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ORIGINAL RESEARCH |
From the Laboratory of Gynecologic Oncology, Division of Gynecologic Oncology, and OB/GYN Epidemiology Center, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital; and Department of Obstetrics and Gynecology, Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Address reprint requests to: Samuel C. Mok, PhD Laboratory of Gynecologic Oncology Brigham and Women’s Hospital 221 Longwood Avenue, RF #472 Boston, MA 02115 E-mail: scmok{at}rics.bwh.harvard.edu
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Abstract |
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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.
The percentage of ovarian cancers resulting from a BRCA1 mutation diagnosed at any age in the general population is estimated to be about 3%, based on a carrier frequency around .06%.1 A much higher carrier frequency for particular mutations of BRCA1 (and BRCA2) is known to occur in ethnic subgroups, especially individuals of Ashkenazi (northern and eastern European) Jewish origin. These mutations include the 185delAG and 5382insC on BRCA1 and the 6174delT mutation on BRCA2.2,3 Population-based studies of Ashkenazi Jews show carrier frequencies for any of these three mutations of 2% to 3%: 0.9% for 185delAG, 0.9–1.5% for 6174delT, and 0.1% for 5382insC.4–6 Accordingly, the percentage of ovarian cancers in Ashkenazi Jewish women associated with one of these mutations should be much greater than the 3% predicted for the general population.
In Israel, the percentage of ovarian cancers associated with any of these three mutations was 45% in one study7 and 62% in another.8 Both studies were based on fewer than 25 cases and might not have been representative of the general population, because cases were recruited from a cancer genetics or tertiary oncology clinic. In a previous study, we recruited cases from a population-based, case-control study of ovarian cancer in eastern Massachusetts and New Hampshire and found that in Jewish women the percentage of ovarian cancers (including borderline ovarian tumors) associated with a 185delAG mutation was six (16%) of 31.9 We have expanded this series to 48 cases and included a search for 6174delT and 5382insC mutations.
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Methods |
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We identified controls by using a random digit-dialing sampling method, supplemented by town population lists for older cases, for which many more calls would have been made to identify control women of comparable age. Controls were matched to cases by town of residence and age within 4 years. Controls were required to have intact ovaries and no personal history of ovarian cancer. Refusal rates were approximately 30% for both recruitment methods. As of May 1997, a total of 523 controls had been studied.
Informed consent was obtained for collection of epidemiologic information and blood, as approved by our institutional review boards. Family history of cancer was defined as cancer in a first-degree relative. Cancers in relatives were not confirmed. We inquired about childhood religious upbringing with Jewish as one category. Although our questionnaire did not further distinguish Ashkenazi from Sephardic, most Jewish people residing in the United States are of northern and eastern European ancestry, hence likely to be Ashkenazi in origin.
Blood samples from cases and controls were taken, and identifying information masked so that sample results could not be linked with names, but only case or control status, cancer type, age at diagnosis, personal history of cancer, and family history of cancer in a first-degree relative. DNA was available for analysis either by extraction from buffy coat specimens, using phenol and chloroform, or recovered from filter paper cards that had been impregnated with buffy coat. In the latter case, a 2-by-4-mm piece of the filter paper was placed in 50 µL of water and heated to 99C to extract the DNA.
Single-stranded conformation polymorphism analysis was performed using three primer sets flanking exons 2 and 20 of the BRCA1 gene and exon 11 of the BRCA2 gene. Primer sequences for BRCA1 185delAG were as follows: forward primer, 5'GAAGTTGT-CATTTTATAAACCTTT-3'; and reverse primer, 5'TGTCTTTTCTTCCCTAGTATGT-3'. Primer sequences for BRCA1 5382insC were as follows: forward primer, 5'ATATGACGTGTCTGCTCCAC-3'; and reverse primer, 5'GGGAATCCAAATTACACAGC-3'. Primer sequences for BRCA2 6174delT were as follows: forward primer, 5'-TTTGTAATGAAGCATCTGAT-ACC-3'; and reverse primer, 5'GGGAAGCTTCATA-AGTCAGTC-3'. DNA sequencing was performed to confirm the mutations. Techniques for single-stranded conformation polymorphism analysis and DNA sequencing were described previously.9
Statistical analyses involved comparison of cases and controls or mutation-positive versus mutation-negative cases by 
2 or Fisher exact test for categoric variables and nonpaired t tests for continuous variables. Confidence intervals (CI) on the proportion of women having BRCA1 or BRCA2 mutations were calculated using the normal approximation to the binomial.
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Results |
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Eight (25%) of 32 Jewish cases with invasive epithelial ovarian cancer carried the 185delAG mutation on BRCA1 and six (19%) carried the 6174delT mutation on BRCA2. No 5382insC mutations were observed in this series of cases and no instances of cases carrying more than one of the preceding mutations were observed. Thus, the overall proportion of invasive ovarian cancers diagnosed in Jewish women that are associated with any of the three germline mutations found more commonly in the Ashkenazi population is 14 of 32, or 44% (95% CI 27%, 61%). No mutations were observed among the 33 Jewish controls, a highly significant difference compared with the frequency in Jewish cases (P < .001). No mutations were observed in the 16 Jewish cases with borderline ovarian tumors.
Table 1
presents characteristics of the cases with and without a 185delAG or 6174delT mutation and of controls. The mean age at diagnosis for cases with either mutation did not differ significantly from that for cases without a mutation or controls. In patients with invasive ovarian cancer, there was no difference in the histologic subtypes in cases with or without mutations. Excluding concurrently diagnosed cancers and basal cell skin cancers, four cases (29%) among the 14 women with a mutation had a personal history of previously diagnosed cancer (3 breast, 1 neuroendocrine) compared with one woman with previous breast cancer among cases without mutations (P = .02), and one woman with previous breast cancer among controls (P = .02). Breast and ovarian cancer in a primary relative was present with approximately equal frequency among cases with and without a mutation.
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Discussion |
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Among cases with mutations, we found an approximately equal proportion of BRCA1 185delAG and BRCA2 6174delT mutations, with no cases of BRCA1 5382insC. In the series of Abeliovich et al,8 there were also approximately equal numbers of the 185delAG and 6174delT mutations, with no 5382insC mutations. However, Levy-Lahad et al7 found similar proportions of all three mutations among their ovarian cancer cases. The population frequency of 5382insC in Ashkenazi Jews is 0.1%,3 tenfold less than frequencies of 185delAG and 6174delT, which might explain why fewer cases of ovarian cancer with this mutation were found in our study. The question of whether different mutations confer different risks of developing ovarian cancer in this population will require further study.
Our series included six women with 185delAG mutations described in a previous study of 31 cases.9 In that report, we described one woman with a mutation who had a serous borderline tumor, which on rereview for the present series, proved to be invasive. In the present series, which included 17 new cases of ovarian cancer, two new 185delAG mutations of BRCA1 and six new 6174delT mutations of BRCA2 were identified, all in women with invasive tumors. Thus, none of the 16 Jewish women with tumors of borderline malignancy in our current series had 185delAG, 5382insC, or 6174delT mutations. Modan et al10 studied 16 Jewish women with borderline tumors and did not find any patient with a BRCA1 185delAG mutation. Berman et al11 reported that none of the 10 Jewish women with borderline tumors had a BRCA2 6174delT mutation. However, in other series of ovarian cancers associated with BRCA1 mutations, there are reports of borderline tumors associated with BRCA1 mutations. Rubin et al12 reported three borderline tumors associated with BRCA1 mutations and Stratton et al13 reported one borderline tumor associated with a BRCA1 mutation.
In the present study, age at diagnosis of ovarian cancer with a mutation did not differ significantly from age at diagnosis of ovarian cancer without a mutation, even with tumors of borderline malignancy excluded. Both Abeliovich et al7 and Levy-Lahad et al8 found that age at diagnosis was not a reliable predictor of mutation. In our previous series, we noted that cases with a 185delAG mutation appeared to have an earlier age at onset. The two new cases of ovarian cancer associated with a 185delAG mutation occurred in women over age 65, highlighting the hazard of making inferences based on a small series of cases.
Patients with a 185delAG or 6174delT mutation were more likely to have a personal history of cancer. Four cases had a previous cancer, three of which were breast. One of the cases without mutation and one of the controls had previous breast cancer. Family history of any type of cancer among first-degree relatives was no different in patients with mutations, patients without mutations, or controls. There was an approximately equal frequency of breast and ovarian cancers among primary relatives of women with and without mutations.
None of the 14 women with mutations had family histories of breast or ovarian cancer significant enough to be described as high-risk pedigrees (ie, two or more primary relatives with ovarian or premenopausal breast cancer). Although family history might be used to refine the probability that ovarian cancer is associated with BRCA1 or BRCA2 mutations, we believe that in Jewish women with invasive ovarian cancer, ethnicity alone is a sufficient criterion for clinicians to offer genetic counseling. Recommendation for BRCA1 or BRCA2 mutation testing in women and their family members is more complex. Counseling must include discussion about the uncertainty of the predictive value of these tests. Whether current screening strategies will modify or prevent ovarian cancer in mutation carriers and whether prophylactic oophorectomy will prevent extra-ovarian disease remain unknown.
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Footnotes |
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Drs. Ross Berkowitz, E. Robert Greenberg, and Judy Garber contributed to this study.
Received May 14, 1998. Received in revised form July 9, 1998. Accepted July 30, 1998.
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2. 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;57:1284–97.[Medline]
3. Neuhausen S, Gilewski T, Norton L, Tran T, McGuire P, Swensen J, et al. Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat Genet 1996;13:126–8.[Medline]
4. Struewing JP, Abeliovich D, Peretz T, Avishai N, Kaback MM, Collins FS, et al. The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 1995;11:198–200.[Medline]
5. Roa BB, Boyd AA, Volcik K, Richards CS. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 1996;14:185–7.[Medline]
6. Oddoux C, Struewing JP, Clayton CM, Neuhausen S, Brody LC, Kaback M, et al. The carrier frequency of the BRCA2 6174delT mutation in Ashkenazi Jewish individuals is approximately 1%. Nat Genet 1996;14:188–90.[Medline]
7. Levy-Lahad E, Catane R, Eisenberg S, Kaufman B, Hornreich G, Lishinsky E, et al. Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: Frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families. Am J Hum Genet 1997;60:1059–67.[Medline]
8. Abeliovich D, Kaduri L, Lerer I, Weinberg N, Amir G, Sagi M, 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;60:510–4.
9. Muto MG, Cramer DW, Tangir J, Berkowitz R, Mok S. Frequency of the BRCA1 185delAG mutation among Jewish women with ovarian cancer and matched population controls. Cancer Res 1996;56:1250–2.
10. Modan B, Gak E, Sade-Bruchim RB, Hirsh-Yechezkel G, Theodor L, Lubin F, et al. High frequency of BRCA1 185delAG mutation in ovarian cancer in Israel. JAMA 1996;276:1823–5.[Abstract]
11. Berman DB, Costalas J, Schultz DC, Grana G, Daly M, Godwin AK. A common mutation in BRCA2 that predisposes to a variety of cancers is found in both Jewish Ashkenazi and non-Jewish individuals. Cancer Res 1996;56:3409–14.
12. Rubin SC, Benjamin I, Behbakht K, Takahashi H, Morgan M, LiVolsi VA, et al. Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med 1996;335:1413–6.
13. Stratton JF, Gayther SA, Russell P, Dearden J, Gore M, Blake P, et al. Contribution of BRCA1 mutations to ovarian cancer. N Engl J Med 1997;336:1125–30.
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