High frequency of BRCA1 and BRCA2 germline mutations in Ashkenazi Jewish ovarian cancer patients, regardless of family history.

To better understand the role of germline BRCA mutations in ovarian cancer in Ashkenazi Jews, we tested 29 consecutive patients admitted to our service for the three mutations common in this ethnic group. These mutations are 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. Six patients had both breast and ovarian cancer, and 23 had ovarian cancer only. In the first group, all women had germline mutations, 2 with each mutation. Of 23 ovarian cancer patients, 11 were carriers (48%): 6 of 185delAG, 2 of 5382insC, and 3 of 6174delT. Regarding family history, of 13 women with no family history, 3 (23%) were carriers. Of 10 women with any family history of breast or ovarian cancer, 8 (80%) were carriers. We discuss possible explanations for this surprisingly high carrier rate, including a high proportion of familial disease coupled with lack of adequate family history, lower penetrance than previously expected, or increasing penetrance in recent generations due to nongenetic factors. Our data suggest that genetic testing is merited in all Ashkenazi women with ovarian cancer, regardless of family history.

Beller U ，Halle D ，Catane R ，Kaufman B ，Hornreich G ，Levy-Lahad E ... -  《GYNECOLOGIC ONCOLOGY》

Founder BRCA 1 and 2 mutations among a consecutive series of Ashkenazi Jewish ovarian cancer patients.

The purpose of this study was to describe the incidence of the three Ashkenazi Jewish founder genetic BRCA 1 and 2 mutations among an unselected, consecutive group of Ashkenazi Jewish ovarian cancer patients. From 7/30/96 to 4/12/99, 92 Ashkenazi Jewish patients with histologically confirmed epithelial ovarian cancer had surgery. All of these patients had DNA extracted from 5-microm sections of their paraffin-embedded surgical specimen tissue blocks using the Qiagen QIAamp tissue extraction kit. A multiplex (triplex) polymerase chain reaction was performed to amplify fragments for the 185delAG, 5382insC, and 6174delT mutations. The products were hybridized with normal and mutant probes for each of the three mutations. All clinical data were collected retrospectively and statistical significance was evaluated using the chi(2) test or a two-tailed Fisher's exact test, depending on the sample size. There were 23 patients positive for one of the three founder BRCA mutations. Fourteen patients were positive for the 185delAG mutation, 2 patients were positive for the 5382insC mutation, and 7 patients were positive for the 6174 delT mutation (61, 9, and 30%, respectively). This represented a 25% incidence (95% CI: 16-34%) of one of the three founder BRCA mutations among our 92 Ashkenazi Jewish ovarian cancer patients. None of the patients was positive for more than one mutation. There was no statistically significant difference in parity, histology, grade, or stage between the BRCA founder mutation positive and negative patients. The difference between the percentage of mutation carriers among patients with one affected first-degree relative (13/22 or 59%) compared to those without at least one affected first-degree relative (10/70 or 14%) was highly significant (P = 0.001). Ashkenazi Jewish ovarian cancer patients represent a group with a high likelihood of being carriers of BRCA 1 and 2 genetic mutations, regardless of family history. As a result, all ovarian cancer patients who are of Ashkenazi Jewish descent should be counseled regarding BRCA 1 and 2 genetic screening, as well as the potential implications of these results for the patient as well as her relatives in terms of prognosis, screening, chemoprevention, and consideration of prophylactic surgical procedures.

Tobias DH ，Eng C ，McCurdy LD ，Kalir T ，Mandelli J ，Dottino PR ，Cohen CJ ... -  《GYNECOLOGIC ONCOLOGY》

Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations.

Satagopan JM ，Boyd J ，Kauff ND ，Robson M ，Scheuer L ，Narod S ，Offit K ... -  《CLINICAL CANCER RESEARCH》

The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%.

Oddoux C ，Struewing JP ，Clayton CM ，Neuhausen S ，Brody LC ，Kaback M ，Haas B ，Norton L ，Borgen P ，Jhanwar S ，Goldgar D ，Ostrer H ，Offit K ... -  《NATURE GENETICS》

Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer.

Neuhausen S ，Gilewski T ，Norton L ，Tran T ，McGuire P ，Swensen J ，Hampel H ，Borgen P ，Brown K ，Skolnick M ，Shattuck-Eidens D ，Jhanwar S ，Goldgar D ，Offit K ... -  《NATURE GENETICS》