 mutation carriersrdquoJournal of the National Cancer Institute vol 94 no 18 pp 1358ndash1365 2002

[175] D Ford D F Easton D T Bishop S A Narod and D EGoldgar ldquoRisks of cancer in BRCA1-mutation carriersrdquo TheLancet vol 343 no 8899 pp 692ndash695 1994

[176] M Taron R Rosell E Felip et al ldquoBRCA1 mRNA expressionlevels as an indicator of chemoresistance in lung cancerrdquoHumanMolecular Genetics vol 13 no 20 pp 2443ndash2449 2004

[177] L A Tobin C Robert P Nagaria et al ldquoTargeting abnormalDNA repair in therapy-resistant breast cancersrdquo MolecularCancer Research vol 10 no 1 pp 96ndash107 2012

[178] H H Vora N G Shah D D Patel T I Trivedi and T JChoksi ldquoBRCA1 expression in leukoplakia and carcinomaof thetonguerdquo Journal of Surgical Oncology vol 83 no 4 pp 232ndash2402003

[179] H M Nawroz-Danish W M Koch W H Westra G Yooand D Sidransky ldquoLack of BRCA2 alterations in primary headand neck squamous cell carcinomardquoOtolaryngologymdashHead andNeck Surgery vol 119 no 1 pp 21ndash25 1998

[180] W Kolch ldquoMeaningful relationships the regulation of theRasRafMEKERK pathway by protein interactionsrdquo Biochem-ical Journal vol 351 no 2 pp 289ndash305 2000

[181] C J Marshall ldquoSpecificity of receptor tyrosine kinase signalingtransient versus sustained extracellular signal-regulated kinaseactivationrdquo Cell vol 80 no 2 pp 179ndash185 1995

[182] V W Lui M L Hedberg H Li et al ldquoFrequent mutation ofthe PI3K pathway in head and neck cancer defines predictivebiomarkersrdquo Cancer Discovery vol 3 no 7 pp 761ndash769 2013

[183] M Toulany U Kasten-Pisula I Brammer et al ldquoBlock-age of epidermal growth factor receptor-phosphatidylinositol3-kinase-AKT signaling increases radiosensitivity of K-RASmutated human tumor cells in vitro by affecting DNA repairrdquoClinical Cancer Research vol 12 no 13 pp 4119ndash4126 2006

[184] S-M Huang J M Bock and P M Harari ldquoEpidermal growthfactor receptor blockade with C225 modulates proliferationapoptosis and radiosensitivity in squamous cell carcinomas ofthe head and neckrdquo Cancer Research vol 59 no 8 pp 1935ndash1940 1999

[185] A Kumar O Fernadez-Capetillo and A C Carrera ldquoNuclearphosphoinositide 3-kinase 120573 controls double-strand breakDNA repairrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 107 no 16 pp 7491ndash74962010

[186] G D Kao Z Jiang AM Fernandes A K Gupta and AMaityldquoInhibition of phosphatidylinositol-3-OH kinaseAkt signalingimpairs DNA repair in glioblastoma cells following ionizingradiationrdquo Journal of Biological Chemistry vol 282 no 29 pp21206ndash21212 2007

[187] M Toulany R Kehlbach U Florczak et al ldquoTargeting ofAKT1 enhances radiation toxicity of human tumor cells byinhibiting DNA-PKcs-dependent DNA double-strand breakrepairrdquo Molecular Cancer Therapeutics vol 7 no 7 pp 1772ndash1781 2008

[188] I Plo C Laulier L Gauthier F Lebrun F Calvo and B SLopez ldquoAKT1 inhibits homologous recombination by inducingcytoplasmic retention of BRCA1 and RAD5rdquo Cancer Researchvol 68 no 22 pp 9404ndash9412 2008

[189] L Li H Wang E S Yang C L Arteaga and F Xia ldquoErlotinibattenuates homologous recombinational repair of chromosomalbreaks in human breast cancer cellsrdquo Cancer Research vol 68no 22 pp 9141ndash9146 2008

[190] P Chinnaiyan S Huang G Vallabhaneni et al ldquoMechanisms ofenhanced radiation response following epidermal growth factorreceptor signaling inhibition by erlotinib (Tarceva)rdquo CancerResearch vol 65 no 8 pp 3328ndash3335 2005

[191] J A Engelman and P A Janne ldquoMechanisms of acquiredresistance to epidermal growth factor receptor tyrosine kinaseinhibitors in non-small cell lung cancerrdquo Clinical CancerResearch vol 14 no 10 pp 2895ndash2899 2008

[192] T J Lynch D W Bell R Sordella et al ldquoActivating mutationsin the epidermal growth factor receptor underlying respon-siveness of non-small-cell lung cancer to gefitinibrdquo The NewEngland Journal of Medicine vol 350 no 21 pp 2129ndash21392004

[193] J Loeffler-Ragg M Witsch-Baumgartner A Tzankov et alldquoLow incidence of mutations in EGFR kinase domain in Cau-casian patients with head and neck squamous cell carcinomardquoEuropean Journal of Cancer vol 42 no 1 pp 109ndash111 2006

[194] J W Lee Y H Soung S Y Kim et al ldquoSomatic mutations ofEGFR gene in squamous cell carcinoma of the head and neckrdquoClinical Cancer Research vol 11 no 8 pp 2879ndash2882 2005

[195] I Schwentner M Witsch-Baumgartner G M Sprinzl et alldquoIdentification of the rare EGFR mutation pG796S as somaticand germline mutation in white patients with squamous cellcarcinoma of the head and neckrdquo Head and Neck vol 30 no8 pp 1040ndash1044 2008

[196] I I Na H J Kang S Y Cho et al ldquoEGFR mutations andhuman papillomavirus in squamous cell carcinoma of tongueand tonsilrdquo European Journal of Cancer vol 43 no 3 pp 520ndash526 2007

[197] M A L S Ali M Gunduz H Nagatsuka et al ldquoExpression andmutation analysis of epidermal growth factor receptor in headand neck squamous cell carcinomardquo Cancer Science vol 99 no8 pp 1589ndash1594 2008


[198] J C Sok F M Coppelli S MThomas et al ldquoMutant epidermalgrowth factor receptor (EGFRvIII) contributes to head andneck cancer growth and resistance to EGFR targetingrdquo ClinicalCancer Research vol 12 no 17 pp 5064ndash5073 2006

[199] H K Gan A H Kaye and R B Luwor ldquoThe EGFRvIII variantin glioblastoma multiformerdquo Journal of Clinical Neurosciencevol 16 no 6 pp 748ndash754 2009

[200] S EWheeler S Suzuki S MThomas et al ldquoEpidermal growthfactor receptor variant III mediates head and neck cancer cellinvasion via STAT3 activationrdquo Oncogene vol 29 no 37 pp5135ndash5145 2010

[201] S K Batra S Castelino-Prabhu C J Wikstrand et al ldquoEpi-dermal growth factor ligand-independent unregulated cell-transforming potential of a naturally occurring human mutantEGFRvIII generdquo Cell Growth and Differentiation vol 6 no 10pp 1251ndash1259 1995

[202] A K Murugan NThi Hong Y Fukui A K Munirajan and NTsuchida ldquoOncogenic mutations of the PIK3CA gene in headand neck squamous cell carcinomasrdquo International Journal ofOncology vol 32 no 1 pp 101ndash111 2008

[203] W Qiu F Schonleben X Li et al ldquoPIK3CA mutations in headand neck squamous cell carcinomardquo Clinical Cancer Researchvol 12 no 5 pp 1441ndash1446 2006

[204] I Fenic K Steger C Gruber C Arens and J WoenckhausldquoAnalysis of PIK3CA andAktprotein kinase B in head and necksquamous cell carcinomardquo Oncology Reports vol 18 no 1 pp253ndash259 2007

[205] Y Cohen N Goldenberg-Cohen B Shalmon et al ldquoMutationalanalysis of PTENPIK3CAAKT pathway in oral squamous cellcarcinomardquo Oral Oncology vol 47 no 10 pp 946ndash950 2011

[206] W M Ongkeko X Altuna R A Weisman and J Wang-Rodriguez ldquoExpression of protein tyrosine kinases in head andneck squamous cell carcinomasrdquo American Journal of ClinicalPathology vol 124 no 1 pp 71ndash76 2005

[207] J R Grandis M F Melhem W E Gooding et al ldquoLevelsof TGF-120572 and EGFR protein in head and neck squamous cellcarcinoma and patient survivalrdquo Journal of the National CancerInstitute vol 90 no 11 pp 824ndash832 1998

[208] K K Ang B A Berkey X Tu et al ldquoImpact of epidermalgrowth factor receptor expression on survival and pattern ofrelapse in patients with advanced head and neck carcinomardquoCancer Research vol 62 no 24 pp 7350ndash7356 2002

[209] S-F HuangW-Y Chuang I-H Chen C-T Liao H-MWangand L-L Hsieh ldquoEGFR protein overexpression and mutationin areca quid-associated oral cavity squamous cell carcinoma inTaiwanrdquo Head and Neck vol 31 no 8 pp 1068ndash1077 2009

[210] E L Abhold A Kiang E Rahimy et al ldquoEGFRkinase promotesacquisition of stem cell-like properties a potential therapeutictarget in head and neck squamous cell carcinoma stem cellsrdquoPLoS ONE vol 7 no 2 Article ID e32459 2012

[211] S Temam H Kawaguchi A K El-Naggar et al ldquoEpidermalgrowth factor receptor copy number alterations correlate withpoor clinical outcome in patients with head and neck squamouscancerrdquo Journal of Clinical Oncology vol 25 no 16 pp 2164ndash2170 2007

[212] L E Morrison K K Jacobson M Friedman J W Schroederand J S Coon ldquoAberrant EGFR and chromosome 7 associatewith outcome in laryngeal cancerrdquo Laryngoscope vol 115 no 7pp 1212ndash1218 2005

[213] J A Bonner P M Harari J Giralt et al ldquoRadiotherapy pluscetuximab for squamous-cell carcinoma of the head and neckrdquo

The New England Journal of Medicine vol 354 no 6 pp 567ndash578 2006

[214] National Comprehensive Cancer Network Head and Neck Can-cers 2012 httpwwwnccnorgprofessionalsphysician glspdfhead-and-neckpdf

[215] J-C Ko S-C Ciou C-M Cheng et al ldquoInvolvement of Rad51in cytotoxicity induced by epidermal growth factor receptorinhibitor (gefitinib Iressa R) and chemotherapeutic agents inhuman lung cancer cellsrdquoCarcinogenesis vol 29 no 7 pp 1448ndash1458 2008

[216] J S Stewart E E Cohen L Licitra et al ldquoPhase III study ofgefitinib comparedwith intravenousmethotrexate for recurrentsquamous cell carcinoma of the head and neckrdquo Journal ofClinical Oncology vol 27 no 11 pp 1864ndash1871 2009

[217] S M Bentzen B M Atasoy F M Daley et al ldquoEpidermalgrowth factor receptor expression in pretreatment biopsiesfrom head and neck squamous cell carcinoma as a predictivefactor for a benefit from accelerated radiation therapy in arandomized controlled trialrdquo Journal of Clinical Oncology vol23 no 24 pp 5560ndash5567 2005

[218] D J Chen and C S Nirodi ldquoThe epidermal growth factorreceptor a role in repair of radiation-induced DNA damagerdquoClinical Cancer Research vol 13 no 22 pp 6555ndash6560 2007

[219] C LiM Iida E FDunnA J Ghia andD LWheeler ldquoNuclearEGFR contributes to acquired resistance to cetuximabrdquo Onco-gene vol 28 no 43 pp 3801ndash3813 2009

[220] D L Wheeler S Huang T J Kruser et al ldquoMechanisms ofacquired resistance to cetuximab role of HER (ErbB) familymembersrdquo Oncogene vol 27 no 28 pp 3944ndash3956 2008

[221] S Misale R Yaeger S Hobor et al ldquoEmergence of KRASmutations and acquired resistance to anti-EGFR therapy incolorectal cancerrdquoNature vol 486 no 7404 pp 532ndash536 2012

[222] K A Frazer D G Ballinger D R Cox et al ldquoA secondgeneration human haplotype map of over 31 million SNPsrdquoNature vol 449 no 7164 pp 851ndash861 2007

[223] I Mahjabeen R M Baig N Masood M Sabir F A Malikand M A Kayani ldquoOGG1 gene sequence variation in head andneck cancer patients in pakistanrdquoAsian Pacific Journal of CancerPrevention vol 12 no 10 pp 2779ndash2783 2011

[224] T Hashimoto K Uchida N Okayama et al ldquoInteraction ofOGG1 Ser326Cys polymorphism with cigarette smoking inhead and neck squamous cell carcinomardquo Molecular Carcino-genesis vol 45 no 5 pp 344ndash348 2006

[225] M Majumder D Indra P D Roy et al ldquoVariant haplotypesat XRCC1 and risk of oral leukoplakia in HPV non-infectedsamplesrdquo Journal of Oral Pathology and Medicine vol 38 no2 pp 174ndash180 2009

[226] K M Applebaum M D McClean H H Nelson C J MarsitB C Christensen and K T Kelsey ldquoSmoking modifies therelationship between XRCC1 haplotypes and HPV16-negativehead and neck squamous cell carcinomardquo International Journalof Cancer vol 124 no 11 pp 2690ndash2696 2009

[227] J Huang F Ye H Chen W Lu and X Xie ldquoThe non-synonymous single nucleotide polymorphisms of DNA repairgene XRCC1 and susceptibility to the development of cervicalcarcinoma and high-risk human papillomavirus infectionrdquoInternational Journal of Gynecological Cancer vol 17 no 3 pp668ndash675 2007

[228] A Kumar M C Pant H S Singh and S KhandelwalldquoAssociated risk of XRCC1 and XPD cross talk and life stylefactors in progression of head and neck cancer in north Indian


populationrdquo Mutation ResearchmdashFundamental and MolecularMechanisms of Mutagenesis vol 729 no 1-2 pp 24ndash34 2012

[229] J Carles M Monzo M Amat et al ldquoSingle-nucleotide poly-morphisms in base excision repair nucleotide excision repairand double strand break genes as markers for response toradiotherapy in patients with Stage I to II head-and-neckcancerrdquo International Journal of Radiation Oncology BiologyPhysics vol 66 no 4 pp 1022ndash1030 2006

[230] G De Castro Jr F S Pasini S A C Siqueira et al ldquoERCC1protein mRNA expression and T19007C polymorphism asprognostic markers in head and neck squamous cell carcinomapatients treated with surgery and adjuvant cisplatin-basedchemoradiationrdquo Oncology Reports vol 25 no 3 pp 693ndash6992011

[231] M Swift D Morrell R B Massey and C L Chase ldquoIncidenceof cancer in 161 families affected by ataxia-telangiectasiardquo TheNew England Journal of Medicine vol 325 no 26 pp 1831ndash18361991

[232] P Sung and H Klein ldquoMechanism of homologous recombi-nation mediators and helicases take on regulatory functionsrdquoNature Reviews Molecular Cell Biology vol 7 no 10 pp 739ndash750 2006

[233] D J Richard E Bolderson L Cubeddu et al ldquoSingle-strandedDNA-binding protein hSSB1 is critical for genomic stabilityrdquoNature vol 453 no 7195 pp 677ndash681 2008

[234] D J Richard K Savage E Bolderson et al ldquoHSSB1 rapidlybinds at the sites of DNA double-strand breaks and is requiredfor the efficient recruitment of theMRNcomplexrdquoNucleic AcidsResearch vol 39 no 5 pp 1692ndash1702 2011

[235] S Nakada R M Yonamine and K Matsuo ldquoRNF8 regulatesassembly of RAD51 atDNAdouble-strand breaks in the absenceof BRCA1 and 53BP1rdquoCancer Research vol 72 no 19 pp 4974ndash4983 2012

[236] E Bolderson N Tomimatsu D J Richard et al ldquoPhosphory-lation of Exo1 modulates homologous recombination repair ofDNA double-strand breaksrdquoNucleic Acids Research vol 38 no6 pp 1821ndash1831 2010

[237] D J Richard L Cubeddu A J Urquhart et al ldquohSSB1 interactsdirectly with the MRN complex stimulating its recruitmentto DNA double-strand breaks and its endo-nuclease activityrdquoNucleic Acids Research vol 39 no 9 pp 3643ndash3651 2011

[238] W Y Mansour T Rhein and J Dahm-Daphi ldquoThe alternativeend-joining pathway for repair of DNA double-strand breaksrequires PARP1 but is not dependent upon microhomologiesrdquoNucleic Acids Research vol 38 no 18 pp 6065ndash6077 2010

[239] K Shinmura H Tao M Goto et al ldquoInactivating mutations ofthe human base excision repair gene NEIL1 in gastric cancerrdquoCarcinogenesis vol 25 no 12 pp 2311ndash2317 2004

[240] T Sliwinski A Walczak K Przybylowska et al ldquoPolymor-phisms of the XRCC3 C722T and the RAD51 G135C genesand the risk of head and neck cancer in a Polish populationrdquoExperimental and Molecular Pathology vol 89 no 3 pp 358ndash366 2010

[241] H Romanowicz-Makowska B Smolarz M Gajęcka et alldquoPolymorphism of the DNA repair genes RAD51 and XRCC2in smoking-and drinking-related laryngeal cancer in a Polishpopulationrdquo Archives of Medical Science vol 8 no 6 pp 1065ndash1075 2012

[242] J Werbrouck K De Ruyck F Duprez et al ldquoSingle-nucleotidepolymorphisms in DNA double-strand break repair genesassociation with head and neck cancer and interaction with

tobacco use and alcohol consumptionrdquo Mutation ResearchmdashGenetic Toxicology and EnvironmentalMutagenesis vol 656 no1-2 pp 74ndash81 2008

[243] Y Cui H Morgenstern S Greenland et al ldquoPolymorphism ofxeroderma pigmentosum group G and the risk of lung cancerand squamous cell carcinomas of the oropharynx larynx andesophagusrdquo International Journal of Cancer vol 118 no 3 pp714ndash720 2006

[244] M B dos Reis R Losi-Guembarovski E M de Souza FonsecaRibeiro et al ldquoAllelic variants of XRCC1 and XRCC3 repairgenes and susceptibility of oral cancer in Brazilian patientsrdquoJournal of Oral Pathology ampMedicine vol 42 no 2 pp 180ndash1852013

[245] E Pawlowska K Janik-Papis M Rydzanicz et al ldquoThe Cys326allele of the 8-oxoguanine DNA N-glycosylase 1 gene as arisk factor in smoking- and drinking-associated larynx cancerrdquoTohoku Journal of Experimental Medicine vol 219 no 4 pp269ndash275 2009

[246] S Kietthubthew H Sriplung W W Au and T IshidaldquoPolymorphism in DNA repair genes and oral squamous cellcarcinoma in Thailandrdquo International Journal of Hygiene andEnvironmental Health vol 209 no 1 pp 21ndash29 2006

[247] P Gresner J Gromadzinska K Polanska E Twardowska JJurewicz and W Wasowicz ldquoGenetic variability of Xrcc3 andRad51 modulates the risk of head and neck cancerrdquo Gene vol504 no 2 pp 166ndash174 2012

[248] Z Zhang Q Shi L-E Wang et al ldquoNo association betweenhOGG1 Ser326Cys polymorphism and risk of squamouscell carcinoma of the head and neckrdquo Cancer EpidemiologyBiomarkers and Prevention vol 13 no 6 pp 1081ndash1083 2004

[249] A Elahi Z Zheng J Park K Eyring T McCaffrey andP Lazarus ldquoThe human OGG1 DNA repair enzyme and itsassociation with orolaryngeal cancer riskrdquo Carcinogenesis vol23 no 7 pp 1229ndash1234 2002

[250] S Ramachandran K Ramadas R Hariharan R RejnishKumar and M Radhakrishna Pillai ldquoSingle nucleotide poly-morphisms of DNA repair genes XRCC1 and XPD and itsmolecular mapping in Indian oral cancerrdquo Oral Oncology vol42 no 4 pp 350ndash362 2006

[251] K Tae H S Lee B J Park et al ldquoAssociation of DNA repairgene XRCC1 polymorphisms with head and neck cancer inKorean populationrdquo International Journal of Cancer vol 111 no5 pp 805ndash808 2004

[252] M Kowalski K Przybylowska P Rusin et al ldquoGenetic poly-morphisms in DNA base excision repair gene XRCC1 and therisk of squamous cell carcinoma of the head and neckrdquo Journalof Experimental and Clinical Cancer Research vol 28 no 1article 37 2009

[253] C-Y Yen S-Y Liu C-H Chen et al ldquoCombinational poly-morphisms of four DNA repair genes XRCC1 XRCC2 XRCC3and XRCC4 and their association with oral cancer in TaiwanrdquoJournal of Oral Pathology and Medicine vol 37 no 5 pp 271ndash277 2008

[254] H-C Tseng M-H Tsai C-F Chiu et al ldquoAssociation ofXRCC4 codon 247 polymorphism with oral cancer susceptibil-ity in Taiwanrdquo Anticancer Research vol 28 no 3A pp 1687ndash1691 2008

[255] C-F Chiu M-H Tsai H-C Tseng et al ldquoA novel singlenucleotide polymorphism in XRCC4 gene is associated withoral cancer susceptibility in Taiwanese patientsrdquoOral Oncologyvol 44 no 9 pp 898ndash902 2008


[256] C-F Chiu M-H Tsai H-C Tseng et al ldquoA novel singlenucleotide polymorphism in ERCC6 gene is associated withoral cancer susceptibility in Taiwanese patientsrdquoOral Oncologyvol 44 no 6 pp 582ndash586 2008

[257] C-F Hsu H-C Tseng C-F Chiu et al ldquoAssociation betweenDNA double strand break gene Ku80 polymorphisms and oralcancer susceptibilityrdquoOral Oncology vol 45 no 9 pp 789ndash7932009

[258] D-T Bau H-C Tseng C-H Wang et al ldquoOral cancer andgenetic polymorphism of DNA double strand break gene Ku70in Taiwanrdquo Oral Oncology vol 44 no 11 pp 1047ndash1051 2008

[259] R E Flores-Obando S M Gollin and C C Ragin ldquoPolymor-phisms in DNA damage response genes and head and neckcancer riskrdquo Biomarkers vol 15 no 5 pp 379ndash399 2010

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


Viral oncoprotein-induced cell cycle

dysregulationTobacco alcohol and other

exogenous carcinogens Ionising radiation

Nonselective cytotoxic chemotherapy

Ionising radiation

Functional genomic stability pathway

polymorphism

Germline DNA repair-deficient syndrome Predisposing

factors

Causative agents

Therapeutic cytotoxic agents

Figure 1 Common genomic stressors in carcinogenesis and therapy

survival benefit [10] although heterogeneity between trialtreatment arms and high loss-to-followup make absolutebenefit difficult to interpret EGFR inhibitor therapy hasemerged as an effective adjuvant in HNSCC and is discussedin detail below

Chromosomalmutation is one of themost readily observ-able features of cancer and has been known to underpinmalignancy for over a hundred years [11] The mechanismbehind most common chromosomal lesions is genomicinstability which is influenced by the interdependent triad ofaccumulating DNA damage defective DNA damage repairand replication stress In HNSCC DNA damage is increasedby exposure to carcinogens (tobacco alcohol and variousregionally specific botanicals) Ineffective repair by a numberof germline variations in the DNA repair pathways longrecognised in congenital repair syndromes such as Fanconianemia have been increasingly implicated as factors inHNSCC particularly in phenotypically silent individualswith single-nucleotide polymorphisms (SNPs) of DNA repairgenes The DNA damage response is a highly conservedpathway that is activated on the basis of a ldquothresholdrdquoof DNA damage events and functions to inhibit cell cycleprogression via checkpoint signalling for either repair orapoptosis as well as directly in the repair of the lesions Thesepathways are known to be constitutively active in dysplasticlesions [12ndash14] This genetically unstable environment drivesmutagenic stress with selective pressure for inactivation ofgrowth restrictingapoptotic processes [13 15] Replicationstress drives the accumulation of DNA lesions in HNSCCand is promoted by genetic loss of cell-cycle checkpointcontrol through mutation and epigenetic loss via oncoviralcoinfection with high-risk human papillomavirus (HPV)

Head and neck squamous-cell carcinoma has a malepredominance and is associated with tobacco alcohol anduse of a number of alkaloid-rich regional stimulants (suchas betel nut) A subset of HNSCC is strongly associated withldquohigh-riskrdquo HPV subtypes 16 and 18 infection [16] that are

present in up to 60ndash80 of nonoral HNSCC and 30 oforal cavity SCC in a Western population [17ndash20] This groupof disease that affects younger patients is proportionallyassociatedwith number of sexual partners and has a distinctlyimproved prognosis and different treatment profile fromHPV-unrelated oropharyngeal HNSCC [21ndash27] as well as adistinct pattern of chromosomal mutation [28 29] Prog-nostic significance in oral cavity SCC is less clear (reviewedin [19]) The association of HPV with oral squamous-cellcarcinoma was observed 30 years ago [30] however theepidemiological changes became more evident over the fol-lowing decades as decreased tobacco use and increased HPVprevalence highlighted this subgroup [16] Viral oncoproteinsE6 and E7 have been implicated as the causative agentsin HPV-associated HNSCC E6-induced ubiquitin-mediatedproteosomal degradation of tumour suppressor p53 causescell-cycle dysregulation and increased replication stress [31ndash33] Oncoprotein E7 binds to and disrupts pRb-mediateddegradation of transcription activator E2F which promotesgenes responsible for cell-cycle progression [34ndash36] Tumoursuppressor protein p16 a CDK4A inhibitor is characteristi-cally elevated in E7-induced pRb suppression to the extentthat p16 levels are typically used as a surrogate marker forHPV-related SCC [37ndash39] E7 has also been shown to induceaberrant centrosome number and mitotic spindle formation[40 41] These proteins function to allow viral replicationin the normally postmitotic upper differentiated epitheliallayers [42] Whole-exome sequencing has shown that HPV-related HNSCC is associated with less instability with a 2-fold lowermutation rate [43] Interestingly while suppressionof the upstream DNA damage response ataxia-telangectasiamutated protein (ATM) and ataxia-telangectasia and Rad3-related protein (ATR) is deleterious forHPVepisome stability[44] cell line studies have shown that the radiosensitivity ofHPV-16 related SCC is attributable in part to a repair defectwith accumulation of unrepaired DNA double strand breaksand resultant cell-cycle arrest [45] This study was conducted















Me

UvCUvC


drugsfailed repair


Base mismatch

8-oxoG lesion


UV radiationRepair
























Table 1




292 (lt00001)403 (lt00001)




NS [343 (0073)]NS [381 (0061)]NS [214 (0061)]


controls



Ku80 c2110-2408GgtA

196 (002)043 (005)043 (001)

NSNS


XPG c1104 047 (lt005)



XRCC3Thr241Met

NSNS








Rad51rs1801321 TT 01 (lt005)




16 (lt005)41 (lt005)




controls




controls

XRCC1 c194c280c399

XPD c751

309 (lt00001)NS

237 (lt00001)210 (0003)



261 (lt005)NS


NS



XPD Lys751Gln

072 (003)NS

064 (0003)175 (0002)



Table 1 Continued




NS


SNPs



XRCC4 c247G1394T

rs28360317rs1805377

204 (lt005)NSNSNS


XRCC4 G1394Trs28360071rs28360217rs1805377

NS155 (lt005)

NSNS


ERCC6c399 (AA)


c1097c1413

182 (lt005)NS

143 (lt005)NSNS



1603 (lt005)(2)NSNS



215 (lt005)NSNSNS









XRCC3Thr241Met

NS074 (lt005)

NS114 (005)

NSNSNSNS

156 (lt005)NSNS

169 (lt005)NSNSNS



NSNS

















SOSPI3-KP

RAS

RAFAKT

mTOR

MEK

ERK


Ku70 Ku80

P

EGFR

Nbs1

BRCA1Rad51

Nuclear transport

DNA damage binding









11 Discussion









References




























































































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology















Me

UvCUvC


drugsfailed repair


Base mismatch

8-oxoG lesion


UV radiationRepair
























Table 1




292 (lt00001)403 (lt00001)




NS [343 (0073)]NS [381 (0061)]NS [214 (0061)]


controls



Ku80 c2110-2408GgtA

196 (002)043 (005)043 (001)

NSNS


XPG c1104 047 (lt005)



XRCC3Thr241Met

NSNS








Rad51rs1801321 TT 01 (lt005)




16 (lt005)41 (lt005)




controls




controls

XRCC1 c194c280c399

XPD c751

309 (lt00001)NS

237 (lt00001)210 (0003)



261 (lt005)NS


NS



XPD Lys751Gln

072 (003)NS

064 (0003)175 (0002)



Table 1 Continued




NS


SNPs



XRCC4 c247G1394T

rs28360317rs1805377

204 (lt005)NSNSNS


XRCC4 G1394Trs28360071rs28360217rs1805377

NS155 (lt005)

NSNS


ERCC6c399 (AA)


c1097c1413

182 (lt005)NS

143 (lt005)NSNS



1603 (lt005)(2)NSNS



215 (lt005)NSNSNS









XRCC3Thr241Met

NS074 (lt005)

NS114 (005)

NSNSNSNS

156 (lt005)NSNS

169 (lt005)NSNSNS



NSNS

















SOSPI3-KP

RAS

RAFAKT

mTOR

MEK

ERK


Ku70 Ku80

P

EGFR

Nbs1

BRCA1Rad51

Nuclear transport

DNA damage binding









11 Discussion









References




























































































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology
















Table 1




292 (lt00001)403 (lt00001)




NS [343 (0073)]NS [381 (0061)]NS [214 (0061)]


controls



Ku80 c2110-2408GgtA

196 (002)043 (005)043 (001)

NSNS


XPG c1104 047 (lt005)



XRCC3Thr241Met

NSNS








Rad51rs1801321 TT 01 (lt005)




16 (lt005)41 (lt005)




controls




controls

XRCC1 c194c280c399

XPD c751

309 (lt00001)NS

237 (lt00001)210 (0003)



261 (lt005)NS


NS



XPD Lys751Gln

072 (003)NS

064 (0003)175 (0002)



Table 1 Continued




NS


SNPs



XRCC4 c247G1394T

rs28360317rs1805377

204 (lt005)NSNSNS


XRCC4 G1394Trs28360071rs28360217rs1805377

NS155 (lt005)

NSNS


ERCC6c399 (AA)


c1097c1413

182 (lt005)NS

143 (lt005)NSNS



1603 (lt005)(2)NSNS



215 (lt005)NSNSNS









XRCC3Thr241Met

NS074 (lt005)

NS114 (005)

NSNSNSNS

156 (lt005)NSNS

169 (lt005)NSNSNS



NSNS

















SOSPI3-KP

RAS

RAFAKT

mTOR

MEK

ERK


Ku70 Ku80

P

EGFR

Nbs1

BRCA1Rad51

Nuclear transport

DNA damage binding









11 Discussion









References




























































































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


Table 1 Continued




NS


SNPs



XRCC4 c247G1394T

rs28360317rs1805377

204 (lt005)NSNSNS


XRCC4 G1394Trs28360071rs28360217rs1805377

NS155 (lt005)

NSNS


ERCC6c399 (AA)


c1097c1413

182 (lt005)NS

143 (lt005)NSNS



1603 (lt005)(2)NSNS



215 (lt005)NSNSNS









XRCC3Thr241Met

NS074 (lt005)

NS114 (005)

NSNSNSNS

156 (lt005)NSNS

169 (lt005)NSNSNS



NSNS

















SOSPI3-KP

RAS

RAFAKT

mTOR

MEK

ERK


Ku70 Ku80

P

EGFR

Nbs1

BRCA1Rad51

Nuclear transport

DNA damage binding









11 Discussion









References




























































































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology
















SOSPI3-KP

RAS

RAFAKT

mTOR

MEK

ERK


Ku70 Ku80

P

EGFR

Nbs1

BRCA1Rad51

Nuclear transport

DNA damage binding









11 Discussion









References




























































































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology








References




























































































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology














































































































































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

Review Article Genome Stability Pathways in Head and Neck...

Documents

Transcript of Review Article Genome Stability Pathways in Head and Neck...