Absence of 185delAG mutation of the BRCA1 gene and 6174delT mutation of the BRCA2 gene in Ashkenazi Jewish men with prostate cancer.

Epidemiological studies have demonstrated a clustering of breast and prostate cancers in some families. Moreover, there is an increase in the number of cases of prostate cancer in families with inherited mutations of the breast cancer susceptibility gene BRCA1. We assessed the role of BRCA1 and BRCA2 in prostate cancer. We tested for the BRCA1 185delAG frameshift mutation, found in 0.9% of Ashkenazi Jews, and the BRCA2 6174delT mutation, found in 1% of Ashkenazi Jews, in Ashkenazi Jewish men with prostate cancer. We studied 60 Ashkenazi men with prostate cancer. A family history was obtained by interview or a self-report questionnaire. Histological confirmation of diagnosis was obtained for all subjects. Ethnic background was confirmed for all subjects by self-report or interview. Mutations of BRCA1 and BRCA2 were detected by amplification of lymphocyte DNA from peripheral blood according to standard polymerase chain reaction (PCR) and dot blot procedures. Patients' ages ranged from 55 to 80 years (mean +/- s.d. 70 +/- 5.25). There were six men with a family history of prostate cancer; three of these had a father with prostate cancer. Five of the men had a family history of breast cancer, in a mother, a sister or an aunt. None of the men had a family history of both breast and prostate cancer. None of the 60 men carried the 185delAG BRCA1 or 6174delT BRCA2 mutations. Of 268 Ashkenazi Jewish women with sporadic breast cancer, tested in an unrelated study, 16 carried either the 185delAG mutation of BRCA1 or the 6174delT mutation of BRCA2. There was a significant difference in the incidence of the BRCA1 and BRCA2 mutations in the breast and prostate cancer cases (P = 0.05, two-tailed Fisher's exact test). The contribution of germline BRCA1 and BRCA2 mutations to prostate cancer incidence is probably small and could be limited to specific subgroups.

Prostate cancer is the most common malignancy found in American men (Boring et al, 1994). Although dietary fat plays a role in the development of this cancer (Pienta and Esper, 1993), and possibly also vasectomy (Giovannucci et al, 1993), family history is one of the strongest risk factors (Whittemore et al, 1995). Indeed, there may be a gene for prostate cancer on the long arm of chromosome 1 (Smith et al, 1997) although there is some evidence that the breast cancer susceptibility genes BRCAJ and BRCA2 may also be involved.
Epidemiological studies have demonstrated a clustering of breast and prostate cancers in some families (Sellers et al, 1994). Moreover, there is an increase in the number of cases of prostate cancer in families with inherited mutations of BRCA] Struewing et al, 1997); loss of heterozygosity studies also implicate BRCA I (Gao et al, 1995 a and b), which is located on the long arm of chromosome 17.
To assess the role of BRCAJ in prostate cancer, Langston et al (1996a) screened for germline BRCAJ mutations in a subset of men from an ongoing population-based case-control study of prostate cancer. Langston et al selected a group of 49 men with prostate cancer in whom genetic factors were most likely to be relevant, and found BRCAI mutations in seven (14.3%) of these men: one known BRCA1 mutation plus six more rare sequence variants. One mutation that Langston et al found was in a Jewish family with multiple cases of prostate cancer and the mutation was 185delAG.
Since BRCA1 and BRCA2 were cloned, many unique mutations of these two genes have been detected in the germ line of individuals with breast and ovarian cancer (Miki et al, 1994;Wooster et al 1994;Friedman et al, 1995). In high-risk pedigrees, female carriers of BRCAJ mutations have an 80-90% lifetime risk of breast cancer and a 40-50% lifetime risk of ovarian cancer . Following the finding of a 185delAG frameshift mutation of BRCAJ in several Ashkenazi Jewish breast/ovarian cancer families, the frequency of this mutation was found to be 0.9% (Struewing et al, 1995). The 6174delT mutation of BRCA2 has a 1% incidence in Ashkenazi Jews (Oddoux et al, 1996). We studied a group of Ashkenazi men with prostate cancer, but failed to find the 185delAG or 6174delT mutations.

SUBJECTS AND METHODS
Participants for our study were found via urology and radiation oncology clinics, and all eligible patients were asked to take part in the study. A family history was obtained by interview or selfreport questionnaire. Histological confirmation of diagnosis was obtained for all subjects. Ethnic background was confirmed for all subjects by self-report or interview. All participants gave informed consent for genetic studies and were not given the option to know their test results. Extensive genetic counselling, covering options for detection and prevention, was available. Although we used mostly sporadic cases of prostate cancer, some germline mutations would still be expected. Indeed, Langston et al (1996b) found BRCAI germline mutations in 10% of a cohort of young women with breast cancer, many without a family history of breast or ovarian cancer. Fitzgerald et al (1996) also noted that these mutations can be present in young women with breast cancer who do not belong to families with multiple affected members.

RESULTS
We studied 60 Ashkenazi men with prostate cancer, ranging in age from 55 to 80 years (mean ± s.d. 70 ± 5.25). There were six men with a family history of prostate cancer, three of whom had a father with prostate cancer. Five of the men had a family history of breast cancer, in a mother, a sister or an aunt. None of the men had a family history of both breast and prostate cancer. None of the 60 men carried the 1 85delAG BRCA] or 6174delT BRCA2 mutations.
Our results in prostate cancer may be compared with our results in breast cancer. Of 268 Ashkenazi Jewish women with sporadic breast cancer previously tested in an unrelated study, 16 carried either the 185delAG mutation of BRCAJ or the 6174delT mutation of BRCA2 (Dr C. Eng, personal communication). There was a significant difference in the incidence of the BRCAJ and BRCA2 mutations in the breast and prostate cancer cases (P = 0.05, two tailed Fisher's exact test).

CONCLUSIONS
A recent epidemiological analysis by Isaacs et al (1995) failed to identify a significantly increased risk of breast cancer among relatives of prostate cancer patients. Our findings are consistent with the findings of Isaacs et al. Furthermore, there is no evidence of genetic linkage between BRCA1 and prostate cancer in high risk families (Eastman, 1996;Stephenson, 1996).
British Journal of Cancer (1998) 78 (6), [771][772][773] The results of our study pertain only to the 1 85delAG mutation of BRCA] and the 6174delT mutation of BRCA2. Nevertheless, the overall contribution of germline BRCAI and BRCA2 mutations to prostate cancer incidence are probably small and could be limited to specific subgroups, such as that studied by Langston et al (1996a). Indeed, a mutation of a tumour-suppressor gene distal to the BRCAJ locus on the long arm of chromosome 17 may make a much greater contribution (Williams et al, 1996). A mutation on chromosome 1 may also play a role (Smith et al, 1997). Larger population-based studies of tumour and normal tissue from men with prostate cancer would be worthwhile as well as a complete analysis of BRCA] and BRCA2 in the subjects.