5382insC Mutation Research Articles

Transitional cell ovarian carcinoma in a BRCA1 mutation carrier

BACKGROUND: BRCA1 mutation carriers are at high risk of developing epithelial ovarian cancer, but the transitional cell variant has not been previously reported in these patients. CASE: A nulligravid, perimenopausal woman underwent exploratory laparotomy for a pelvic mass, ascites, and omental caking. Intraoperatively, frozen section of a tumor implant revealed high-grade epithelial ovarian carcinoma. Optimal surgical cytoreduction was performed. The final surgical pathology confirmed International Federation of Gynecology and Obstetrics stage IIIC transitional cell ovarian carcinoma. Her family history was significant for a sister with premenopausal breast cancer and a paternal aunt with ovarian cancer. The patient was counseled and elected to undergo genetic testing. Comprehensive gene sequence analysis detected the germline BRCA1 5382insC mutation. CONCLUSION: Transitional cell ovarian carcinoma is a rare histologic variant of epithelial ovarian cancer that may occur in BRCA1 mutation carriers.

Analysis of 5382insC (BRCA1) and 6174delT (BRCA2) mutations in 382 healthy Chilean women with a family history of breast cancer.

Breast cancer is the most common malignancy among women. Chilean studies reveal that this cancer presents the third highest mortality rate. A family history of breast cancer is one of the major risk factors for the development of this disease. BRCA1 and BRCA2 are the two main hereditary breast cancer susceptibility genes, and mutations in these genes are related to inherited breast cancer. In specific populations only some mutations have been found to be associated with susceptibility. The purpose of this study was to establish the frequency of 5382insC (BRCA1) and 6174delT (BRCA2) germline mutations in 382 healthy Chilean women with at least two relatives affected with breast cancer and in probands and their relatives from 8 high risk families for breast cancer, using mismatch PCR assay. The results obtained showed that 5382insC and 6174delT mutations were not found in either of the groups studied. The ethnic origin of the contemporary Chilean population and the data reported in the literature suggest that these mutations may be absent or have a very low frequency in this population.. This genetic study is part of a breast cancer screening program that also includes annual mammography and clinical breast examination over a five-year period. Strategies to reduce morbidity and mortality associated with breast cancer lie in early detection in women with genetic risk.

Germ line BRCA1 & BRCA2 mutations in Greek breast/ovarian cancer families: 5382insC is the most frequent mutation observed

BRCA1 and BRCA2 genes were screened for loss-of-function mutations in a series of 85 patients having at least one first- or second-degree relative affected by breast and/or ovarian cancer. All BRCA1 exons and BRCA2 exons 10 and 11 were screened with a combination of methods including SSCP, PTT and direct sequencing. We have found disease-associated mutations in 14 families (16.5%), eleven in BRCA1 and three in BRCA2. The known founder mutation 5382insC of BRCA1 was identified in seven unrelated families. The other mutations identified include the non-sense R1751X, the splice junction variant 5586G>A of BRCA1 and three frameshifts, 2024del5, 3034del4, and 6631del5, of BRCA2. Nine out of these 14 families had a family history of three or more breast/ovarian cancer cases. A large number of polymorphic or unclassified variants is also reported. Combined with our previously published data 5382insC was found in nine out of 20 families (45%), suggesting that this mutation may represent a common founder mutation in the Greek population.

Three primary malignancies related to BRCA mutation successively occurring in a BRCA1 185delAG mutation carrier

The 185delAG and 5382insC mutations in the BRCA1 gene and the 6174delT mutation in the BRCA2 gene (the Ashkenazi mutations) have been found to be significantly more common among Jews of eastern European ancestry (1 in 40, 2.5%) in comparison to the general population (1 in 800 to 1 in 300, 0.12–0.33%). Carriers of these mutations, especially the BRCA1 185delAG mutation, have a significantly increased lifetime risk of breast and ovarian carcinoma and other carcinomas as compared to non-carriers. A case of three primary malignancies related to the BRCA1 185delAG mutation successively occurring in a carrier of this mutation, is described. The patient successively developed breast carcinoma, ovarian micropapillary serous carcinoma and peritoneal papillary serous carcinoma. Immunohistochemical staining results have indicated that these tumors are three separate primary malignancies. This case illustrates that ovarian serous borderline tumors (including micropapillary serous carcinoma) and peritoneal papillary serous carcinomas should be considered, like breast and ovarian carcinomas, tumors expressed in BRCA mutation carriers.

Search for Frequent Mutations in Genes Predisposing to Breast Cancer

DNA of oncological patients, including Ashkenazi Jews and Slavs, living in St. Petersburg was collected, and the resultant collection was screened for three common mutations of genes BRCA1andBRCA2by means of heteroduplex analysis. The mutation 5382insC in exon 20 of the BRCA1gene was found in four unrelated patients, including three Slavs and one Ashkenazi Jew, with a positive family history of breast cancer. The mutations 185delAG and 6174delT in the BRCA1and BRCA2genes, respectively, which are typical of Ashkenazi Jewish patients with breast cancer, were not found in the patients of either ethnicity living in St. Petersburg, although the 6174delT mutation was found in the control group of Ashkenazi Jews. A new 12-nucleotide duplication g.71741ins12nt found in intron 20 of the BRCA1gene was described. The high frequency of the 5382insC mutation in the BRCA1gene in patients with familial breast cancer in both St. Petersburg and Moscow indicates that Russian families with the history of breast cancer should be primarily tested for this mutation.

BRCA1 and BRCA2 mutations in Turkish breast/ovarian families and young breast cancer patients.

To date, BRCA1 and BRCA2 mutations in breast and/or ovarian patients have not been characterized in the Turkish population. We investigated the presence of BRCA mutations in 53 individuals with a personal and family history of breast and/or ovarian cancer, and 52 individuals with a personal history of breast cancer diagnosed below age 50 without additional family history. We have identified 11 mutations (nine BRCA1 and two BRCA2) using combined techniques involving protein truncation test, direct sequencing and heteroduplex analysis. We found eight out of 53 patients (15.1%) with a family history to carry BRCA gene mutations (seven BRCA1 and one BRCA2). Of these, four were found in 43 families presenting only breast cancer histories, and four were found in families presenting ovarian cancer with or without breast cancer. We also demonstrated two BRCA1 and one BRCA2 mutations in three out of 52 (5.8%) early-onset breast cancer cases without additional family history. Three of nine BRCA1 and both BRCA2 mutations detected in this study were not reported previously. These mutations may be specific to the Turkish population. The BRCA1 5382insC mutation, specific to Ashkenazi and Russian populations, was found twice in our study group, representing a possible founder mutation in the Turkish population. © 2000 Cancer Research Campaign

Founder BRCA 1 and 2 Mutations among a Consecutive Series of Ashkenazi Jewish Ovarian Cancer Patients

Objective. 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.Materials and methods. 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-μm 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 χ2 test or a two-tailed Fisher's exact test, depending on the sample size.Results. 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).Conclusions. 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.

BRCA1 germline mutations in women with uterine serous papillary carcinoma

Objective: To determine the possible effects and incidence of BRCA1 and BRCA2 germline mutations in uterine serous papillary carcinoma. Methods: We screened DNA from 12 women with uterine serous papillary carcinoma for BRCA1 and BRCA2 germline mutations common in the Jewish population (BRCA1–185delAG and 5382insC, BRCA2–6174delT). In women with germline mutations, tumor DNA was screened for loss of heterozygosity at the appropriate loci. Results: Nine women were of Jewish Ashkenazi origin and three were non-Ashkenazi. Two of nine Ashkenazi women were carriers of germline mutations: one 185delAG mutation and one 5382insC mutation. Five women had histories of breast carcinoma before diagnosis of uterine serous papillary carcinoma. Family histories of seven women had at least one first-degree relative with malignant disease. Of those, four had at least one first-degree relative with breast, ovarian, or colon carcinoma. Both carriers had strong family histories of breast-ovarian carcinoma. Loss of heterozygosity analysis found loss of the wild-type BRCA1 allele in the primary uterine tumors. Conclusion: BRCA1 germline mutations were observed in two of nine of the women in this series. The loss of heterozygosity in the tumor tissue of the carriers, coupled with the high frequency of family and patient histories of breast or ovarian malignancies, suggest that uterine serous papillary carcinoma might be a manifestation of familial breast-ovarian cancer.

High frequency of recurrent mutations in BRCA1 and BRCA2 genes in Polish families with breast and ovarian cancer.

Germ-line mutations in BRCA1 and BRCA2 genes result in a significantly increased risk of breast and ovarian cancer. Other genes involved in an increased predisposition to breast cancer include the TP53 gene, mutated in Li-Fraumeni syndrome. To estimate the frequency of germ-line mutations in these three genes in Upper Silesia, we have analyzed 47 breast/ovarian cancer families from that region. We found five different disease predisposing mutations in 17 (36%) families. Twelve families (25.5%) carried known BRCA1 mutations (5382insC and C61G), four families (8.5%) carried novel BRCA2 mutations (9631delC and 6886delGAAAA), and one family (2%) harbored novel mutation 1095del8 in the TP53 gene, which is the largest germline deletion in coding sequence of this gene identified thus far. The 5382insC mutation in BRCA1 was found in 11 families and the 9631delC mutation in BRCA2 occurred in three families. These two mutations taken together contribute to 82% of all mutations found in this study, and 30% of the families investigated harbor one of these mutations. The very high frequency of common mutations observed in these families can only be compared to that reported for Ashkenazi Jewish, Icelandic, and Russian high-risk families. This frequency, however, may not be representative for the entire Polish population. The observed distribution of mutations will favor routine pre-screening of predisposed families using a simple and cost-effective test.

Single-Strand Conformation Polymorphism Analysis by Capillary and Microchip Electrophoresis: A Fast, Simple Method for Detection of Common Mutations in BRCA1 and BRCA2

As a result of intensive studies on hereditary breast and ovarian cancers, two breast cancer susceptibility genes, BRCA1 and BRCA2, have been identified. In each gene, a small number of specific mutations have been found at relatively high frequency in certain ethnic populations. The mutations, 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2, have been identified as common mutations in the Ashkenazi Jewish population, with a combined frequency of 2.0 to 2.5%. Women who have one of the above three common mutations are at a high risk of developing breast or ovarian cancer. Consequently, accurate and cost-effective detection of these three mutations may have important implications for risk assessment in susceptible women and men. In this report, we describe a fast and simple capillary electrophoresis (CE)-based method using a polymer network for screening the three common mutations in BRCA1 and BRCA2. Fluorescent dye-labeled primers (6-FAM-tagged) were used to amplify three DNA fragments of 258, 296, and 201 bp for detection of the 185delAG, 5382insC, and 6174delT mutations, respectively. After the PCR products were denatured, a single-strand conformation polymorphism (SSCP) profile could be obtained for each mutation in less than 10 min by CE in a polymer network. We demonstrate the potential provided by translating this assay to the microchip format where the SSCP analysis is complete in 120 s, representing only a fraction of the reduction in analysis time that can be achieved with microchip technology. The speed and simplicity of the SSCP methodology for detection of these mutations make it attractive for use in the clinical diagnostic laboratory.

Frequency of BRCA1 Mutation 5382insC in German Breast Cancer Patients

Objective.The aim of the study was to determine the frequency of the BRCA1 mutation 5382insC in German breast cancer patients with and without prior knowledge of a family history of breast cancer.Methods.Two groups of breast cancer patients were tested for the presence or absence of the 5382insC mutation using a PCR primer mismatch assay. A sample of 248 patients unrelated by genealogy was selected based on a history of breast and/or ovarian cancer in the families. In addition, a population-based sample of 800 unselected breast cancer patients was included in the analysis. Three intragenic DNA markers D17S1323, D17S1322, and D17S855, located at BRCA1 introns 12, 19, and 20, respectively, were utilized for allelic association studies as well as for haplotype analysis in 4 breast/ovarian cancer families.Results.The 5382insC mutation was identified in 10/248 (4.0%) familial breast cancer patients and in 8/800 (1.0%) unselected cases. Allelic association studies and haplotype analysis revealed an association of allele Nos. “6” at D17S1323 (χ2value = 9.34,P= 0.007), “5” at D17S1322 (χ2value = 3.62,P= 0.171), and “4” at D17S855 (χ2value = 11.34,P= 0.002) with the mutation 5382insC.Conclusion.5382insC constitutes a frequent BRCA1 mutation in German breast cancer patients. The significant allelic association between this mutation and two intragenic DNA markers (D17S1323, D17S855) and the elevated allele frequency at marker D17S1322 suggest an ancient founder in the German breast cancer population. The PCR primer mismatch assay described herein provides a rapid and reliable detection method for the recurrent 5382insC mutation and will be useful for the analysis of large breast cancer populations.

Survival after breast cancer in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers.

Studies of survival following breast and ovarian cancers in BRCA1 and/or BRCA2 mutation carriers have yielded conflicting results. We undertook an analysis of a community-based study of Ashkenazi Jews to investigate the effect of three founder mutations in BRCA1 and BRCA2 on survival among patients with breast or ovarian cancer. We collected blood samples and questionnaire data from 5318 Ashkenazi Jewish volunteers. The blood samples were tested for 185delAG (two nucleotide deletion) and 5382insC (single nucleotide insertion) mutations in BRCA1 and the 6174delT (single nucleotide deletion) mutation in BRCA2. To estimate survival differences in the affected relatives according to their BRCA1 and/or BRCA2 mutation carrier status, we devised and applied a novel extension of the kin-cohort method. Fifty mutation carriers reported that 58 of their first-degree relatives had been diagnosed with breast cancer and 10 with ovarian cancer; 907 noncarriers reported 979 first-degree relatives with breast cancer and 116 with ovarian cancer. Kaplan-Meier estimates of median survival after breast cancer were 16 years (95% confidence interval [CI] = 11-40) in the relatives of carriers and 18 years (95% CI = 15-22) in the relatives of noncarriers, a difference that was not statistically significant (two-sided P = .87). There was also no difference in survival times among the 126 first-degree relatives with ovarian cancer. We found no survival difference between patients with breast or ovarian cancer who were inferred carriers of BRCA1 and/or BRCA2 mutations and noncarriers. Carriers of BRCA1 and BRCA2 mutations appeared to have neither better nor worse survival prognosis.

Hereditary Breast Cancer in Latvia: Mutation Analysis of the BRCA1 Gene

Breast cancer is the main cause of death from malignant diseases in Latvian women. However, there have been no data concerning hereditary breast cancer from this region so far. Mutation screening of the breast cancer susceptibility genes BRCA1 and BRCA2 in high-risk Hungarian and Russian breast/ovarian cancer families indicated that founder effects of both genes in Central and Eastern Europe are considerable (Ramus, S.J. et al. 1997; Gayther, S.A. et al. 1997). In this study we determined the spectrum of BRCA1 mutations in 23 breast cancer patients treated at the Latvian Oncology Center in the period of 1995 to 1998. The entire coding region and splice sites of the BRCA1 gene were screened for mutations using SSCP, Heteroduplex Analysis and Protein Truncation Test followed by direct sequencing. The family histories in our cases were considerably less pronounced than those in other studies of highrisk families: 5 patients were considered to be members of high-risk families (3 or more breast cancers and/or 1 ovarian cancer in the family), 10 patients were from moderate risk families (2 cases in family) and 8 early onset breast cancer patients (< 40 yrs.) reported no family history. Three different mutations (5382insC, Cys61Gly and 4153delA ) have been identified in 8 patients out of 23 examined. Interestingly, most 5382insC mutations were identified in patients of Russian nationality. One hundred additional incident breast cancer patients have been screened for exons 5 and 20 of BRCA1 and two more 5382insC mutations were identified, both patients were of Russian nationality. Results of p53 mutation frequency in sporadic breast cancer patients and BRCA1 mutation carriers as well as data on erbB-2/neu amplification will also be presented. Predominance of a limited number of founder mutations in Latvian patients facilitates identification of mutation carriers in this population. Abstract

Strong founder effects in BRCA1 mutation carrier breast cancer patients from Latvia. Mutation in brief no. 258. Online.

Germ-line mutations of the BRCA1 gene account for approximately half of the cases of hereditary breast/ovarian cancers. We have screened index patients from 15 breast cancer families and 8 sporadic breast cancer patients from Latvia for mutations in all coding exons of the BRCA1 gene, using combined Heteroduplex Analysis/SSCP followed by direct sequencing of the variants. BRCA1 germ-line mutations proved to be frequent in Latvian breast cancer patients, also in moderate-risk families and sporadic patients. Out of 23 cases a total of 8 patients (35%) exhibited three different mutations (5382insC, C61G, 4153delA). Interestingly, these three recurrent mutations accounted for all mutations in our sample set and no unique mutation was found. The 5382insC and C61G mutations accounted for 63% (5/8) and 25% (2/8) of all mutations, respectively. Allelotyping suggested a common founder in each recurrent mutation. Additional one-hundred hospital-based incident breast cancer patients were screened for the three mutations and 4 other 5382insC mutation carriers were identified (4%). Patients with C61G and 4153delA mutations were all Latvians, whilst the majority of 5382insC carriers (7/9=78%) were of Russian ethnicity, which is intriguing for the supposed Baltic origin of this mutation.

A population-based study of BRCA1 and BRCA2 mutations in jewish women with epithelial ovarian cancer

Objective: To determine the frequency of BRCA1 mutations 185delAG and 5382insC and BRCA2 mutation 6174delT in Jewish women with ovarian cancer and in matched controls in a population-based study. Methods: Forty-eight Jewish women with epithelial ovarian cancer (32 invasive and 16 borderline) and 33 Jewish control subjects were obtained from a population-based, case-control study of ovarian cancer in eastern Massachusetts and New Hampshire. Mutational analysis on exons 2 and 20 of BRCA1 and exon 11 of BRCA2 was conducted on blood samples from patients and controls. Results: Fourteen (44%) of 32 Jewish patients with invasive epithelial ovarian cancer carried either a 185delAG mutation of BRCA1 ( n = 8) or a 6174delT mutation on BRCA2 ( n = 6). Neither of these mutations was identified in 16 women with borderline ovarian tumors or in 33 controls. No 5382insC mutation of BRCA1 was identified in any of the patients or control subjects in the series. Family history did not predict mutation status. Conclusion: BRCA1 185delAG and BRCA2 6174delT mutations are frequent in Jewish women with invasive epithelial ovarian cancer, irrespective of family history. Genetic counseling might be warranted in women with invasive epithelial ovarian cancer based on Jewish ethnicity alone.

A Population-Based Study of BRCA1 and BRCA2 Mutations in Jewish Women With Epithelial Ovarian Cancer

In Brief Objective To determine the frequency of BRCA1 mutations 185delAG and 5382insC and BRCA2 mutation 6174delT in Jewish women with ovarian cancer and in matched controls in a population-based study. Methods Forty-eight Jewish women with epithelial ovarian cancer (32 invasive and 16 borderline) and 33 Jewish control subjects were obtained from a population-based, case-control study of ovarian cancer in eastern Massachusetts and New Hampshire. Mutational analysis on exons 2 and 20 of BRCA1 and exon 11 of BRCA2 was conducted on blood samples from patients and controls. Results Fourteen (44%) of 32 Jewish patients with invasive epithelial ovarian cancer carried either a 185delAG mutation of BRCA1 (n = 8) or a 6174delT mutation on BRCA2 (n = 6). Neither of these mutations was identified in 16 women with borderline ovarian tumors or in 33 controls. No 5382insC mutation of BRCA1 was identified in any of the patients or control subjects in the series. Family history did not predict mutation status. Conclusion BRCA1 185delAG and BRCA2 6174delT mutations are frequent in Jewish women with invasive epithelial ovarian cancer, irrespective of family history. Genetic counseling might be warranted in women with invasive epithelial ovarian cancer based on Jewish ethnicity alone. BRCA1 185delAG and BRCA2 6174delT mutations are frequent in Jewish women with invasive epithelial ovarian cancer, irrespective of family history.

A high proportion of mutations in the BRCA1 gene in German breast/ovarian cancer families with clustering of mutations in the 3' third of the gene.

We have analyzed 61 German breast and breast/ovarian cancer families for BRCA1 mutations using single-strand conformation polymorphism analysis (SSCP) followed by sequencing. Forty-seven of the families had at least three cases (at least two under 60 years) and 14 families had only two cases of breast/ovarian cancer (at least one under 50 years). Twenty-eight families were breast/ovarian and 33 were breast cancer-only families. Eighteen mutations in BRCA1 were detected in 11/28 breast/ovarian cancer families and 7/33 breast cancer families and none in the families with only two cases. We identified 17 truncation mutations (8 frameshift, 7 nonsense and 2 splice variants) and one missense mutation. Seven of these are novel and two, the 5382insC and 5622C-->T mutations, occurred in two apparently unrelated families. The genotype of the two families with the 5382insC mutation is compatible with the rare haplotype segregating with the 5382insC mutation in different populations, further supporting its European origin. One unclassified missense alteration, R841W, was found in one family but did not segregate with the disease, suggesting that it is more likely a polymorphism. We also report and discuss the sequence of several new unclassified single-nucleotide changes first identified by SSCP. Of the 18 mutations, 13 occurred in the 3' third of the gene (end of exon 11-24) and ovarian cancers were found in eight of these families.

Frequency and Carrier Risk Associated with Common BRCA1 and BRCA2 Mutations in Ashkenazi Jewish Breast Cancer Patients

Based on breast cancer families with multiple and/or early-onset cases, estimates of the lifetime risk of breast cancer in carriers of BRCA1 or BRCA2 mutations may be as high as 85%. The risk for individuals not selected for family history or other risk factors is uncertain. We determined the frequency of the common BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) mutations in a series of 268 anonymous Ashkenazi Jewish women with breast cancer, regardless of family history or age at onset. DNA was analyzed for the three mutations by allele-specific oligonucleotide hybridization. Eight patients (3.0%, 95% confidence interval [CI] 1.5%-5.8%) were heterozygous for the 185delAG mutation, two (0.75%, 95% CI 0.20-2.7) for the 5382insC mutation, and eight (3.0%, 95% CI 1.5-5.8) for the 6174delT mutation. The lifetime risk for breast cancer in Ashkenazi Jewish carriers of the BRCA1 185delAG or BRCA2 6174delT mutations was calculated to be 36%, approximately three times the overall risk for the general population (relative risk 2.9, 95% CI 1.5-5.8). For the 5382insC mutation, because of the low number of carriers found, further studies are necessary. The results differ markedly from previous estimates based on high-risk breast cancer families and are consistent with lower estimates derived from a recent population-based study in the Baltimore area. Thus, presymptomatic screening and counseling for these common mutations in Ashkenazi Jewish women not selected for family history of breast cancer should be reconsidered until the risk associated with these mutations is firmly established, especially since early diagnostic and preventive-treatment modalities are limited.

An evaluation of common breast cancer gene mutations in a population of Ashkenazi Jews.

OBJECTIVES: In view of the recent reports of recurrent mutations in BRCA1 and BRCA2 in the Ashkenazi Jewish population, we have undertaken to assess the frequency of these mutations in...

The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.

Carriers of germ-line mutations in BRCA1 and BRCA2 from families at high risk for cancer have been estimated to have an 85 percent risk of breast cancer. Since the combined frequency of BRCA1 and BRCA2 mutations exceeds 2 percent among Ashkenazi Jews, we were able to estimate the risk of cancer in a large group of Jewish men and women from the Washington, D.C., area. We collected blood samples from 5318 Jewish subjects who had filled out epidemiologic questionnaires. Carriers of the 185delAG and 5382insC mutations in BRCA1 and the 6174delT mutation in BRCA2 were identified with assays based on the polymerase chain reaction. We estimated the risks of breast and other cancers by comparing the cancer histories of relatives of carriers of the mutations and noncarriers. One hundred twenty carriers of a BRCA1 or BRCA2 mutation were identified. By the age of 70, the estimated risk of breast cancer among carriers was 56 percent (95 percent confidence interval, 40 to 73 percent); of ovarian cancer, 16 percent (95 percent confidence interval, 6 to 28 percent); and of prostate cancer, 16 percent (95 percent confidence interval, 4 to 30 percent). There were no significant differences in the risk of breast cancer between carriers of BRCA1 mutations and carriers of BRCA2 mutations, and the incidence of colon cancer among the relatives of carriers was not elevated. Over 2 percent of Ashkenazi Jews carry mutations in BRCA1 or BRCA2 that confer increased risks of breast, ovarian, and prostate cancer. The risks of breast cancer may be overestimated, but they fall well below previous estimates based on subjects from high-risk families.