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1 CE: satish ED: susan Op: srini CEJ: LWW_CEJ_ Original article 1 BRCA1 mutations and prostate cancer in Poland Cezary Cybulski a, Bohdan Górski a, Jacek Gronwald a, Tomasz Huzarski a, Tomasz Byrski a, Tadeusz Dębniak a, Anna Jakubowska a, Dominika Wokołorczyk a, Bartłomiej Gliniewicz b, Andrzej Sikorski b, Małgorzata Stawicka c, Dariusz Godlewski c, Zbigniew Kwias d, Andrzej Antczak d, Kazimierz Krajka e, Wojciech Lauer e, Marek Sosnowski f, Paulina Sikorska-Radek g, Krzysztof Bar h, Robert Klijer h, Zdrojowy Romuald i, Bartosz Małkiewicz i, Andrzej Borkowski j, Tomasz Borkowski j, Marek Szwiec k, Marek Posmyk l, Steven A. Narod m and Jan Lubiński a Evidence to date that BRCA1 mutation carriers are at an increased risk of prostate cancer is mixed both positive and negative studies have been published. To establish whether or not inherited variation in BRCA1 influences prostate cancer risk we genotyped 1793 men with prostate cancer in Poland and 4570 controls for three founder mutations (C61G, 4153delA and 5382insC). A BRCA1 mutation was present in 0.45% of the cases and 0.48% of the controls (odds ratio = 0.9; P = 1.0). The odds ratios varied substantially by mutation. The 5382insC mutation is the most common of the three founder mutations. It was detected only in one case (0.06%), whereas it was seen in 0.37% of controls (P = 0.06). In contrast, the 4153delA was more common in prostate cancer cases (0.22%) than in controls (0.04%) (odds ratio = 5.1; 95% confidence interval: ; P = 0.1). The C61G mutation was also found in excess in cases (0.17%) compared with controls (0.07%) (odds ratio = 2.6; 95% confidence interval: ; P = 0.5). Eight men with prostate cancer carried a mutation. Only one of these carried the 5382insC mutation, compared with 17 of 22 individuals with mutations in the control population (P = 0.003). These data suggest that the 5382insC mutation is unlikely to be pathogenic for prostate cancer in the Polish population. The presence of one of the other alleles was associated with an increased risk for prostate cancer (odds ratio = 3.6; 95% confidence interval: ; P = 0.045); in particular for familial prostate cancer (odds ratio = 12; 95% confidence interval: ; P = ). We consider that the risk of prostate cancer in BRCA1 carriers varies with the position of the mutation. European Journal of Cancer Prevention 00: c 2007 Lippincott Williams & Wilkins. European Journal of Cancer Prevention 2007, 00: Keywords: BRCA1, hereditary, prostate cancer a Department of Genetics and Pathology, International Hereditary Cancer Center, b Clinic of Urology, Pomeranian Medical University, Szczecin, c Cancer Prevention and Epidemiology Center, d Clinic of Urology, Medical Academy, Poznan, e Clinic of Urology, Medical Academy, Gdansk, f Clinic of Urology, Medical Academy, g Clinic of Urology Regional Hospital, Łódź, h Clinic of Urology, Medical Academy, Lublin, i Clinic of Urology, Medical Academy, Wrocław, j Clinic of Urology, Medical Academy, Warszawa, k Regional Oncology Hospital, Olsztyn, l Regional Oncology Hospital, Białystok, Poland and m Centre for Research on Womens Health, Toronto Ontario, Canada Correspondence to Cezary Cybulski, Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, ul. Połabska 4, Szczecin, Poland Tel: ; fax: ; cezarycy@sci.pam.szczecin.pl Received 28 April 2006 Accepted 15 September 2006 Introduction Identifying risk factors for prostate cancer is potentially important both for screening and prevention. One of the established risk factors for prostate cancer is a positive family history of prostate cancer. Continuing interest exists in identifying DNA variants, which are associated with an increased risk of prostate cancer. Several epidemiological and association studies suggest that there is an increased risk of prostate cancer in men who carry a BRCA1 mutation (Ford et al., 1994; Struewing et al., 1997; Warner et al., 1999; Giusti et al., 2003). A multicenter study of 699 BRCA1 families, however, did not support this association (Thompson and Easton, 2002a) and several negative studies have been published as well (Gayther et al., 2000; Sinclair et al., 2000; Ikonen et al., 2003; Zuhlke et al., 2004). In Poland, there are three common founder alleles in BRCA1 (C61G, 4153delA and 5382insC), which, in total, account for 90% of all BRCA1 mutations (Gorski et al., 2004). To establish if inherited variation in BRCA1 influences prostate cancer risk in Poland, we genotyped 1793 cases of prostate cancer and 4570 controls. Poland is well suited for this study because of the high frequency of c 2007 Lippincott Williams & Wilkins

2 2 European Journal of Cancer Prevention 2007, Vol 00 No 00 three BRCA1 founder mutations and the relative genetic homogeneity of the Polish population. Methods We studied prostate cancer cases diagnosed between 1999 and 2005 in 13 centers situated throughout Poland. This study was initiated in Szczecin in 1999 and was extended to include Białystok and Olsztyn in 2002, and Opole in Nine other centers began recruiting participants in 2005 (Koszalin, Gdańsk, Lublin, Łódź, Warszawa, Wrocław, Poznań, Rzeszów, Sucha Beskidzka). Altogether, 1793 unselected prostate cancer cases were collected. Study participants were asked to participate at the time of diagnosis or during an outpatient visit to an oncology clinic. Study participants were unselected for age or family history. The patient participation rate exceeded 75%. The mean age of diagnosis was 67.3 years (range years). All patients who agreed to participate and signed informed consent, participated within 6 months from diagnosis. Family histories were obtained from each participant. Two hundred and twenty-nine patients (12.8%) had one or more first- or second-degree relative with prostate cancer (familial cases). The control group consisted of a mix of 2000 newborn children from 10 hospitals throughout Poland (Szczecin, Bialystok, Gorzow, Katowice, Wroclaw, Poznan, Opole, Lodz and Rzeszow), 1570 adults selected at random form the rolls of three family doctors practicing in the Szczecin region and 1000 individuals from Szczecin who submitted blood for paternity testing. In total there were 4570 population controls. Mutation analysis for the common Polish mutations was performed as described previously (Debniak et al., 2003; Gorski et al., 2005). The 4153delA and 5382insC mutations were detected using a multiplex-specific polymerase chain reaction (PCR) assay. The third mutation (C61G) generates a novel restriction enzyme site in exon 5. This mutation is detected after digesting amplified DNA with AvaII. To avoid false results in all reactions positive and negative controls were used. All mutations were confirmed by sequencing. Statistical analysis included the comparison of the proportions of the prevalence of the allele in cases and controls. Odds ratios (ORs) were generated from 2 2 tables and statistical significance was assessed using the Fisher exact test. The study was approved by the Ethics Committee of Pomeranian Medical University in Szczecin. Results A BRCA1 mutation was seen in eight of 1793 (0.45%) cases and in 22 of 4570 (0.48%) controls (OR = 0.9; P = 1.0) (Table 1). The risks, however, were different for all mutations. The 5382insC is the most frequent mutation of the three Polish founder mutations. The Table 1 Associations between BRCA1 mutations and prostate cancer risk Unselected cases, N = 1793 Controls, N =4570 OR 95% CI P value Total BRCA1 positive 8 (0.45%) 22 (0.48%) C61G 3 (0.17%) 3 (0.07%) delA 4 (0.22%) 2 (0.04%) insC 1 (0.06%) 17 (0.37%) C61G or 4153delA 7 (0.39%) 5 (0.11%) OR, Odds ratio; CI, confidence interval. a When the 5382insC is excluded as unlikely pathogenic for prostate cancer in the Polish population. 5382insC mutation was detected only in 0.06% of cases, compared with 0.37% of controls (OR = 0.15; P = 0.06). Only one of eight (12.5%) men with prostate cancer and a BRCA1 mutation carried the 5382insC mutation, compared with 17 of 22 (77.3%) individuals with mutations in the control population (P = 0.003). In contrast, the 4153delA was more common in cases than in controls (0.22% versus 0.04%; OR = 5.1; P = 0.1). The C61G mutation was also more frequent in cases than in controls (0.17% versus 0.07%; OR = 2.6; P = 0.5). A statistical test of homogeneity of the OR rejected the null hypothesis that the ORs associated with the three mutations were similar (P = 0.008). Two hundred and twenty-nine men were present with prostate cancer and a family history of prostate cancer. A BRCA1 mutation was found in three of 229 (1.3%) familial prostate cancer cases, compared with five of 4570 controls [OR = 12; 95% confidence interval (CI) ; P = ]. The 4153delA mutation was present in one familial case (OR = 10.0; P = 0.3) and the C61G was responsible for two other prostate cancer families (OR = 13.4; P = 0.008). The family with the 4153delA mutation contained two men with prostate cancer and the families with the C61G mutation contained four and five men with prostate cancer. We sought to establish if BRCA1 mutation segregated with prostate cancer in these families. We were able to obtain blood samples from additional relatives from families with the C61G (Fig. 1). In the first family the mutation was detected in the proband s aunt (affected by bilateral breast cancer); this suggests that the deceased father (affected with prostate cancer) also carried the C61G allele. Thus, in this family, two of four men with prostate cancer were likely to be mutation carriers and we were unable to establish the genotype of the other two cases. In the second family, the C61G mutation was detected in the proband s cousin, suggesting that father and uncle of the proband (both affected by prostate cancer) also carried the C61G mutation. In this family, three of the four men affected

3 BRCA1 and prostate cancer Cybulski et al. 3 Fig. 1 Family 1 C61G Prostate 72 Prostate 70 Prostate Prostate 60 Breast 38 Breast Prostate 49 Kidney Family 2 C61G psu 70 Prostate 75 Prostate 70 Breast 49 Prostate Prostate Family delA + Prostate 70 Ovary 52 Prostate 72 Breast 46 Kidney 45 Pedigrees of BRCA1 mutation positive cases with familial prostate cancer from a series of 1793 men with unselected prostate cancer. The type of cancer and age of diagnosis are indicated next to the symbol. A ( + ) near the symbol indicates the presence of the mutation. A dot near the symbol indicates deceased men with prostate cancer who were likely to be BRCA1 mutation carriers. A ( ) indicates the absence of the mutation. PSU, primary cancer site unknown. by prostate cancer carried the C61G alteration, and the other was uninformative. Five of seven men who carried BRCA1 C61G or 4153delA mutation were diagnosed with prostate cancer of Gleason grade 7 or higher, compared with 35% of noncarriers (P = 0.056). The mean age at diagnosis in the men who carried BRCA1 mutation was similar to that observed in noncarriers (66.6 versus 67.3 years). Discussion We observed increased risks for prostate cancer associated with the BRCA1 4153delA and the C61G mutations. One of these two mutations was seen in significant excess in men with unselected prostate cancer (OR = 3.6; P = 0.05), but this observation was based on only seven men with prostate cancer and a BRCA1 mutation. The two mutations were seen in excess in men with familial prostate cancer (OR = 12; P = ), but again, the numbers were small. The C61G mutation alone was associated with familial prostate cancer (OR = 13.4; P = 0.008). Furthermore, two of the three C61G carriers from a series of unselected cases had strong family histories of prostate cancer (which contained four and five men with prostate cancer). Segregation analysis suggested that five of the nine men with prostate cancer in these families carried the C61G variant and the genotypes of the other four cases could not be determined. In total, these data support the idea that the C61G mutation confers an increased risk of prostate cancer in Poland. A positive association between prostate cancer and the 4153delA variant was also seen, but the evidence is less compelling. Although this alteration was more common in unselected and in familial cases than in controls (OR 5.1 and 10, respectively), these differences were not statistically significant.

4 4 European Journal of Cancer Prevention 2007, Vol 00 No 00 In contrast, the 5382insC mutation does not seem to confer an increased risk of prostate cancer in Poland. This mutation was under-represented in cases compared to controls (0.06 versus 0.37%). Only one (12.5%) of the cases with a BRCA1 mutation carried the 5382insC mutation, whereas this mutation constituted 77% of all BRCA1 mutations seen in the control group (P = 0.003). The 5382insC mutation is also founder allele in the Ashkenazi Jewish population. On the basis of two large epidemiologic studies of breast cancer patients, the risk of prostate cancer among carriers of Ashkenazi founder BRCA1 mutations (185delAG and 5382insC) appears to be twice that of noncarriers (Struewing et al., 1997; Warner et al., 1999). When the data, however, from seven other studies of Ashkenazi Jews with unselected prostate cancer is combined (Lehrer et al., 1998; Nastiuk et al., 1999; Hubert et al., 1999; Vazina et al., 2000; Giusti et al., 2003; Hamel et al., 2003; Kirchhoff et al., 2004) the evidence is less strong. The 185delAG mutation was seen in 1.4% of 1654 cases versus 0.91% of 9371 population controls (OR = 1.5; P = 0.09), and the 5283insC mutation was seen in 0.32% of 1544 cases versus 0.27% of 8867 population controls (OR = 1.2; P = 0.92). Other studies, in non-jewish populations, have found little or no evidence of an increased risk for prostate cancer in BRCA1 carriers (Gayther et al., 2000; Sinclair et al., 2000; Thompson and Easton, 2002a; Ikonen et al., 2003; Zuhlke et al., 2004). The risk of prostate cancer, therefore, seems to be dependent on the type and/or location of the BRCA1 mutation. Genotype phenotype correlations have also been suggested for breast and ovarian cancer risk (Rennert et al., 2005; Gronwald et al., 2006). It has been reported that the breast cancer risk associated with mutations in the central region of BRCA1 (nucleotides ) is lower than for mutations located elsewhere (Thompson and Easton, 2002b). It has also been reported that ovarian cancer risk may be lower for mutations, which are localized in 3 0 end of BRCA1 gene (Gayther et al., 1995; Holt et al., 1996; Neuhausen et al., 1996). It is also possible that mutations in the 3 0 end of BRCA1 (such as the 5382insC) confer a lower risk of prostate cancer than mutations located elsewhere (such as the C61G and 4153delA), but further studies are needed. BRCA1 acts in the same pathway as BRCA2, NBS1, CHEK2 and ATM proteins. Three of these (BRCA2, NBS1 and CHEK2) are also probable prostate cancer susceptibility genes. The relative risk of developing prostate cancer by age 56 years for men with a deleterious BRCA2 mutation was reported to be 23-fold (Edwards et al., 2003). Germline mutations in CHEK2 and NBS1 have also been reported to predispose to prostate cancer (Dong et al., 2003; Seppala et al., 2003; Cybulski et al., 2004). We included men and women, of all ages, in the control group. The control group is used to estimate with accuracy the frequency of BRCA1 alleles in the underlying Polish population. The allele frequency should not be dependent on age or sex, but on ethnic group; the frequency of the BRCA1 alleles was similar in the newborn (0.45%) and adult (0.50%) population, in the men (0.55%) and women (0.46%) adult controls. Therefore, there is no reason to believe that age or sex are important confounders of the observed association. For a rare diseaselike prostate cancer (life-time risk of prostate cancer is 2% in the Polish men) the frequency of the allele (exposure) in the general population is a good estimate of the frequency of the allele in the unaffected population. It is important that cases and controls have the same ethnic background. Poland is mainly populated by ethnic Poles, and within Poland, geographic mixture has been achieved, largely due to extensive migration after the Second World War. Our cases were recruited from 13 centers throughout Poland. Our control group was drawn both from the adult population of Szczecin and from newborns in 10 cities throughout Poland. No statistical difference exists in the BRCA1 allele frequencies in the newborns recruited from the Szczecin metropolitan region compared with other Polish cities. In addition, a large multicenter study of 122 BRCA1 positive families with hereditary breast and breast ovarian cancer did not show greater than expected variation in the prevalence or spectrum of mutations in the different regions of Poland. We consider that a problem of population stratification and the composition of our control group are unlikely to explain the observed results. Furthermore, the heterogeneity of our results is due to variation in the allele frequency among cases, not among controls. In summary, we investigated the role of three Polish BRCA1 founder mutations in the etiology of prostate cancer. It appears that the C61G or the 4153delA mutations are pathogenic for prostate cancer. In contrast, the 5382insC mutation does not seem to increase the risk of prostate cancer in the Polish population. It is important that other studies of genotype/phenotype correlations in BRCA1 mutation carriers in other populations be conducted in order to confirm these results. These observations have important implications for the screening and prevention of cancer in men with BRCA1 mutations. References Cybulski C, Górski B, Dębniak T, Gliniewicz B, Mierzejewski M, Masojć B, et al. (2004). NBS1 is a prostate cancer susceptibility gene. Cancer Res 64: Cybulski C, Gorski B, Huzarski T, Masojc B, Mierzejewski M, Debniak T, et al. (2004). CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 75:

5 BRCA1 and prostate cancer Cybulski et al. 5 Dong X, Wang L, Taniguchi K, Wang X, Cunningham JM, McDonnell SK, et al. (2003). Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet 72: Debniak T, Gorski B, Cybulski C, Jakubowska A, Kurzawski G, Kladny J, et al. (2003). Increased risk of breast cancer in relatives of malignant melanoma patients from families with strong cancer familial aggregation. Eur J Cancer Prev 12: Edwards SM, Kote-Jarai Z, Meitz J, Hamoudi R, Hope Q, Osin P, et al. (2003). Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet 72:1 12. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE (1994). Risks of cancer in BRCA1-mutation carriers. Lancet 343: Gayther SA, Warren W, Mazoyer S, Russel PA, Harrington PA, Chiano M, et al. (1995). Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation. Nat Genet 11: Gayther SA, de Foy KA, Harrington P, Pharoah P, Dunsmuir WD, Edwards SM, et al. (2000). The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. Cancer Res 60: Giusti RM, Rutter JL, Duray PH, Freedman LS, Konichezky M, Fisher-Fischbein J, et al. (2003). A twofold increase in BRCA mutation related prostate cancer among Ashkenazi Israelis is not associated with distinctive histopathology. J Med Genet 40: Gorski B, Jakubowska A, Huzarski T, Byrski T, Gronwald J, Grzybowska E, et al. (2004). A high proportion of founder BRCA1 mutations in Polish breast cancer families. Int J Cancer 110: Gorski B, Cybulski C, Huzarski T, Byrski T, Gronwald J, Jakubowska A, et al. (2005). Breast cancer predisposing alleles in Poland. Breast Cancer Res Treat 92: Gronwald J, Huzarski T, Byrski B, Medrek K, Menkiszak J, Monteiro AN, et al. (2006). Cancer risks in first degree relatives of BRCA1 mutation carriers: effects of mutation and proband disease status. J Med Genet 43: Hamel N, Kotar K, Foulkes WD (2003). Founder mutations in BRCA1/2 are not frequent in Canadian Ashkenazi Jewish men with prostate cancer. BMC Med Genet 4:7. Holt JT, Thompson ME, Szabo C, Robinson-Benion C, Arteaga CL, King MC, Jensen RA (1996). Growth retardation and tumour inhibition by BRCA1. Nat Genet 12: Hubert A, Peretz T, Manor O, Kaduri L, Wienberg N, Lerer I, et al. (1999). The Jewish Ashkenazi founder mutations in the BRCA1/BRCA2 genes are not found at an increased frequency in Ashkenazi patients with prostate cancer. Am J Hum Genet 65: Ikonen T, Matikainen MP, Syrjakoski K, Mononen N, Koivisto PA, Rokman A, et al. (2003). BRCA1 and BRCA2 mutations have no major role in predisposition to prostate cancer in Finland. J Med Genet 40:e98. Kirchhoff T, Kauff ND, Mitra N, Nafa K, Huang H, Palmer C, et al. (2004). BRCA mutations and risk of prostate cancer in Ashkenazi Jews. Clin Cancer Res 10: Lehrer S, Fodor F, Stock RG, Stone NN, Eng C, Song HK, McGovern M (1998). Absence of 185delAG mutation of the BRCA1 gene and 6174delT mutation of the BRCA2 gene in Ashkenazi Jewish men with prostate cancer. Br J Cancer 78: Nastiuk KL, Mansukhani M, Terry MB, Kularatne P, Rubin MA, Melamed J, et al. (1999). Common mutations in BRCA1 and BRCA2 do not contribute to early prostate cancer in Jewish men. Prostate 40: Neuhausen SL, Mazoyer S, Friedman L, Stratton M, Offit K, Caligo A, et al. (1996). Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. Am J Hum Genet 58: Rennert G, Dishon S, Rennert HS, Fares F (2005). Differences in the characteristics of families with BRCA1 and BRCA2 mutations in Israel. Eur J Cancer Prev 14: Seppala EH, Ikonen T, Mononen N, Autio V, Rokman A, Matikainen MP, et al. (2003). CHEK2 variants associate with hereditary prostate cancer. Br J Cancer 89: Sinclair CS, Berry R, Schaid D, Thibodeau SN, Couch FJ (2000). BRCA1 and BRCA2 have a limited role in familial prostate cancer. Cancer Res 60: Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M (1997). The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336: Thompson D, Easton DF, Breast Cancer Linkage Consortium (2002a). Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94: Thompson D, Easton D, Breast Cancer Linkage Consortium (2002b). Variation in BRCA1 cancer risks by mutation position. Cancer Epidemiol Biomarkers Prev 11: Warner E, Foulkes W, Goodwin P, Meschino W, Blondal J, Paterson C, et al. (1999). Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst 91: Vazina A, Baniel J, Yaacobi Y, Shtriker A, Engelstein D, Leibovitz I, et al. (2000). The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel. Br J Cancer 83: Zuhlke KA, Madeoy JJ, Beebe-Dimmer J, White KA, Griffin A, Lange EM, et al. (2004). Truncating BRCA1 mutations are uncommon in a cohort of hereditary prostate cancer families with evidence of linkage to 17q markers. Clin Cancer Res 10:

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