Affiliations of authors: M. S. Brose, B. L. Weber (Department of Medicine and Abramson Family Cancer Research Institute), K. A. Calzone, J. E. Stopfer, K. L. Nathanson (Department of Medicine), University of Pennsylvania Cancer Center, Philadelphia; T. R. Rebbeck, Department of Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia.
Correspondence to: Barbara Weber, M.D., Abramson Family Cancer Research Institute at The University of Pennsylvania Cancer Center, BRB II/II, Rm. 514, 421 Curie Blvd., Philadelphia, PA 19104 (e-mail: weberb{at}mail.med.upenn.edu).
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ABSTRACT |
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INTRODUCTION |
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SUBJECTS AND METHODS |
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BRCA1 mutation carriers were identified either on the basis of direct genetic testing or as presumed carriers. Presumed carriers were defined as being in the line of descent between two tested mutation carriers or between a mutation carrier and an individual with breast or ovarian cancer (Fig. 1).
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RESULTS |
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The study included 461 (95%) Caucasian participants among a total of 483 participants. The remainder represented small numbers of African-Americans, Asians, and Native Americans. All patients were either self- or physician-referred for a perceived elevated risk of breast or ovarian cancer. We identified 642 known or presumed mutation carriers from 147 families, representing 58 different mutations in BRCA1. Only family members with information on current age or age of death were included because these data are required for age adjustment of the observed cancer rates. Using these criteria, data on 483 mutation carriers (381 females, 102 males) of 642 eligible participants were analyzed (Table 1). Among the 483 participants, there were 316 tested mutation carriers and 167 presumed carriers. Because exact age of diagnosis was considered as the minimum criterion for considering a family report credible, individuals without an age at diagnosis were included in the analysis but were considered unaffected. Two hundred twenty-seven (60%) of the 381 women in the study had a diagnosis of breast cancer (Table 2
). The average age at censoring for all individuals in the analysis was 56 years: 51 years for tested carriers and 63 years for presumed carriers (P<.001). One hundred seventy-nine (37%) of 483 participants had Ashkenazi Jewish founder mutations (26% 185delAG, 11% 5382insC). Two hundred fifteen (45%) mutations were in exons 110, 149 (31%) were in exon 11, and 119 (25%) were in exons 1224.
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The cumulative age-adjusted risk up to age 110 for female breast cancer in this group was 78.3% (95% CI = 74.1% to 82.4%), and the cumulative age-adjusted risk to age 70 was 72.8% (95% CI = 67.9% to 77.7%) (Fig. 2). The SEER lifetime risk estimate for breast cancer is 12.86% (11). Lifetime estimates are defined by SEER to age 95 or older (11). There were four cases of male breast cancer among the 102 male BRCA1 mutation carriers (3.9%), for a cumulative age-adjusted risk of male breast cancer of 5.8% (95% CI = 1.3% to 10.4%). This is 53 times higher than the risk in the general male population, estimated at 0.011% (11).
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Families used for linkage analysis are ascertained through these clinics, and because of concern that these families may bias cancer risk estimates upward, we performed an analysis with families grouped as suitable or not suitable for linkage and compared these data to the overall analysis. There was no statistically significant difference between the cumulative age-adjusted lifetime rate of breast cancer in families used for linkage analysis (86.0%, 95% CI = 79.0% to 93.1%) and that in families not suitable for linkage analysis (76.4%, 95% CI = 71.5% to 81.3%) or that in the sample as a whole (78.0%, 95% CI = 74.1% to 82.5%). It was surprising, however, that the age-adjusted ovarian cancer rate in families used for linkage (35.7%, 95% CI = 26.0% to 45.5%) was statistically significantly lower than both the rate in families not suitable for linkage analysis (54.2%, 95% CI = 48.5% to 60.0%) and that in the sample as a whole (40.1%, 95% CI = 35.2% to 45.0%).
One source of bias in calculating risk estimates that could limit the application of the findings to non-Jewish women would occur if Ashkenazi Jewish women with the founder mutations 185delAG and 5382insC had different cancer risks than non-Ashkenazi Jewish women with BRCA1 mutations. To address this issue, we compared the age-adjusted rate of female breast and ovarian cancer between the individuals of Ashkenazi Jewish descent and the rest of the sample. The age-adjusted rates of breast and ovarian cancer for women with either founder mutation were not statistically significantly different from those in non-Ashkenazi Jewish women. For breast cancer, the risk to age 70 was 76.0% (95% CI = 69.1% to 82.8%) in Ashkenazi Jewish women and 78.0% (95% CI = 72.7% to 83.4%) in non-Ashkenazi Jewish women. For ovarian cancer, the risks were 45.8% (95% CI = 37.8% to 53.7%) and 51.1% (95% CI = 44.7% to 57.6%) for Ashkenazi Jewish women and non-Ashkenazi Jewish women, respectively.
Because unaffected family members may be more likely than those with cancer to have incomplete data, leading to another source of bias, we conducted a separate analysis of excluded individuals. Of the 77 excluded females, 33 had breast cancer, for an observed risk estimate of 42.8% (95% CI = 37.2% to 48.4%), which was statistically significantly lower than the observed cumulative estimate of 57.5% (95% CI = 55.0% to 60.0%) for those from whom we had complete data. Thirteen of the excluded women had ovarian cancer, for an observed rate of ovarian cancer of 16.8% (95% CI = 12.6% to 21.0%), which was not statistically significantly different from the estimate of 24.7% (95% CI = 22.5% to 26.9%) in those with complete data. None of the 63 excluded males had breast cancer. Of note, age-adjusted rates, which we believe are more informative than observed rates, cannot be calculated for the excluded individuals because incomplete age data was the exclusion criterion in all cases.
Other Cancer Risks
In addition to breast and ovarian cancer, four other cancers (colon, pancreatic, gastric, and fallopian tube) occurred statistically significantly more often in BRCA1 mutation carriers than in the general population (P<.05). Other cancers evaluated but not present at greater frequencies than in the general population include uterine, cervical, brain, leukemia, bladder, kidney, thyroid, head and neck, and lymphoma. The cumulative age-adjusted lifetime risk of colon cancer among BRCA1 mutation carriers was 11.1% (95% CI = 8.3% to 13.9%), twice that of SEER population estimates of 5.6%. The cumulative age-adjusted lifetime risk of pancreatic cancer was 3.6% (95% CI = 1.9% to 5.3%), three times the estimated 1.3% population risk, and the cumulative age-adjusted lifetime risk of gastric cancer was 5.5% (95% CI = 3.4% to 7.5%), four times the population risk of 0.8%. All population risks are based on SEER estimates (11).
The cumulative age-adjusted lifetime risk of fallopian tube cancer in this clinic-based population was 3.0% (95% CI = 1.3% to 4.7%). Population risk estimates for this cancer are difficult to obtain because it is rare, but using an estimate of the frequency of fallopian tube cancer among all gynecologic malignancies of 0.5% (12) and the combined risk of ovarian, uterine, and cervical cancer in the population of 5.2% (11), we estimate the risk of fallopian tube cancer in the general population to be approximately 0.025%. Thus, the risk of fallopian tube cancer in this study population represents a 120-fold increase over the estimated population risk.
In the evaluation of the excluded individuals, 3 (4%) of 77 females and 9 (14%) of 63 males had an additional cancer. Although the numbers are small, and therefore not reliable, other cancer rates in the excluded individuals are lower than the observed rates in those included in the analysis, at 8.1% and 21.6% for females and males, respectively. As noted above, cancer rates in the excluded individuals are not age adjusted.
The observed incidence of prostate cancer among all male BRCA1 mutation carriers was 2.9%. Prostate cancer risk to age 60 was 1.4%, similar to the estimated 1.86% in the general population. The cumulative age-adjusted lifetime risk in mutation carriers was 6.2% (95% CI = 1.5% to 10.8%), statistically significantly lower than the 15.91% lifetime risk of prostate cancer in the general population (11) but possibly an underestimate due to the small numbers of older men included in this analysis.
Finally, the cumulative age-adjusted lifetime risk of any cancer diagnosis in this group of BRCA1 mutation carriers, other than breast and ovarian cancer, was 13.8% (95% CI = 10.7% to 16.9%). Of note, the overall risk of cancers other than of the female breast and ovary was statistically significantly higher for men than women, with cumulative age-adjusted lifetime risks of 26.1% (95% CI = 17.5% to 34.6%) and 10.3% (95% CI = 7.2% to 13.3%), respectively.
Risk of Second Cancers
Of 222 women in the study with breast cancer, 49 (22%) had a contralateral or asynchronous ipsilateral breast cancer not thought clinically to represent local recurrence. The cumulative age-adjusted lifetime risk of a second breast cancer diagnosis in this group was estimated at 40.5% (95% CI = 34.1% to 47.0%). Thirty-three (15%) of the 222 women with breast cancer subsequently developed ovarian cancer, for a cumulative age-adjusted lifetime risk of ovarian cancer after a breast cancer diagnosis of 18.8% (95% CI = 13.6% to 23.9%). Eighteen (8%) of 222 women with breast cancer were diagnosed with a subsequent cancer other than breast or ovarian cancer, for a cumulative age-adjusted lifetime risk of 9.7% (95% CI = 5.8% to 13.6%).
Average Age at Cancer Diagnosis
The average age at female breast cancer diagnosis in this study of BRCA1 mutation carriers, as in many others, was 42 years (95% CI = 40 to 44 years), and the average age at ovarian cancer diagnosis was 52 years (95% CI = 50 to 53 years). These ages are 20 and 10 years younger, respectively, than population averages (13). The average age at male breast cancer diagnosis was 53 years (95% CI = 45 to 60 years), compared with 69 years in the general population. The average age at colon cancer diagnosis was 65 years (95% CI = 59 to 71 years), compared with 72 years in the general population. Although the risk of uterine cancer was not increased in this clinic-based population, the average age at uterine cancer diagnosis was 50 years (95% CI = 40 to 60 years), compared with the population average of 66 years. [All population-based ages at diagnosis were taken from (13).]
Cancer Risk by Mutation Location
We did not detect a difference in the cumulative age-adjusted risk of breast cancer based on mutation location within the BRCA1 gene. However, the cumulative age-adjusted lifetime risk of ovarian cancer in women with mutations in exons 1224 was statistically significantly higher than that in women with mutations in exons 111 (Fig. 3). That is, the cumulative age-adjusted lifetime risk of ovarian cancer for women with BRCA1 mutations in exons 111 was 43.8% (95% CI = 37.9% to 49.7%) and for women with mutations in exons 1224 was 75.9% (95% CI = 68.5% to 83.3%). We also compared the risk associated with either Ashkenazi Jewish founder mutation to other mutations in the same portions of the BRCA1 gene and found no statistically significant differences between the two risks. However, when we examined the lifetime risk of ovarian cancer, we found a statistically significantly lower lifetime ovarian cancer risk in carriers of the 185delAG mutation as compared with the 5382insC mutation (P<.05), consistent with the genotypephenotype association seen in the overall analysis when we compared ovarian cancer risk for carriers of mutations in exons 111 compared with carriers of mutations in exons 1224 (Fig. 3
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DISCUSSION |
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In addition, we calculated age-adjusted risk of cancer by decade to account for the lower numbers of older individuals in the study. This deficit is presumably due to decreased survival in cancer-prone families, the lack of testing availability during most of the older individuals' lives, and our inability to assign them as presumed carriers, given limited information on the preceding generation. Finally, consideration of prophylactic surgery was not included in this analysis. Prophylactic oophorectomy decreases the risk of breast cancer in BRCA1 mutation carriers by approximately 50% (15); therefore, adjusting for oophorectomy would result in higher breast cancer risk than we have reported here.
Another source of bias in our ascertainment and study design is the potential for differential data on affected and unaffected individuals within a family, because family members may be more likely to recall information on individuals with cancer. In this study, exact age at diagnosis was the minimal amount of information required to consider a family report of cancer credible. Thus, if age at diagnosis was not available, an individual was included in the analysis but considered unaffected. However, because we could not evaluate age-adjusted risk if current age or age of death was unavailable, individuals without these data were excluded from the analysis. These criteria are expected to have offsetting effectswe may have considered some affected individuals as unaffected, biasing the results toward lower cancer risk estimates, and excluded some individuals who may have a lower likelihood of being affected, biasing the results toward higher risk estimates.
As with breast cancer, ovarian cancer risk estimates in this study (40.7%) were intermediate between those derived from families selected for one or more cases of ovarian cancer [63% (4)] and from a volunteer population [16% (6)]. However, BRCA1 mutation carriers identified from sequential Ashkenazi Jewish breast cancer cases (16) and the BCLC study families (14) have estimated ovarian cancer risks of 46% and 44%, respectively. The similarity of ovarian cancer risk estimates in these studies and the current study suggests that genetic and environmental modifying factors may be more important for breast cancer than for ovarian cancer, making ovarian cancer risk estimates less variable. Again, our estimates may be slightly lower than the true risk of ovarian cancer in our population because we have not corrected for prophylactic oophorectomy, which is our current recommendation for all women with a BRCA1 mutation after completion of childbearing.
Although male breast cancer is widely associated with BRCA2 mutations (4), the breast cancer risk in men with BRCA1 mutations is often overlooked. A study of 237 families with four or more breast cancers found that 20 (77%) of 26 male breast cancer cases were due to BRCA2 mutations, but just five (19%) were due to BRCA1 mutations (5). The cumulative age-adjusted risk of breast cancer in male BRCA1 mutation carriers in the current study represents a 53-fold increase in risk compared with population rates. Because of relatively small numbers (four of 102 male BRCA1 mutation carriers), the CI is wide, but even the lower 95% CI boundary represents a 10-fold increase over the estimated population risk. The cumulative age-adjusted risk of prostate cancer was not elevated in male BRCA1 mutation carriers in this study; however, the average age of male BRCA1 mutation carriers was 62. Given the average age of prostate cancer diagnosis of 70 years in the general population (13), modest changes in cumulative age-adjusted prostate cancer risk would be unlikely to be detected in this study.
Colon, pancreatic, and gastric cancer were found to occur more frequently in this study of a clinic-based sample than in the general population. Colon cancer risk in BRCA1 mutation carriers has varied between studies, with BCLC data (14) suggesting a fourfold increase, whereas other studies (6) report no increase over general population risk. The cumulative age-adjusted risk of colorectal cancer in the current study was a moderate but statistically significant twofold increase in risk (P<.05). We also estimate a threefold increase in pancreatic cancer risk and a fourfold increase in gastric cancer risk. Only one previous study of BRCA1 mutation carriers from Sweden (17) reported an increased risk of gastric cancer in BRCA1 mutation carriers (almost a sixfold increase). Moreover, a series of gastric cancer patients diagnosed before age 35 documented allelic loss flanking BRCA1 in 12 of 27 cases (44%) (18), suggesting a possible mechanistic link between BRCA1 and the development of gastric cancer. Pancreatic cancer has not been noted in previous studies in association with BRCA1 mutations.
We estimate a 120-fold increase in risk for fallopian tube cancer in BRCA1 mutation carriers, based on an estimated incidence in the population of 0.025%. Several case reports (1922) suggest an association between fallopian tube carcinoma and BRCA1 mutations, but ours is the first large study to provide evidence of such an association. Even when using the lower bound of the 95% CI as a conservative estimate, risk of fallopian tube cancer in BRCA1 mutation carriers is 48 times that of the general population. These data strongly support our recommendation that both fallopian tubes should be removed during prophylactic oophorectomy.
Results from genotypephenotype association studies in BRCA1 mutation carriers are inconsistent. Small differences in cancer risks between mutation locations have been seen in other studies (23,24), but the current study did not show variation in risk of breast cancer by mutation location within the gene, possibly because a larger sample size is needed. Our results do suggest an association between increased ovarian cancer risk and mutations in the 3' region of BRCA1, which encodes the BRCA1 carboxyl terminus (BRCT) motifs and is required for transcriptional co-activation of p53-dependent promoters (25). However, previous studies (23,26,27) have suggested that mutations in the 5' region of BRCA1 were associated with a higher risk of ovarian cancer. A recent study of incident ovarian cancer cases tested for germline BRCA1 mutations suggested a consistent risk of ovarian cancer association with mutations throughout BRCA1 but an increased risk of breast cancer associated with mutations in the 3' region of BRCA1 (24). Finally, the largest study to date, by the BCLC (28), suggests an increased risk of ovarian cancer and a decreased risk of breast cancer associated with mutations in the central region of BRCA1 (predominantly exon 11). However, in the BCLC study, ovarian cancers that occurred after the age of 70 were excluded, whereas in our analysis, these cancers contributed to the higher risk of ovarian cancer associated with mutations in the C-terminal region.
Despite the statistical significance of the increased ovarian cancer risk associated with mutations in the 3' region noted in the current study, in the absence of consistent results from multiple studies, it is difficult to definitively assign differential ovarian cancer risk to any specific gene region. From a clinical perspective, the most conservative approach is to counsel all BRCA1 mutation carriers to undergo prophylactic oophorectomy after completion of childbearing because all estimates of increased risk are greatly in excess of population risks regardless of mutation position, and effective surveillance for ovarian cancer does not exist.
In summary, we have presented estimates for breast and ovarian cancer risk for BRCA1 mutation carriers from a cancer risk evaluation program in North America. These estimates are statistically significantly higher than most population-based estimates (P<.05) but lower than early estimates based on families ascertained for linkage studies. In addition, these data support an increased risk of colon, gastric, male breast, and fallopian tube cancer in BRCA1 mutation carriers and provide the first evidence of an increased risk for pancreatic cancer. In this population of BRCA1 mutation carriers, the risk of breast cancer does not vary by mutation location, although, in contrast to previous reports, we report an increase in ovarian cancer risk associated with mutations in the 3' region of BRCA1. We believe that these data may provide the most relevant cancer risk estimates to date for use in advising women who have undergone genetic testing for BRCA1 mutations in cancer risk evaluation clinics in the United States.
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NOTES |
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REFERENCES |
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1 National Center for Biotechnology Information. OMIMTM. Online Mendelian Inheritance in Man. Baltimore (MD): Johns Hopkins University. (For BRCA1 [MIM Number: 113705]. [Last accessed: 8/12/02]. Available at: http://www.ncbi.nlm.nih.gov/omim/.
2 Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 1990;250:16849.[Medline]
3 Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266:6671.[Medline]
4 Easton DF, Ford D, Bishop DT. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 1995;56:26571.[Medline]
5 Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 1998;62:67689.[Medline]
6 Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 1997;336:14018.
7 Fodor FH, Weston A, Bleiweiss IJ, McCurdy LD, Walsh MM, Tartter PI, et al. Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients. Am J Hum Genet 1998;63:4551.[Medline]
8 Hopper JL, Southey MC, Dite GS, Jolley DJ, Giles GG, McCredie MR, et al. Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Australian Breast Cancer Family Study. Cancer Epidemiol Biomarkers Prev 1999;8:7417.
9 Antoniou AC, Gayther SA, Stratton JF, Ponder BA, Easton DF. Risk models for familial ovarian and breast cancer. Genet Epidemiol 2000;18:17390.[Medline]
10 Thompson D, Easton D. Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 2002;94:512.
11 Ries LA, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, et al., editors. SEER cancer statistics review, 19731999. Bethesda (MD): National Cancer Institute; 2002.
12 Markman M, Zaino R, Fleming P, Barakat R. Carcinoma of the fallopian tube. In Hoskins W, Perez C, Young R, editors. Principles and practice of gynecologic oncology. 2nd ed. Philadelphia (PA): Lippincott-Raven; 1997. p. 102538.
13 Perkins C, Kwong S, Morris C, Cohen R, Allen M, Wright WE. Cancer in California 2001. Sacramento (CA): California Department of Health Services, Cancer Surveillance Section; December 2000.
14 Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 1994;343:6925.[Medline]
15 Rebbeck TR, Levin AM, Eisen A, Snyder C, Watson P, Cannon-Albright L, et al. Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 1999;91:14759.
16 Satagopan JM, Offit K, Foulkes W, Robson ME, Wacholder S, Eng CM, et al. The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev 2001;10:46773.
17 Johannsson O, Loman N, Moller T, Kristoffersson U, Borg A, Olsson H. Incidence of malignant tumors in relatives of BRCA1 and BRCA2 germline mutation carriers. Eur J Cancer 1999;35:124857.[Medline]
18 Semba S, Yokozaki H, Yasui W, Tahara E. Frequent microsatellite instability and loss of heterozygosity in the region including BRCA1 (17q21) in young patients with gastric cancer. Int J Oncol 1998;12:124551.[Medline]
19 Tonin P, Weber B, Offit K, Couch F, Rebbeck TR, Neuhausen S, et al. Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families. Nat Med 1996;2:117983.[Medline]
20 Paley PJ, Swisher EM, Garcia RL, Agoff SN, Greer BE, Peters KL, et al. Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at surgical prophylaxis. Gynecol Oncol 2001;80:17680.[Medline]
21 Sobol H, Jacquemier J, Bonaiti C, Dauplat J, Birnbaum D, Eisinger F. Fallopian tube cancer as a feature of BRCA1-associated syndromes. Gynecol Oncol 2000;78:2634.[Medline]
22 Zweemer RP, van Diest PJ, Verheijen RH, Ryan A, Gille JJ, Sijmons RH, et al. Molecular evidence linking primary cancer of the fallopian tube to BRCA1 germline mutations. Gynecol Oncol 2000;76:4550.[Medline]
23 Gayther SA, Warren W, Mazoyer S, Russell PA, Harrington PA, Chiano M, et al. Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation. Nat Genet 1995;11:42833.[Medline]
24 Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Kwan E, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 2001;68:70010.[Medline]
25 Chapman MS, Verma IM. Transcriptional activation by BRCA1. Nature 1996;382:6789.[Medline]
26 Friedman LS, Szabo CI, Ostermeyer EA, Dowd P, Butler L, Park T, et al. Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families. Am J Hum Genet 1995;57:128497.[Medline]
27 Shattuck-Eidens D, McClure M, Simard J, Labrie F, Narod S, Couch F, et al. A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. Implications for presymptomatic testing and screening. JAMA 1995;273:53541.[Abstract]
28 Thompson D, Easton D. Variation in BRCA1 cancer risks by mutation position. Cancer Epidemiol Biomarkers Prev 2002;11:32936.
Manuscript received March 21, 2002; revised July 2, 2002; accepted August 14, 2002.
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