Portal de Periódicos da CAPES

The Jewish Ashkenazi Founder Mutations in the BRCA1/BRCA2 Genes Are Not Found at an Increased Frequency in Ashkenazi Patients with Prostate Cancer

1999; Elsevier BV; Volume: 65; Issue: 3 Linguagem: Inglês

10.1086/302525

1537-6605

Ayala Hubert, Tamar Peretz, Orly Manor, Luna Kaduri, Naomi Wienberg, Israela Lerer, Michal Sagi, Dvorah Abeliovich,

Male Breast Health Studies

To the Editor: BRCA1 and BRCA2, the predisposing genes for breast cancer (BC) and ovarian cancer (OC), have been suggested to increase the risk of prostate cancer (PrC) in male carriers (Ford et al. Ford et al., 1994Ford D Easton DF Bishop DT Narod SA Goldgar DE Breast Cancer Linkage Consortium Risks of cancer in BRCA1-mutation carriers.Lancet. 1994; 343: 692-695Abstract PubMed Scopus (1581) Google Scholar; Thorlacius et al. Thorlacius et al., 1996Thorlacius S Olafsadottir G Tryggvadottir L Neuhausen S Jonasson JG Tavtigian SV Tulinius H et al.A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotype.Nat Genet. 1996; 13: 117-119Crossref PubMed Scopus (453) Google Scholar; Struewing et al. Struewing et al., 1997Struewing JP Hartge P Wacholder S The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.N Engl J Med. 1997; 336: 1401-1408Crossref PubMed Scopus (1900) Google Scholar); however, no direct evidence exists to confirm this hypothesis. A population with a high carrier frequency of BRCA1 and BRCA2 germinal mutations allows a direct approach to studying the role BRCA1 and BRCA2 play in the development of PrC; if germinal mutations in BRCA1 and BRCA2 increase the risk of PrC in carriers, it is to be expected that the carrier frequency in PrC patients will be higher than in the general population, as was demonstrated in female patients diagnosed with BC and OC (Ford et al. Ford et al., 1995Ford D Easton DF Peto J Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence.Am J Hum Genet. 1995; 57: 1457-1462PubMed Google Scholar; Claus et al. Claus et al., 1996Claus EB Schildkraut JM Thompson WD Risch NJ The genetic attributable risk of breast and ovarian cancer.Cancer. 1996; 77: 2318-2324Crossref PubMed Scopus (584) Google Scholar, Abeliovich et al. Abeliovich et al., 1997Abeliovich D Kaduri L Lerer I Weinberg N Amir G Sagi M Zlotogora J et al.The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women.Am J Hum Genet. 1997; 60: 505-514PubMed Google Scholar). In the Ashkenazi Jewish population, three founder mutations, 185delAG and 5382insC in the BRCA1 gene and 6174delT in the BRCA2 gene, exist at a high frequency (2.5%) (Struewing et al. Struewing et al., 1995Struewing JP Abeliovich D Peretz T Avishai N Kaback MM Collins FS Brody LC The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals.Nat Genet. 1995; 11: 198-200Crossref PubMed Scopus (577) Google Scholar; Oddoux et al. Oddoux et al., 1996Oddoux C Struewing JP Clayton CM Neuhausen S Brody LC Kaback M Haas B et al.The carrier frequency of the BRCA2 6174delT mutation in Ashkenazi Jewish individuals is approximately 1%.Nat Genet. 1996; 14: 188-190Crossref PubMed Scopus (314) Google Scholar; Roa et al. Roa et al., 1996Roa BB Boyd AA Volcik K Richards CS Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2.Nat Genet. 1996; 14: 185-187Crossref PubMed Scopus (595) Google Scholar; Fodor et al. Fodor et al., 1998Fodor FH Weston A Bleiweiss IJ McCurdy LD Walsh MM Tartter PI Brower ST et al.Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients.Am J Hum Genet. 1998; 63: 45-51Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar). To assess the contribution of the BRCA1/BRCA2 germinal mutations to PrC morbidity, we analyzed the Ashkenazi founder mutations in two groups (with the same age distribution) of Ashkenazi men, a group of unselected PrC patients, and a control group of men with no history of cancer. The study was designed around the fact that, in families known to segregate BRCA1/BRCA2 mutations, men with PrC were noted sporadically. It was thus assumed that, if BRCA1 and BRCA2 play a role in the development of PrC, they do so as risk modifiers rather than as major dominant genes, and therefore will not be confined to familial cases. Patients diagnosed with adenocarcinoma of the prostate (n=87) were recruited from the oncology outpatient clinic at Sharett Institute, Hadassah Hebrew University Hospital, with no preselection. The patients signed an informed-consent form approved by the hospital's ethics committee. Each patient was interviewed regarding his family history. Clinical and pathological records were the sources of the clinical data. The control group included 87 healthy men with no history of cancer. These men were approached in Jerusalem-area homes for the elderly and were asked to participate in the study; if they agreed, they signed an informed-consent form. Their blood samples were kept anonymous, labeled only with the patients' ages and origins (table 1). The median age was 71 years at the time of diagnosis for the patients with PrC and 72 years at the time of blood sampling for the control group (table 2). The mutations were analyzed as described elsewhere (Abeliovich et al. Abeliovich et al., 1997Abeliovich D Kaduri L Lerer I Weinberg N Amir G Sagi M Zlotogora J et al.The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women.Am J Hum Genet. 1997; 60: 505-514PubMed Google Scholar).Table 1Study Group of Ashkenazi Patients with PrC and Control Group: Age at Diagnosis, Cancer History, and the Ashkenazi BRCA1/BRCA2 Founder MutationsNo. of Subjects Diagnosed or Testedat Age (in Years)Group 80UnknownGroupTotalAll subjectsaTotal number of Ashkenazi patients treated in Sharett Oncology Institute from January 1991 to July 1997.197214229…253PrC study group1436383587 Carriers…1bPatient A, carrying mutation 185delAG.1cPatient B, carrying mutation 6174delT.1dPatient C, carrying mutation 185delAG.……3 Carriers with second primary tumorePatient A had chronic lymphocytic leukemia; patient B had BC at age 59 years.…11………2 Carriers with cancer in family……1………1 Noncarriers with second primary tumorfSecond primary tumors included melanoma (n=3) and tumors of the bladder (n=2), lung (n=1), rectum (n=2), and kidney and colon in the same patient.……44…19 Noncarriers with cancer in familygSix patients had first-degree relatives with PrC; eight patients had first-degree relatives with BC, including one male relative.…210111226Control group…3273126387 Carriers…2hCarriers of mutation 185delAG.…1iCarrier of mutation 6174delT.………a Total number of Ashkenazi patients treated in Sharett Oncology Institute from January 1991 to July 1997.b Patient A, carrying mutation 185delAG.c Patient B, carrying mutation 6174delT.d Patient C, carrying mutation 185delAG.e Patient A had chronic lymphocytic leukemia; patient B had BC at age 59 years.f Second primary tumors included melanoma (n=3) and tumors of the bladder (n=2), lung (n=1), rectum (n=2), and kidney and colon in the same patient.g Six patients had first-degree relatives with PrC; eight patients had first-degree relatives with BC, including one male relative.h Carriers of mutation 185delAG.i Carrier of mutation 6174delT. Open table in a new tab Table 2Clinicopathological Characteristics of PatientsStage (No. of Patients)PSAaIn mg/ml. at Diagnosis (No. of Patients)Gleason Score (No. of Patients)Noncarrier patients A (5) 5.9 (3) 5.4 (5) B (35) 13.6 (28) 5.9 (31) C (27) 32.8 (21) 6.2 (24) D (12) 37.4 (10) 7.6 (5)Carrier patients B (patient AbCarrier of mutation 185delAG.) 60 >8 B (patient BcCarrier of mutation 6174delT.) 47 8 B (patient CbCarrier of mutation 185delAG.) 60 7a In mg/ml.b Carrier of mutation 185delAG.c Carrier of mutation 6174delT. Open table in a new tab The risk of developing PrC is age-dependent and is determined by differential exposure to environmental factors. In addition, positive family history is a major risk factor for developing PrC at an early age (Steinberg et al. Steinberg et al., 1990Steinberg GD Carter BS Beaty TH Childs B Walsh PC Family history and the risk of prostate cancer.Prostate. 1990; 17: 337-347Crossref PubMed Scopus (525) Google Scholar; Spitz et al. Spitz et al., 1991Spitz MR Currier RD Fueger JJ Babaian RJ Newell GR Familial patterns of prostate cancer: a case-control analysis.J Urol. 1991; 146: 1305-1307Abstract Full Text PDF PubMed Scopus (158) Google Scholar; Whittemore et al. Whittemore et al., 1995Whittemore AS Wu AH Kolonel LN John EM Gallagher RP Howe GR West DW et al.Family history and prostate cancer risk in black, white, and Asian men in United States and Canada.Am J Epidemiol. 1995; 141: 732-740PubMed Google Scholar). It is assumed that ∼10% of all cases of PrC and half of the cases diagnosed at an early age (<60 years) are dominantly inherited. Linkage analyses in families with multiple cases of PrC pointed to a PrC-susceptibility gene (or group of genes) on chromosome 1 (Smith et al. Smith et al., 1996Smith JR Freije D Carpten JD Gronberg H Xu J Isaacs SD Brownstein MJ et al.Major susceptibility locus for prostate cancer on chromosome 1 suggested by genome-wide search.Science. 1996; 274: 1371-1374Crossref PubMed Scopus (640) Google Scholar; Grönberg et al. Grönberg et al., 1997aGrönberg H Damber L Damber J-E Iselius L Segregation analysis of prostate cancer in Sweden: support to dominant inheritance.Am J Epidemiol. 1997; 146: 552-557Crossref PubMed Scopus (154) Google Scholara; Berthon et al. Berthon et al., 1998Berthon P Valeri A Cohen-Akenine A Drelon E Paiss T Wohr G Latil A et al.Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2- 43.Am J Hum Genet. 1998; 62: 1416-1424Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar; Schaid et al. Schaid et al., 1998Schaid DJ McDonnell SK Blute ML Thibodeau SN Evidence for autosomal dominant Inheritance of prostate cancer.Am J Hum Genet. 1998; 62: 1425-1438Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar), and, recently, an X-linked gene was suggested (Xu et al. Xu et al., 1998Xu J Meyers D Freije D Isaacs S Wiley K Nusskern D Ewing C et al.Evidence for a prostate cancer susceptibility locus on the X chromosome.Nat Genet. 1998; 20: 175-179Crossref PubMed Scopus (370) Google Scholar). It can be argued that BRCA1 and BRCA2 markedly reduce the age at onset of PrC and that therefore the effect of BRCA1/BRCA2 will be shown only in patients diagnosed with PrC at age <60 years, whereas in our study only five patients were ascertained in this age group. However, since 2.5% of Ashkenazi males are BRCA1/BRCA2 carriers, it would be expected that an excess of Ashkenazi men will develop PrC at age <60 years. The stratification of the ages at diagnosis in the study group was similar to that of PrC patients in Israel, and only rarely are patients diagnosed before age 50 years (Israel Cancer Registry, Israel Cancer Registry, 1994Israel Cancer Registry Prostate cancer.in: In: Cancer in Israel. Ministry of Health, State of Israel1994: 19-21Google Scholar). The data of Struewing et al. (Struewing et al., 1997Struewing JP Hartge P Wacholder S The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.N Engl J Med. 1997; 336: 1401-1408Crossref PubMed Scopus (1900) Google Scholar) also support the view that there is no excess of Ashkenazi patients with PrC diagnosed at age 30). The three carrier patients were diagnosed at stage B with Gleason scores of 7, 8, and >8, higher than the average (5.9) for the noncarrier patients at stage B and similar to the average at stage D. The clinicopathological records of the patients indicated that the tumors in the three carriers were highly proliferative. This may suggest that mutations in BRCA1 and BRCA2 may have some role in the progression of the disease. A similar observation was made of PrC in patients who belong to HPC1-linked families (Grönberg et al. Grönberg et al., 1997bGrönberg H Isaacs SD Smith JR Carpten JD Bova SG Freije D Xu J et al.Characteristics of prostate cancer in families potentially linked to the hereditary prostate cancer 1 (HPC1) locus.JAMA. 1997; 278: 1251-1255Crossref PubMed Google Scholarb) and in BRCA1-associated breast cancers (Eisinger et al. Eisinger et al., 1996Eisinger F Stoppa-Lyonnet D Longy M Kerangueven F Noguchi T Bailly C Vincent-Salomon A et al.Germline mutation at BRCA1 affects the histoprognostic grade in hereditary breast cancer.Cancer Res. 1996; 56: 471-474PubMed Google Scholar; Marcus et al. Marcus et al., 1996Marcus JN Watson P Page DL Narod SA Lenoir GM Tonin P Linder-Stephenson L et al.Hereditary breast cancer: patholobiology, prognosis, and BRCA1 and BRCA2 gene linkage.Cancer. 1996; 77: 697-709Crossref PubMed Scopus (412) Google Scholar; Blackwood and Weber Blackwood and Weber, 1998Blackwood AM Weber BL BRCA1 and BRCA2: from molecular genetics to clinical medicine.J Clin Oncol. 1998; 16: 1969-1977PubMed Google Scholar; Robson et al. Robson et al., 1998Robson M Gilewski T Haas B Levin D Borgen P Rajan P Hirschaut Y et al.BRCA-associated breast cancer in young women.J Clin Oncol. 1998; 16: 1642-1649Crossref PubMed Scopus (275) Google Scholar). However, this conclusion is based on three patients and should be confirmed in a larger number of patients. The frequency of carriers in the study group of PrC patients and in the group of healthy men was 3.4% (95% CI 1.48%–5.4%), which is within the range of the population frequency (2.5%) (Fodor et al. Fodor et al., 1998Fodor FH Weston A Bleiweiss IJ McCurdy LD Walsh MM Tartter PI Brower ST et al.Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients.Am J Hum Genet. 1998; 63: 45-51Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar). In order to detect a minor difference between the two groups, a much larger sample was needed. Instead, we chose a different approach in which we calculated the expected percentage of carriers of BRCA1/BRCA2 founder mutations among the PrC patients, on the basis of the existent risk figures: 16% by age 70 years and 39% by age 80 years (Struewing et al. Struewing et al., 1997Struewing JP Hartge P Wacholder S The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.N Engl J Med. 1997; 336: 1401-1408Crossref PubMed Scopus (1900) Google Scholar). Assuming that we follow Ashkenazi men from age 50 years through age 80 years, we further assumed that the rate of carriers is 2.5% and that among the carriers the average risk of developing PrC prior to age 80 years is ∼20%. We would then expect that every year 33 of 100,000 new Ashkenazi patients with PrC would be carriers of any of the BRCA1/BRCA2 founder mutations. Israeli data show that the number of new cases among Ashkenazi men at this age (50–80 years), is ∼260 in 100,000 (Israel Cancer Registry, Israel Cancer Registry, 1994Israel Cancer Registry Prostate cancer.in: In: Cancer in Israel. Ministry of Health, State of Israel1994: 19-21Google Scholar); hence the carriers would be ∼13% of the patients (33/260). We had 87 patients, and therefore expected 11 carriers in our study group, but observed 3. The difference between the expected and observed result is highly significant (P<.0005 in the exact-binomial test). The size of the sample enables a power of ⩾80% for detecting a difference in carriers of 2.5% in the control group and at least 12.5% in the patients group. It is interesting to note that the strong association found among Israeli females between ethnic origin and breast cancer is not evident for prostate cancer. The age-standardized rate of breast cancer among Jewish women born in Europe or America (i.e., having an Ashkenazi origin) is 1.57 times that of Jewish women born in North Africa (non-Ashkenazi origin), whereas the respective rate for men having prostate cancer is 0.9 (Israel Cancer Registry, Israel Cancer Registry, 1994Israel Cancer Registry Prostate cancer.in: In: Cancer in Israel. Ministry of Health, State of Israel1994: 19-21Google Scholar). The age-adjusted rate of PrC (per 100,000) in Israeli Jewish men by place of birth is 32.2 for those born in Europe and North America (Ashkenazi Jews), 32.5 for men born in Africa and Asia, and 43.5 for men born in Israel (Israel Cancer Registry, Israel Cancer Registry, 1994Israel Cancer Registry Prostate cancer.in: In: Cancer in Israel. Ministry of Health, State of Israel1994: 19-21Google Scholar). We therefore suggest that the contribution of BRCA1/BRCA2 germinal mutations to PrC morbidity is negligible. Our conclusion is in agreement with other studies in which PrC patients were tested directly (Langston et al. Langston et al., 1996Langston AA Stanford JL Wicklund KG Thompson JD Blazej RG Ostrander EA Germ-line BRCA1 mutations in selected men with prostate cancer.Am J Hum Genet. 1996; 58: 881-885PubMed Google Scholar; Johannesdottir et al. Johannesdottir et al., 1996Johannesdottir G Gudmundsson J Bergthorsson JT Arason A Agnarsson BA Eiriksdottir G Johannsson OT et al.High prevalence of the 999del5 mutation in Icelandic breast and ovarian cancer.Cancer Res. 1996; 56: 3663-3665PubMed Google Scholar; Wilkens et al. Wilkens et al., 1999Wilkens EP Freije D Xu J Nusskern DR Suzuki H Isaacs SD Wiley K et al.No evidence for a role of BRCA1 or BRCA2 mutations in Ashkenazi Jewish families with hereditary prostate cancer.Prostate. 1999; 39: 280-284Crossref PubMed Scopus (45) Google Scholar) and with some of the epidemiological studies (Isaacs et al. Isaacs et al., 1995Isaacs SD Kiemeney LALM Baffoe-Bonnie A Beaty TH Walsh PC Risk of cancer in relatives of prostate cancer probands.J Natl Cancer Inst. 1995; 87: 991-996Crossref PubMed Scopus (118) Google Scholar; McCahy et al. McCahy et al., 1996McCahy PJ Harris CA Neal DE Breast and prostate cancer in the relatives of men with prostate cancer.Br J Urol. 1996; 78: 552-556Crossref PubMed Google Scholar). However, our conclusion contradicts other epidemiological studies (Arason et al. Arason et al., 1993Arason A Barkadottier RB Egilsson V Linkage analysis of chromosome 17q markers and breast-ovarian cancer in Icelandic families, and possible relationship to prostatic cancer.Am J Hum Genet. 1993; 52: 711-717PubMed Google Scholar; Ford et al. Ford et al., 1994Ford D Easton DF Bishop DT Narod SA Goldgar DE Breast Cancer Linkage Consortium Risks of cancer in BRCA1-mutation carriers.Lancet. 1994; 343: 692-695Abstract PubMed Scopus (1581) Google Scholar; Thorlacius et al. Thorlacius et al., 1996Thorlacius S Olafsadottir G Tryggvadottir L Neuhausen S Jonasson JG Tavtigian SV Tulinius H et al.A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotype.Nat Genet. 1996; 13: 117-119Crossref PubMed Scopus (453) Google Scholar; Struewing et al. Struewing et al., 1997Struewing JP Hartge P Wacholder S The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.N Engl J Med. 1997; 336: 1401-1408Crossref PubMed Scopus (1900) Google Scholar), in which the data were based on information received about first-degree relatives of carriers, while the PrC patients themselves were not analyzed. It would be interesting to explore the possibility of other sources of variation, such as environmental factors that affect BRCA1/BRCA2 carriers to a greater extent than noncarriers and to which men in Israel are not exposed.