Cancer syndrome 1

Cancer syndrome

Familial adenomatous polyposis is a cancer syndrome where there are hundreds tothousands of benign adenomas in the colon.

A cancer syndrome is a geneticdisorder in which genetic mutations inone or more genes predispose theaffected individuals to thedevelopment of cancers and may alsocause the early onset of these cancers.Cancer syndromes often show not onlya high lifetime risk of developingcancer, but also the development ofmultiple independent primary tumors.Many of these syndromes are causedby mutations in tumor suppressorgenes, genes that are involved inprotecting the cell from turningcancerous. Other genes that may beaffected are DNA repair genes,oncogenes and genes involved in theproduction of blood vessels(angiogenesis). Common examples ofinherited cancer syndromes arehereditary breast-ovarian cancer syndrome and hereditary non-polyposis colon cancer (Lynch syndrome).

Background

Hereditary cancer syndromes underlie 5 to 10% of all cancers.[1] Scientific understanding of cancer susceptibilitysyndromes is actively expanding: additional syndromes are being found, the underlying biology is becoming clearer,and commercialization of diagnostic genetics methodology is improving clinical access.[citation needed] Given theprevalence of breast and colon cancer, the most widely recognized syndromes include hereditary breast-ovariancancer syndrome (HBOC) and hereditary non-polyposis colon cancer (HNPCC, Lynch syndrome).

Some rare cancers are strongly associated with hereditary cancer predisposition syndromes. Genetic testing shouldbe considered with adrenocortical carcinoma; carcinoid tumors; diffuse gastric cancer; fallopian tube/primaryperitoneal cancer; leiomyosarcoma; medullary thyroid cancer; paraganglioma/pheochromocytoma; renal cellcarcinoma of chromophobe, hybrid oncocytic, or oncocytoma histology; sebaceous carcinoma; and sex cord tumorswith annular tubules.

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Genetics

Example pedigree chart of autosomal dominantinheritance. Many cancer syndromes are inherited

in this manner.

Less commonly, cancer syndromes are inheritedin an autosomal recessive manner. In this

example pedigree chart the only person that willhave an increased risk of cancer is the

homozygous recessive male in the secondgeneration; although there are many carriers of

the gene.

Two copies of every gene are present in all cells of the body and eachone is called an allele. Most cancer syndromes are transmitted in amendelian autosomal dominant manner. In these cases, only one faultyallele has to be present for an individual to have a predisposition tocancer. Individuals with one normal allele and one faulty allele areknown as heterozygous. A heterozygous individual and a person withtwo normal alleles (homozygous) will have a 50% chance of producingan affected child. The mutation in the inherited gene is known as agermline mutation and a further mutation in the normal allele results inthe development of cancer. This is known as Knudson's two hithypothesis, where the first hit of the gene is the inherited mutation andthe second hit occurs later in life. As only one allele needs to bemutated (as compared to both in so called "sporadic cancers"), theindividual has a higher chance of developing the cancer than thegeneral population.[citation needed]

Less often, syndromes may be transmitted as an autosomal recessivetrait. Both alleles of a gene must be mutated in autosomal recessivedisorders for an individual to have a predisposition to cancer. A personwith two recessive alleles is known as homozygous recessive . Bothparents must have at least one faulty allele in order for a child to behomozygous recessive. If both parents have one mutant allele and onenormal allele (heterozygous) then they have a 25% chance ofproducing a homozygous recessive child (has predisposition), 50%chance of producing a heterozygous child (carrier of the faulty gene)and 25% chance of produced a child with two normal alleles.

Examples of autosomal dominant cancer syndromes are autoimmunelymphoproliferative syndrome (Canale-Smith syndrome),BeckwithWiedemann syndrome (although 85% of cases are sporadic),[citation needed] BirtHoggDub syndrome,Carney syndrome, familial chordoma, Cowden syndrome, dysplastic nevus syndrome with familial melanoma,familial adenomatous polyposis, hereditary breast-ovarian cancer syndrome, hereditary diffuse gastric cancer(HDGC), hereditary non-polyposis colon cancer (Lynch syndrome), HowelEvans syndrome of eosophageal cancerwith tylosis, juvenile polyposis syndrome, Li-Fraumeni syndrome, multiple endocrine neoplasia type 1/2, multipleosteochondromatosis, neurofibromatosis type 1/2, nevoid basal cell carcinoma syndrome (Gorlin syndrome),Peutz-Jeghers syndrome, familial prostate cancer, hereditary leiomyomatosis renal cell cancer (LRCC), hereditarypapillary renal cell cancer (HPRCC), hereditary paraganglioma-pheochromocytoma syndrome, retinoblastoma,tuberous sclerosis, von Hippel-Lindau disease and Wilm's tumor.

Examples of autosomal recessive cancer syndromes are ataxia telangiectasia, Bloom syndrome, Fanconi anemia,MUTYH-associated polyposis, Rothmund-Thomson syndrome, Werner's syndrome and Xeroderma pigmentosum.

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SyndromesAlthough cancer syndromes exhibit an increased risk of cancer, the risk varies. For some of these diseases, cancer isnot their primary feature. The discussion here focuses on their association with an increased risk of cancer.

Fanconi anemiaFanconi anemia (FA) is a disorder with a wide clinical spectrum, including: early onset and increased risk of cancer;bone marrow failure; and congenital abnormalities. The most prominent manifestations of this disorder are thoserelated tohematopoeisis (production of blood by the bone marrow); these include aplastic anemia, myelodysplasticsyndrome and acute myeloid leukemia. Hepatic tumors andsquamous cell carcinomas of the esophagus, oropharynxand uvula are solid tumors commonly linked to FA. Congenital abnormalities include: skeletal anomalies (especiallythose affecting the hands), cafe au lait spots and hypopigmentation. To date, the genes known to cause FA are:FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN,FANCO, FANCP and BRCA2 (previously known as FANCD1). Inheritance of this syndrome is primarily autosomalrecessive, but FANCB can be inherited from the maternal or paternal x-chromosome (x-linked recessiveinheritance). The FA pathway is involved in DNA repair when the two strands of DNA are incorrectly joinedtogether (interstrand crosslinks). Many pathways are coordinated by the FA pathway for this including nucleotideexcision repair, translesion synthesis and homologous recombination.

Familial adenomatous polyposisFamilial adenomatous polyposis (FAP) is an autosomal dominant syndrome that massively increases the risk ofcolorectal cancer. Around 1 in 8000 people will have this disease and it has approximately 100% penetrance. Anindividual with this disease will have hundreds to thousands of benign adenomas throughout their colon, which willin most cases progress to cancer. Other tumors increased in frequency include; osteomas, adrenal adenomas andcarcinomas, thyroid tumors and desmoid tumors. The cause of this disorder is a mutated APC gene, which isinvolved in -catenin regulation. Faulty APC causes -catenin to accumulate in cells and activate transcriptionfactors involved in cell proliferation, migration, differentiation and apoptosis (programmed cell death).

Hereditary breast and ovarian cancerHereditary breast-ovarian cancer syndrome (HBOC) is an autosomal dominant genetic disorder caused by geneticmutations of the BRCA1 and BRCA2 genes. In women this disorder primarily increases the risk of breast andovarian cancer, but also increases the risk of fallopian tube carcinoma and papillary serous carcinoma of theperitoneum. In men the risk of prostate cancer is increased. Other cancers that are inconsistently linked to thissyndrome are pancreatic cancer, male breast cancer, colorectal cancer and cancers of the uterus and cervix. Geneticmutations account for approximately 7% and 14% of breast and ovarian cancer, respectively, and BRCA1 andBRCA2 account for 80% of these cases. BRCA1 and BRCA2 are both tumor supressor genes implicated inmaintaining and repairing DNA. Mutations in these genes allow further damage to DNA, which can lead to cancer.

Hereditary non-polyposis colon cancerHereditary non-polyposis colon cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant cancer syndrome that increases the risk of colorectal cancer. It is caused by genetic mutations in DNA mismatch repair (MMR) genes, notably MLH1, MSH2, MSH6 and PMS2. In addition to colorectal cancer many other cancers are increased in frequency. These include; endometrial cancer, stomach cancer, ovarian cancer, cancers of the small bowel and pancreatic cancer. HNPCC is also associated with an early onset of colorectal cancer. MMR genes are involved in repairing DNA when the bases on each strand of DNA do not match. Defective MMR genes allow continuous insertion and deletion mutations in regions of DNA known as microsatellites. These short repetitive sequences of DNA become unstable, leading to a state of microsatellite instability (MSI). Mutated microsatellites are

Cancer syndrome 4

often found in genes involved in tumor initiation and progression, and MSI can enhance the survival of cells, leadingto cancer.

Although the majority of Fanconi anemia casesare inherited in an autosomal recessive manner,those caused by FANCB are inherited throughx-linked recessive inheritance. This example

pedigree chart shows how inheritance of x-linkedFanconi anemia might occur through several

generations.

Hereditary paraganglioma-pheochromocytomasyndrome

Most cases of familial paraganglioma are caused by mutations in thesuccinate dehydrogenase (SDH; succinate:ubiquinone oxidoreductase)subunit genes (SDHD, SDHAF2, SDHC, SDHB).

PGL-1 is associated with SDHD mutation, and most PGL-1 individualswith paraganglioma have affected fathers rather than affected mothers.PGL1 and PGL2 are autosomal dominant with imprinting. PGL-4 isassociated with SDHB mutation, and is associated with a higher risk ofpheochromocytoma, as well as renal cell cancer and non-medullarythyroid cancer.[2]

Li-Fraumeni syndrome

Li-Fraumeni syndrome is an autosomal dominant syndrome primarilycaused by mutations in the TP53 gene, which greatly increases the risk of many cancers and is also highly associatedwith early onset of these cancers. Cancers linked to this disorder include; soft tissue sarcomas (often found inchildhood), osteosarcoma,breast cancer, brain cancer, leukaemia and adrenocortical carcinoma. Individuals withLi-Fraumeni syndrome often have multiple independent primary cancers. The reason for the large clinical spectrumof this disorder may be due to other gene mutations that modify the disease. The protein produced by the TP53 gene,p53, is involved in cell cycle arrest, DNA repair and apoptosis. Defective p53 may not be able to properly performthese processes, which may be the reason for tumor formation. Because only 60-80% of individuals with the disorderhave detectable mutations in TP53, other mutations in the p53 pathway may be involved in Li-Fraumeni syndrome.

MUTYH-associated polyposisMUTYH-associated polyposis shares most of its clinical features with FAP; the difference is that it's an autosomalrecessive disorder caused by mutations in the MUTYH DNA repair gene. Tumors with increased risk in this disorderare colorectal cancer, gastric adenomas and duodenal adenomas.

Micrograph showing keratocystic odontogenictumour, a common finding in nevoid basal cell

carcinoma syndrome. H&E stain.

Nevoid basal cell carcinoma syndrome

Nevoid basal cell carcinoma syndrome (NBCCS), also known asGorlin syndrome, is an autosomal dominant cancer syndrome in whichthe risk of basal cell carcinoma is very high. The disease ischaracterized by basal cell nevi, jaw keratocysts and skeletalabnormalities. Estimates of NBCCS prevalence varies, but isapproximately 1 in 60000. The presence of basal cell carcinoma ismuch higher in white than black individuals; 80% and 38%,respectively. Odontogenic keratocysts are found in approximately 75%of individuals with the disease and often occur early in life. The mostcommon skeletal abnormalities occur in the head and face, but otherareas are often affected such as the rib cage. The causative genetic mutation of this disease occurs in the PTCH gene,

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and the product of PTCH is a tumor suppressor involved in cell signaling. Although the exact role of this protein inNBCCS is not known, it is involved in the hedgehog signaling pathway, known to control cell growth anddevelopment.

Von HippelLindau diseaseVon HippelLindau (VHL) disease is a rare, autosomal dominant genetic condition that predisposes individuals tobenign and malignant tumors. The most common tumors in VHL are central nervous system and retinalhemangioblastomas, clear cell renal carcinomas, pheochromocytomas, pancreatic neuroendocrine tumours,pancreatic cysts, endolymphatic sac tumors and epididymal papillary cystadenomas. VHL results from a mutation inthe von HippelLindau tumor suppressor gene on chromosome 3p25.3.

Xeroderma pigmentosumXeroderma pigmentosum (XP) is an autosomal recessive disorder characterized by sensitivity to ultra-violet (UV)light, massively increased risk of sunburn and increased risk of skin cancers. The risk of skin cancer is more than10000 times that of normal individuals and includes many types of skin cancer, including melanoma andnon-melanoma skin cancers. Also, sun exposed areas of the tongue, lips and eyes have an increased risk of becomingcancerous. XP may be associated with other internal cancers and benign tumors.[citation needed] In addition to cancer,some genetic mutations that cause XP are associated with neurodegeneration. XP may be caused by geneticmutations in 8 genes, which produce the following enzymes: XPA, XPB, XPC, XPD, XPE, XPF, XPG and Pol .XPA-XPF are nucleotide excision repair enzymes that repair UV light-damaged DNA and faulty proteins will allowthe build up of mutations caused by UV light. Pol is a polymerase, which is an enzyme involved in DNAreplication. There are many polymerases, but pol is the enzyme that replicates UV light-damaged DNA. Mutationsin this gene will produce a faulty pol enzyme that cannot replicate DNA with UV light damage. Individuals withmutations of this gene have a subset of XP; XP-variant disease.

References[1][1] Banks KC, Moline JJ, Marvin ML, Newlin AC, Vogel KJ. 10 rare tumors that warrant a genetics referral. Fam Cancer. 2013 Mar;12(1):1-18.

doi: 10.1007/s10689-012-9584-9. PMID 23377869[2] Neumann HP, Pawlu C, Peczkowska M et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene

mutations. JAMA. 2004;292(8):943. PMID 15328326

Article Sources and Contributors 6

Article Sources and ContributorsCancer syndrome Source: http://en.wikipedia.org/w/index.php?oldid=594029755 Contributors: Andrew.e.gibson, Anrnusna, Bernstein0275, Caoimhin74, DMacks, DVdm, Daj198, Eleassar,Fabrictramp, FeatherPluma, Imyoung, Inferior Olive, Jytdog, LittleC 8226, Magioladitis, MelanieN, Novangelis, Pageeditor01, Rjwilmsi, Sadads, Shalom Yechiel, Simoncaulton, WhatamIdoing,Wouterstomp, 8 anonymous edits

Image Sources, Licenses and ContributorsFile:Polyposis.jpg Source: http://en.wikipedia.org/w/index.php?title=File:Polyposis.jpg License: Creative Commons Attribution-Sharealike 3.0 Contributors: User:Caoimhin74File:Autosomal dominant.png Source: http://en.wikipedia.org/w/index.php?title=File:Autosomal_dominant.png License: Creative Commons Attribution-Sharealike 3.0 Contributors:User:SimoncaultonFile:Autosomal recessive.png Source: http://en.wikipedia.org/w/index.php?title=File:Autosomal_recessive.png License: Creative Commons Attribution-Sharealike 3.0 Contributors:User:SimoncaultonFile:sex linked inheritance.png Source: http://en.wikipedia.org/w/index.php?title=File:Sex_linked_inheritance.png License: Creative Commons Attribution-Sharealike 3.0 Contributors:User:SimoncaultonFile:Keratocystic_odontogenic_tumour - intermed mag.jpg Source: http://en.wikipedia.org/w/index.php?title=File:Keratocystic_odontogenic_tumour_-_intermed_mag.jpg License: CreativeCommons Attribution-Sharealike 3.0 Contributors: Nephron

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Cancer syndromeBackgroundGenetics SyndromesFanconi anemiaFamilial adenomatous polyposisHereditary breast and ovarian cancerHereditary non-polyposis colon cancerHereditary paraganglioma-pheochromocytoma syndromeLi-Fraumeni syndromeMUTYH-associated polyposisNevoid basal cell carcinoma syndromeVon HippelLindau diseaseXeroderma pigmentosum

References

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