The Prostate 59:132^140 (2004)

AnalysisoftheMacrophageScavengerReceptor1Genein SwedishHereditaryand Sporadic ProstateCancer

Fredrik Lindmark,1 Bjorn-Anders Jonsson,2 Anders Bergh,2 Par Stattin,3

S. Lilly Zheng,4 Deborah A. Meyers,4 Jianfeng Xu,4 and Henrik Gronberg1*1Departmentof Radiation Sciences,Oncology,Universityof Ume�,Ume�, Sweden

2DepartmentofMedical Biosciences, Pathology,Universityof Ume�,Ume�, Sweden3Departmentof Surgicaland Perioperative Sciences,UrologyandAndrology,Universityof Ume�,Ume�, Sweden

4Center forHumanGenomics,Wake Forest University SchoolofMedicine,Winston-Salem,NorthCarolina

BACKGROUND. The macrophage scavenger receptor 1 (MSR1) gene on chromosome 8p22was recently reported as a candidate gene for hereditary prostate cancer (HPC). Here, wefurther elucidate the role of MSR1 in both Swedish families with HPC and in a cohort ofunselected prostate cancer.METHODS. DNA samples from 83 Swedish HPC families and 215 unselected populationbased cases of prostate cancer as well as 425 age-matched controls were genotyped.RESULTS. A total of 18 variants were identified, including 2 exonic, 7 intronic changes, and9 changes in the 50- or 30-uncoding region. Of the two exonic changes, one previously reportedtruncation mutation was identified, a R293X nonsense mutation. This mutation was found in 2 ofthe 83 (2.4%) HPC families. The R293X mutation was found more frequently in men with PC(4.9%) than in unaffected men (2.7%), consistent with previous published results, however ourresults were not significant (P¼ 0.16). To additionally test for potential association of commonsequence variants and increased risk for the disease, five common polymorphisms (PRO3,INDEL1, IVS5-57, P275A, INDEL7) were genotyped in the group of 215 prostate cancer casesand 425 age-matched controls. No association between any of the five common sequencevariants and prostate cancer were found.CONCLUSION. Our results suggest that mutations inMSR1 gene might play a role in prostatecancer susceptibility, particularly the R293X mutation. This study warrants further investiga-tions of the role of MSR1 in prostate cancer etiology. Prostate 59: 132–140, 2004.# 2003 Wiley-Liss, Inc.

KEY WORDS: prostate cancer; macrophage scavenger receptor 1; genetic; association

INTRODUCTION

In many developed countries, prostate cancer is themost frequently diagnosed malignancy in men. In year2000, 7,454 Swedish men were diagnosed for thedisease, which makes to the most common canceramong Swedish men [1]. The majority of cases withprostate cancer are sporadic, but existence of familialclustering has been recognized for a long time. Severalstudies in the last decade have shown familial cluster-ing of prostate cancer, suggesting a heritable form of thedisease [2–4]. Generally, the relative risk for hereditaryprostate cancer increases with an increase in the

number of affected individuals in the families andwith a decrease in the age at diagnosis of prostatecancer in relatives [2,5]. Segregation analysis suggests

Grant sponsor: Swedish Cancer Society (Cancerfonden); Grantsponsor: Stiftelsen for strategisk forskning; Grant sponsor:Vasterbottens Lans Landsting.

*Correspondence to: Prof. Henrik Gronberg, MD, Department ofRadiation Sciences, Oncology, University of Umea, 901 87 Umea,Sweden. E-mail: Henrik.Gronberg@oc.umu.seReceived 26 March 2003; Accepted 6 October 2003DOI 10.1002/pros.10367Published online 12 December 2003 in Wiley InterScience(www.interscience.wiley.com).

� 2003 Wiley-Liss, Inc.

that familial clustering can be explained as an auto-somal dominant inheritance [2], although autosomalrecessive, X-linked inheritance, and a multifactorialmodel of inheritance also have been suggested [6–8].

Identification of several prostate cancer susceptibil-ity loci have been reported in the last 6 years; hereditaryprostate cancer 1 (HPC1) region on 1q24-1q25 [9],chromosomal region 1q42–q43 [10], chromosomalregion 1p36 [11], chromosome X [12], chromosome20 [13]. Subsequent studies have yielded conflictingevidence, some confirming linkage and others findingno evidence of linkage and so far only two putativesusceptible genes have been identified (ELAC2 [14],RNASEL [15]). But these two findings can only explain afew percent of HPC cases. The lack of strong con-firmatory evidence of linkage for susceptibility locidescribed so far highlights the difficulties in mappinggenes associated with hereditary prostate cancer.

Recently, evidence for linkage of prostate cancer to aregion site on chromosome 8p22-23 were demonstrated[16], this linkage was confirmed by our group inSwedish HPC families [17]. In a subsequent study, Xuet al. reported results of genetic analyses that indicatethat mutations in the macrophage scavenger receptor1 (MSR1) gene, located at 8p22-23, may be associatedwith risk of prostate cancer [18].

The MSR1 protein encodes a homotrimeric integralmembrane protein. It has six distinct structuraldomains: the amino-terminal cytoplasmic domain, atransmembrane domain, a a-helical coiled coil domain,a collagenous domain, and the scavenger receptorcysteine-rich carboxy-terminal domain [19]. Functionalstudies have shown that the receptor can bind to abroad range of ligands [20]. All substances have thecommon property that they are polyanionic. Theseligands include modified lipoproteins (acetylated oroxidized low-density lipoprotein), Gram-positive andGram-negative bacteria, certain polynucleotides, andsome sulphated polysaccharides. The function of thereceptor in vivo is still unclear but a number of studieshave suggested that these receptors may play a role inthe recognition and clearance of foreign pathogenicsubstances and damaged or apoptotic cells [20–22].

In this study, we genotyped DNA samples from83 Swedish HPC families and 215 unselected popula-tion based cases of prostate cancer as well as 425 agematched controls, in order to evaluate the role ofmutations in the MSR1 gene in prostate cancer.

MATERIALSANDMETHODS

Subjects

The subjects studied were from two differentstudy populations. The first population consisted of

83 Swedish families, from all over Sweden, with threeor more first-degree relatives with prostate cancerwho were selected from an ongoing HPC researchproject [23]. The mean numbers of affected prostatecancer cases were 4.5/family with a mean age atdiagnosis of 67 years. One man with prostate cancerfrom each family was selected for screening of theMSR1 gene.

The second study population was from The North-ern Sweden Health and Disease Cohort (NSHDC) [24].Men are recruited to the NSHDC through the Vaster-botten Intervention Project (VIP) and the NorthernSweden part of the WHO study for Monitoring ofTrends and Cardiovascular Disease Study (MONICA).VIP is an on-going population-based interventionstudy initiated in 1985 that aims to decrease mortalitydue to cardiovascular disease and cancer by advocatinga healthy diet and lifestyle to the general public. VIPinvites all persons residing in the county of Vaster-botten, total population 260,000, to participate in ahealth survey when they reach the ages of 30, 40, 50, and60 years. In December 2002, a total of 35,494 men hadbeen recruited. Approximately half of the population ofVasterbotten has been enrolled into VIP [25]. MONICAincludes 2,704 men, recruited in 1986, 1990, and 1994,who are also a population-based sample from thecounties of Vasterbotten and Norrbotten. The methodsfor collection, processing, and storage of blood sampleswere identical in the MONICA and VIP projects. Allparticipants signed an informed consent form. Allincident cases of prostate cancer and deaths thatoccurred in the cohort were identified by linkage withcancer and all-cause mortality registries, respectively,using an individual identification number as theidentity link. Approximately 97% of cases have beenestimated to be ascertained through such registries [26].We identified 215 incident cases of prostate cancer(mean age 63 years) for which DNA was available. Dataon patient and tumor characteristic were obtainedthrough medical records. Two control subjects wereselected for each case subject from all members aliveand free of cancer at the time of diagnosis of the case ineach subcohort, and matching the index case subject onsex, age (� 6 months), date (� 2 months) at recruitment.Controls were randomly selected within each group ofeligible subjects if more than two subjects matched tothe case were identified. If no suitable control subjectswere found in this procedure, less than two controlsubjects was accepted. We identified 425 eligiblecontrol subjects. The controls were on average 66 yearsat the time of recruitment in this study. The serum PSAlevels were measured with standard methods on 75%of the controls at the time of recruitment. The ResearchEthical committee at Umea University Hospital ap-proved this study.

MSR1Mutations and ProstateCancer Risk 133

PCRAmplif|cation

Genomic DNA from leukocytes was extracted usingstandard techniques. All PCR reactions except thereaction for exon 7 were performed in a final volume of30 ml containing 40 ng of genomic DNA, each primer at0.5 mM, each dNTP at 0.2 mM, 1.5–2.5 mM MgCl2,15 mM Tris-HCl, 50 mM KCl, and 0.6 U of AmpliTaqGold (Applied Biosystems). For exon 7 the PCRreaction was done in a volume of 10 ml containing30 ng of genomic DNA, each primer at 0.2 mM, eachdNTP at 0.4 mM, 1.5 mM MgCl2, 20 mM Tris-HCl,50 mM KCl, and 0.5 U of Taq polymerase (Lifetechnologies). All PCR reactions were carried out in aGeneAmp 9600 Thermal Cycler (Perkin Elmer) with atouch down PCR protocol.

Mutation Screening

The entire coding sequence, exon-intron junctions,promoter regions and 50- and 30-untranslated regions ofMSR1 were screened for mutations using DHPLC(Denaturing High-Performance Liquid Chromatog-raphy), on a WAVE DNA fragment analysis system(Transgenomic, Crewe, UK) [27]. To enhance hetero-duplex formation, the untreated PCR products wereheat denatured at 958C for 5 min, followed by gradualreannealing to 208C over 50 min. PCR products wereautomatically loaded on a DNAsepTM column (Trans-genomic) and eluted at a flow rate of 0.9 ml/min with alinear acetonitrile gradient. The values of the buffergradients (buffer A 0.1 M trietylammoniumacetate pH 7;buffer B 0.1 trietylammoniumacetate, 25% acetonitrilepH 7) and start and end points of the gradient weredetermined by Wavemaker 3.4.4 software (Transge-nomic) for each amplicon. Analysis per amplifiedsample took 6.8 min including column regenerationand equilibration to starting conditions. Samples wereanalyzed at melting temperatures (Tm) determined bythe help of the characteristic melting profile calculatedby Wavemaker on the basis of the sequence for eachPCR fragment. Temperatures were chosen to covereach melting domain that differed with at least 38C.Data analysis was based on visual inspection andcomparison with normal controls that were included ineach run. Heterozygous elution profiles were detectedas distinct elution peaks from homozygous wild-typepeaks. A full list of PCR primers sequences, DHPLC runtemperatures, and methods used are available uponrequest. We screened for rare mutations in MSR1 andconsequently the method was not adapted to screenhomozygotes for common sequence variants.

SequencingAnalysis

The sequence variants were confirmed by directsequencing of the corresponding PCR products. Prior

to sequencing, all PCR products were purified usingMicroSpinTM S-400 HR columns (Amersham Bios-ciences) to remove dNTPs and excess primers. Allsequencing reactions were carried out using dye-terminator chemistry (BigDye, Applied Biosystems).The sequencing products were purified using Auto-SeqTM G-50 columns (Amersham Biosciences) beforeloaded onto an ABI PrismTM 377 DNA sequencer.

SingleNucleotide Polymorphisms (SNP)Analysis

SNPs were genotyped on the MassARRAY system(SEQUENOM, Inc., San Diego, California). PCR reac-tion was performed in total volume of 5 ml with 10 ng ofgenomic DNA, 2.5 mM of MgCl2, 0.1 U of HotStarTaqpolymerase, (QIAGEN, Inc., Valencia, CA), 200 mM ofdNTP, and 200 nM of primer. The PCR reaction startedat 958C for 15 min followed by 45 cycles of 958C for20 sec, 508C for 30 sec, and 728C for 1 min with finalextension of 728C for 3 min. The hME reaction wasperformed in total volume of 9 ml with 50 mM d/ddNTPeach, 0.063 U/ml of Thermo Sequenase (both fromSEQUENOM, Inc.) and 600 nM of extension primer.The cycling conditions were 948C for 2 min followed by55 cycles of 948C for 5 sec, 528C for 5 sec, and 728C for5 sec. After cleaning up the hME reaction productswith SpectroCLEAN, the products were transferred toSpectroCHIP using SpectroPOINT then scan throughSepctroREADER. Genotyping was done using Spectro-TYPER (all from SEQUENOM, Inc.).

AccessionNumbers

Nucleotide: D13263 Human MSR1 promoter andexon 1; D90187 Human mRNA for scavenger receptortype I; D90188 Human mRNA for scavenger receptortype II; AF037351 Human macrophage scavengerreceptor type III, mRNA; Genomic: NT_015280.5.

StatisticalMethods

Tests for Hardy–Weinberg Equilibrium (HWE) forall sequence variants and for linkage disequilibrium(LD) between all pairs of sequence variants were basedon 10,000 permutations of the Fisher’s probability teststatistic (Weir, 1996), as implemented in the softwareGenetic Data Analysis (GDA). Preserved genotypeswere used in order to prevent within-locus disequili-brium from affecting the significance of disequilibriumin pairwise comparisons. Unconditional logistic regres-sion was used to test for association between genotypesand affection status.

RESULTS

Among the men with hereditary prostate cancer(n¼ 83), who were screened for potential sequence

134 Lindmarket al.

variants, a total of 12 novel variants (3 intronic and 9 in50-or 30-uncoding regions) and 6 previously reportedvariants (2 exonic, 4 intronic) were identified (Fig. 1,Tables I and II).

All rare mutations, with the exception of R293X,being observed in only one family each. The previouslyreported nonsense mutation R293X is located in exon

6 and was found in 2 of the 83 families. To determine ifR293X co-segregate with PC, all family members withavailable DNA were genotyped. However, due to thefew numbers of affected men in these two families, itwas not possible to determine whether the mutationsegregated with the disease (Fig. 2). The two probandshad the base substitution C!T that is predicted to

Fig. 1. Overview over identified sequences variants in theMSR1 gene.A: It illustrates sequence variants found in intron sequence and in50 -untranslatedregion,while (B) describesvariants in the codingregion, 50 - and30 -noncodingregion.Thenumbers in theboxesrefer to exonnumbers.Whiteboxesindicate thecodingregion,whilegrayboxesindicate50 - or30 -noncodingregion.

TABLE I. RareMSR1GermlineMutations in Prostate Cancer Patients andUnaffectedControls

Sequence variants(position)a

Consequence/region

Previouslyreported/novel

HPC cases(n¼ 83);no. (%)

PC cases(n¼ 215);no. (%)

Controls(n¼ 425);no. (%) P-valuec

PRO4 G>A (�14730) Promoter Novel 1 — — —�33 A>Gb (�14637) 50-UTR Novel 1 — — —IVS1þ 11A>G (�14598) Intron 1 Novel 1 — — —IVS3� 4 A>G (9117) Splice acceptor site Novel 1 0 0 —IVS4þ 3 A>G (9536) Splice donor site Novel 1 0 0 —877 C>Tb (22906) R293X Previously reported 2 (2.4) 10 (4.9) 10 (2.7) 0.161643 G>Cb (70163) 30-UTR Novel 1 — — —1872 G>Ab (70392) 30-UTR Novel 1 — — —

aPositions (bp) are based on the initiation codon (ATG) from MSRI genomic DNA (NT_015280).bNucleotide position in reference to the cDNA starting at the A in the start codon.cFisher’s exact test (two-sided) between PC cases and controls.

MSR1Mutations and ProstateCancer Risk 135

result in the conversion of an arginine codon to atermination codon. In addition, we evaluated furtherthe association between this mutation and prostatecancer by screening a group of unrelated men withprostate cancer (n¼ 215) with age-matched controls(n¼ 425). The R293X mutation was found morefrequently in men with prostate cancer (10 individuals,4.9%) than in their matched controls (10 individuals,2.7%,P¼ 0.16). In Table III, the clinical characteristics ofthe 12 R293X mutation carriers are listed. The mean ageof prostate cancer was 63.5 versus 63.1 years betweenR293X carriers and noncarriers (P¼ 0.65). The medianPSA levels at time of recruitment were 1.34 versus 1.04between R293X carriers and noncarriers in unaffectedcontrols (P¼ 0.66). However, in five of nine unaffectedcarriers the PSA values were over 1.0 at the age 49–59.

Two potential pathogenic mutations, IVS3-4 A>Gand IVS4þ 3 A>G, located in the splice donor regionand splice acceptor region of exon 4, were observedin one family each. None of these two mutationswere identified when screening the group of unselectedmen with prostate cancer or age-matched healthycontrols.

Besides the three rare mutations described above,we decided to elucidate the importance of five commonsequence variants found in the mutation screening ofMSR1. The five sequence variants included a SNP in thepromoter region (PRO3), a 15-bp insertion/deletion of‘‘GAATGCTTTATTGTA’’ in intron 1 (INDEL1), a SNPin intron 5 (IVS5-57), a missense mutation in exon6 (P275A), and a 3-bp insertion/deletion of ‘‘TTA’’ inintron 7 (INDEL7). The location and frequency of eachof the sequence variants are listed in Table IV. None of

the variants were in association with PC. The genotypefrequencies among the controls of all five-sequencevariants were in HWE proportions.

The first three sequence variants (PRO3, INDEL1,IVS5-57) were in strong linkage disequilibrium (LD), asthe tests for pair-wise LD among them were all highlysignificant (all P< 0.000001). The last two variants alsohad LD between them (P< 0.000001). There was no LDbetween the two groups, the first three and the last twovariants.

DISCUSSION

Analysis of the MSR1 gene revealed a germline non-sense mutation in exon 6 (R293X) in 2 of our 83 families(2.4%), and in the case/control cohort the R293Xmutation was found more frequently in PC cases(4.9%) than in matched controls (2.7%) (P¼ 0.16).However, due to the few numbers of affected men inthese two families, it was not possible to determinewhether the mutation segregated with the disease. Thefrequency of the R293X mutation in the HPC familiesand the control population are similar, but such a com-parison is not adequate, as the families are recruitedfrom all over Sweden while the control populationis from the geographic area of Vasterbotten. In fact,the frequency of the R293X mutation in Caucasian HPCfamilies from the recent study of Xu et al. is similarto our findings (3.8% versus 2.4%). In the unselectedcase/control series, the R293X mutation was twice ascommon among cases compared to controls, howevernot significant. The choice of control population mightexplain some of the differences between our resultand the previous report [18]. The men in the control

TABLE II. Frequencies ofMSRICommonSequenceVariantsa in CasesWithHPC

Sequence variant (position)bConsequence/

regionPreviously

reported/novelHPC-cases, no.

(%) (n¼ 83)

PRO1 C>T (�15110) Promoter Novel 12 (14.5)PRO2 A>G (�15026) Promoter Novel 12 (14.5)PRO3 A>G (�14742) Promoter Previously reported 7 (8.4)INDEL1c (�14458) Intron 1 Previously reported 8 (9.6)IVS5�57 C>A (22790) Intron 5 Previously reported 5 (6)823 C>Gc (22852) P275A Previously reported 8 (9.6)INDEL 7d (34504) Intron 7 Previously reported 8 (9.6)1486 A>Ge (70006) 30-UTR Novel 5 (6)1596 T>Ce (70116) 30-UTR Novel 5 (6)1781 G>Ae (70301) 30-UTR Novel 4 (4.8)

aAll cases are heterozygote for the sequence variant. The screening method was not adapted toscreen for homozygotes.bPositions (bp) are based on the initiation codon (ATG) from MSR1 genomic DNA (NT_015280).cþ and � indicate with and without the 15-bpsequence ‘‘GAATGCTTTATTGTA.’’dþ and � indicate with and without the 3-bp sequence ‘‘TTA.’’eNucleotide position in reference to the cDNA starting at the A in the start codon.

136 Lindmarket al.

population in this study were on average 66 years atrecruitment, an age in which only 15% of all prostatecancer has been diagnosed. Thus, it is likely that afraction of the unaffected R293X carriers will even-tually develop prostate cancer. Another difference isthat Xu et al. only included men with PSA< 4 and anormal prostate examination. If the R293X mutationincreases the risk for PC by two and the frequency is 3%in the general population, a much larger case/controlstudy is needed to significantly verify this.

The R293X mutation in exon 6 results in a truncationof the MSR1 protein. The truncation leads to a deletion

of several functional domains, including the ligand-binding domain and the cysteine-rich domain. Experi-mental studies have demonstrated that a MSR1 mutantharboring a similar truncating mutation as, R293X,have a dominant-negative phenotype when expressedin vitro [28]. This might lead to a reduced or abolishedability to bind ligands and further a decrease in uptakeand degradation of pathogenic substances.

In addition to the nonsense mutation, two rarepotential splice site mutations, IVS3� 4 and IVS4þ 3,were identified. Both mutations were observed in onefamily each. Several studies have shown that mutations

Fig. 2. Pedigrees representing the two families with the R293X mutation in MSR1 identified in this study (with minor changes in familystructure to protectconfidentiality).Fully filledboxes indicatemen affectedwithprostate cancer.Half-filledboxes and circles representmenand women, respectively, with other types of cancer.Open boxes and circles indicate unaffectedmen and women, respectively. Deceasedindividuals are indicated with a line bisecting the box or circle. A superscripted circle indicates that a DNA sample from that individual wasavailable and their genotype is known; a filled superscripted circle indicates carriers of the R293X mutation, and an open circle indicatesnoncarriers.Ageatdiagnosisofprostate cancerorother typesofcancer ismarkedunder filledboxesorcircle.

MSR1Mutations and ProstateCancer Risk 137

situated in similar positions as IVS3� 4 and IVS4þ 3 canlead to exon skipping, intron retention or insertions anddeletions due to utilization of cryptic splice sites [29–31].However, to determine whether these two mutationsaffect MSR1 mRNA splicing, further studies is needed.

Besides the rare MSR1 mutations, we also identifiedfive common sequence variants, previously reportedby Xu et al. [2002] [18] to be associated with prostatecancer (Table IV). The haplotype data and LD betweenthe sequence variants are in line with Xu et al. [2002][18]. But in contrast to previously reported data, we

found no association between any of the five commonsequence variants and prostate cancer and there wereno significant differences between cases and controlsin allele frequencies of the five sequence variants(Table IV).

CONCLUSION

We identified several sequence variants, both noveland previously reported, when screening theMSR1 genefor mutations. Although not statistically significant,we did note the same trend toward higher frequency of

TABLE III. Clinical Characteristics ofMSRIR293XMutationCarriers

Cases Age dx. Stage Tumor gradec Treatment PSA Other

NSHDa

Case 1 50 T1a, N0, M0 Highly diff. TUR-P 23Case 2 60 T2, N0, M0 Moderately diff. Radical prost. 4 Family history positiveCase 3 64 T2, NX, MX Highly diff. No treatment Not availableCase 4 58 T1c, N0, M0 Highly diff. No treatment 6Case 5 66 T2, NX, M0 Highly diff. Radiation 10 Hereditary prostate cancerCase 6 67 T1c, N0, M0 Moderately diff. Radical prost. 6 —Case 7 67 T2, N0, M0 Highly diff. Radiation 7 Hereditary prostate cancerCase 8 61 T2, N0, M0 Highly diff. Radiation 25 Family history positiveCase 9 67 T2, N0, M0 Highly diff. Radiation 18 Relaps 6 years; 6/7

biopsied positive.Case 10 68 T1c, NX, MX Highly diff. Hormones 16HPCb (no.)

1–20 70 Not available Not available Not available Not available —46–10 54 T2, N0, M0 Moderately diff. Radical prost. 3 Extensive tumor growth

aNorthern Sweden Health and Disease Cohort.bHereditary prostate cancer.cTumor grade; highly differentiated¼WHO1 or Gleason score 2–5, moderately differentiated¼WHO2 or Gleason score 6–7, poorlydifferentiated¼WHO3 or Gleason score 8–10.

TABLE IV. Frequencies of Five SelectedMSRISequenceVariants in Prostate Cancer Patients andUnaffected Controls

SNPs Genotype

Genotype frequencies no. (%) Allele frequencies (%)

P-valuesControls Cases OR (95% CI) OR (95%CI) Allele Controls Cases

PRO3 AA 355 (88.1) 186 (89.4)AG 47 (11.7) 19 (9.1) 0.77 (0.44, 1.35)GG 1 (0.2) 3 (1.4) 5.73 (0.59, 55.43) 0.88 (0.51, 1.49) G 6.1 6.0 1.000

INDEL1 �/� 372 (88.2) 190 (90.0)�/þ 50 (11.8) 21 (10.0) 0.82 (0.48, 1.41)þ/þ 0 (0) 0 (0) 0.82 (0.48, 1.41) þ 5.9 5.9 0.935

IVS5-57 CC 381 (93.8) 196 (94.7)CA 24 (5.9) 10 (4.8) 0.81 (0.38, 1.73)AA 1 (0.2) 1 (0.5) 1.94 (0.12, 31.24) 0.86 (0.41, 1.77) A 3.2 2.9 0.795

P275A CC 385 (94.4) 190 (92.7)CG 21 (5.1) 15 (7.3) 1.45 (0.73, 2.87)GG 2 (0.5) 0 (0) 1.32 (0.67, 2.59) C 96.9 96.3 0.547

INDEL7 �/� 369 (94.6) 185 (93.4)�/þ 20 (5.1) 13 (6.6) 1.30 (0.63, 2.66)þ/þ 1 (0.3) 0 (0) 1.24 (0.61, 2.52) — 97.2 96.7 0.617

138 Lindmarket al.

the R293X mutation in unselected prostate cancer casesthan in the controls, as previously reported. In addition,two potential splice site mutations were identified intwo families with HPC. Our results suggest thatmutations in MSR1 gene might play a role in prostatecancer susceptibility, particularly the R293X mutation.This study warrants further investigations of the role ofMSR1 in prostate cancer etiology.

ACKNOWLEDGMENTS

The authors thank all the study subjects in the here-ditary prostate cancer study and NSHDC. A specialthanks to Prof. Goran Hallmans, the head of theNSHDC Biobank.

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