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Journal of Clinical Oncology, Vol 26, No 1 (January 1), 2008: pp. 20-25 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.6905 Effect of BRCA1/2 Mutations on Long-Term Survival of Patients With Invasive Ovarian Cancer: The National Israeli Study of Ovarian Cancer
From the Cancer and Radiation Epidemiology Unit, Gertner Institute; Department of Oncogenetics, Chaim Sheba Medical Center, Tel Hashomer; Department of Gynecology, Haemek Medical Center, Afula; and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Corresponding author: Angela Chetrit, MSc, Gertner Institute, Chaim Sheba Medical Center, Hashomer, 52621, Israel; e-mail: angelac{at}gertner.health.gov.il
Purpose To evaluate the long-term survival of ovarian cancer (OvC) patients in total and by BRCA1/2 mutation status. Patients and Methods In a nationwide case-control study on OvC conducted in Israel between 1994 and 1999, 779 Jewish women with epithelial invasive OvC were tested for the three Ashkenazi Jewish founder mutations in BRCA1 (185delAG; 5382insC) and BRCA2 (6174delT) genes and followed for survival up to 2003. Of the 605 women of Ashkenazi origin, 213 (35.2%) carried a mutation in the BRCA1/2 genes. Clinical characteristics were abstracted from the patients' medical records. The Kaplan-Meier method, log-rank tests, and stepwise Cox regression model were used for survival analyses. Results The 5-year survival rate for the entire group was 39%. Median survival for carriers was significantly longer than for noncarriers (53.7 v 37.9 months, respectively; P = .002). This differential survival was pronounced among women diagnosed at stages III to IV (5-year survival rates of 38.1% and 24.5% for carriers and noncarriers, respectively; P < .001) and for women with poor grade (45.4% v 31.5%, for carriers and noncarriers, respectively; P < .001). These results remained significant after controlling for age at diagnosis, grade, and morphology. This benefit in prognosis was seen for both BRCA1 and BRCA2 carriers compared with noncarriers. During the study period (median follow-up, 6.2 years), being a BRCA1/2 mutation carrier decreased the mortality rate by 28%. Conclusion This study confirms that, among Ashkenazi OvC patients, BRCA1/2 mutations are associated with improved long-term survival. This may be due to distinct clinical behavior and/or to a better response to chemotherapy.
Ovarian cancer (OvC) is a relatively rare disease with a high case fatality rate. Despite aggressive surgery and chemotherapy treatment, the prognosis of OvC patients is poor, with an overall 5-year survival rate of approximately 50%. Approximately 75% of the patients are diagnosed with advanced-stage disease (stage III to IV), and among these patients, the 5-year survival rate is approximately 30%.1,2 A family history of breast and/or ovarian cancer is reported in approximately 5% to 15% of OvC cases, and a reasonable proportion of these cases are associated with germline mutations in either the BRCA1 or the BRCA2 genes.3-7 Among Ashkenazi Jews, predominant mutations have been identified in both BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) genes. These three mutations have a combined population frequency of 2 to 2.5%.8,9 The prevalence of these genes in unselected invasive OvC patients of Ashkenazi origin was found to be close to 30% and may reach 50% or more in patients with a first-degree family history of breast cancer and/or OvC.5,8-12 The estimated lifetime risk (penetrance) of developing OvC in female carriers of BRCA1/2 mutations ranges in different reports between 15% and 54%.13,14 Several studies have investigated the possible effects of BRCA1/2 mutations on clinical and pathologic characteristics of OvC as well as on prognosis and survival rates of the patients,5,15-21 but the results were inconclusive. Some of these studies have demonstrated a more favorable survival for epithelial invasive OvC patients who are BRCA1/2 carriers, compared with noncarrier OvC women,16-18,20 but other investigators did not find a survival benefit in BRCA1/2 mutation carriers.19,21 This issue has been investigated extensively among breast cancer patients, and the results show similar or worse survival among carriers compared with noncarrier cases.22 A recent Israeli study demonstrated similar breast cancer specific mortality rates for carriers of a BRCA founder mutation and noncarriers.23 On the basis of a nationwide case-control study on OvC, we previously reported24 an improved survival among patients who are BRCA1/2 mutation carriers compared with noncarrier women after a median follow-up of 2.5 years. The 3-year survival rates were 65.8% among carriers compared with 51.9% among noncarriers (P < .001) The objectives of the present study were to evaluate the overall survival of OvC patients and to investigate long-term survival of BRCA1/2 mutation carriers. Specifically, we compared survival rates between BRCA1/2 carriers and noncarriers while adjusting for demographic and clinical known prognostic factors in a homogenous group of Jewish Ashkenazi patients.
This report is based on a nationwide case-control study conducted in Israel between 1994 and 1999 to examine environmental and genetic risk factors for OvC. The study population included all incident pathologically confirmed Jewish cases of epithelial OvC (code 183.0 of the International Classification of Disease [ICD9]) that were diagnosed in all-gynecologic departments in Israel. The patients were interviewed while hospitalized using a detailed questionnaire covering known and suspected risk factors for OvC. Of 1,226 women with epithelial invasive OvC who were recruited onto the study, 1,036 (84.5%) were successfully interviewed. Since 1996, when genetic tests for BRCA1/2 mutations became available, we added a genetic component to the originally designed epidemiologic study. Therefore, from that point on, we collected blood samples for DNA extraction. To complete the genetic testing for the patients already recruited, all patients were approached by their gynecologist and, after giving their consent to this part of the study, blood samples or tumor tissues were collected. Analysis of the founder mutations in BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT), were performed using standard laboratory methods. A multiplex polymerase chain reaction was designed to amplify the exons containing the three mutations with the use of fluorescence-labeled primers in a single reaction. Samples available for testing included peripheral blood or paraffin-embedded tissue sections. Details on the methodologic aspects of this study are available in previous publications.5,6,24 Of the 1,036 invasive OvC patients who completed a personal interview, 779 were tested for BRCA1/2 mutations and followed for survival up to July 2003. A comparison of the BRCA1/2 tested and the 257 nontested cases showed no significant differences between the two groups with respect to age at diagnosis and ethnic origin; however, more patients in the tested group were diagnosed at stages III to IV and had a positive family history of breast and/or ovarian cancer (data not shown). The Ashkenazi origin category was defined as women born in Europe-America or in Israel with at least one parent from Europe-America. Clinical characteristics were abstracted from medical records and original surgery and pathology reports. Information on patients' vital status was updated through the Israel Population Registry. Patients were followed for up to 9 years (median, 6.2 years; range, 4.2 to 9.4 years). The study received the approval of the institutional review board and the Ministry of Health. Inform consent for the genetic analysis was obtained from all study subjects. Overall survival was estimated using the Kaplan-Meier method. Because a full BRCA1 and BRCA2 mutation sequencing was not performed and, consequently, we could not appropriately evaluate the existence of mutations among the non-Ashkenazi population, the comparison between carriers and noncarriers was performed on the Ashkenazi group only. Survival was assessed for carriers and noncarriers using the Kaplan-Meier method, and survival curves were compared using the log-rank test. Five-year survival, median survival time, and 95% CIs, were presented for mutation carriers and noncarriers by demographic and clinical factors known to influence survival such as age, stage, morphology, and grade. A stepwise Cox regression analysis was performed to evaluate the effects of BRCA1/2 mutation status and clinical characteristics on survival.
Table 1 shows the median and 5-year survival rates of the study population by clinical characteristics. The 5-year survival rate for the entire group was 39%. Poor survival was found in women with more advanced disease, expressed by high grade or stage. Better survival was seen among women diagnosed at an early age, from 50% 5-year survival in women diagnosed at age less than 50 years to approximately 20% in women at age 70 years and above. Premenopausal women had better survival than menopausal women (51% v 35% respectively). No differences in survival were observed between serous and nonserous morphology.
Of the total study population, 605 (77.7%) were of Ashkenazi origin and 174 were classified as non-Ashkenazi. Of the latter group, only 16 women were found to carry one of the three mutations tested (12, one and three women carried the 185delAG, 5362insC and 6174delT mutations, respectively). No significant differences in survival were observed between women from Ashkenazi and non-Ashkenazi ancestry. Table 2 presents the median and 5-year survival rates for carriers and noncarriers among Ashkenazi OvC patients by selected characteristics. Of the 605 patients of Ashkenazi origin, 213 (35.2%) were BRCA1/2 carriers; 141 (23.3%) were BRCA1-185delAG, 18 (3.0%) were BRCA1-5382insC, and 54 (8.9%) were BRCA2-6174delT mutation carriers. Median survival for carriers was significantly longer compared with the noncarriers (53.7 v 37.9 months; respectively; P = .002). Among women diagnosed at stages I to II, 74% were still alive at 5 years of follow-up with no significant difference between carriers and noncarriers. The improved survival for carriers was seen in women diagnosed at stages III and IV (Fig 1). Five-year survival rates in women diagnosed at stage III were 38.3% for carriers compared with 27.1% for noncarriers, (P = .002) and at stage IV, 35.7% for carriers compared with 7.7% for noncarriers (P = .01). Improved survival for carriers was also found among women with high-grade tumors (poorly differentiated/anaplastic) compared with noncarriers (5-year survival rates of 45.4% v 31.5%; P < .001). The difference in survival between carriers and noncarriers persisted in serous and nonserous morphologic type (excluding the mucinous tumor cases), as well as for women diagnosed at age 60 years and older and for menopausal women (Table 2).
The advantage in survival of OvC patients diagnosed at stages III to IV remained statistically significant for both BRCA1 and BRCA2 carriers compared with noncarriers; median survivals of 45.1 (95% CI, 38.8 to 52.4) and 52.5 months (95% CI, 38.7 to 82.6) were observed among carriers of BRCA1 and BRCA2 respectively compared with 33.5 months (95% CI, 27.8 to 36.7) in noncarriers. The difference in survival between BRCA1 and BRCA2 carriers was not statistically significant (P = .2). Table 3 presents survival of OvC patients diagnosed at stages III to IV adjusted for age, grade, and morphology controlling for each other. Being a BRCA1/2 mutation carrier independently decreases death rates by 28% (hazard ratio [HR] = 0.72; 95% CI, 0.58 to 0.91). Age at diagnosis was also found to be an independent factor associated with survival (HR = 1.03 for an increment of 1 year; 95% CI, 1.02 to 1.04). Being a BRCA1 carrier reduced death rates by 18% (HR = 0.82; 95% CI, 0.63 to 1.05) and being a BRCA2 carrier by 46% (HR = 0.54; 95% CI, 0.36 to 0.80) compared with noncarriers.
In the current report, we present a comprehensive evaluation of demographic and clinical characteristics on survival of OvC patients. Specifically, we evaluated the impact of BRCA1/2 mutations on survival among Ashkenazi Jewish OvC patients. We extended the previous follow-up period reported in our last publication on survival of BRCA1/2 associated and sporadic OvC cases24 to reach a median follow-up period of 6.2 years (maximum, 9.4 years). In this report, we added analyses controlling for demographic and selected clinical characteristics and stratified by type of gene. This analysis confirmed our previous observation that OvC patients who are BRCA1/2 mutation carriers have an improved survival rate compared with noncarriers. A 5-year survival rate of 46% was seen among carriers compared with 34% among noncarriers (P = .002). This advantage in survival of mutation carriers was shown to be an independent protective factor regardless of age at diagnosis, histologic type, stage, and grade of disease. To the best of our knowledge, 12 published studies have assessed the impact of BRCA1/2 mutations on survival of OvC patients (Table 4). Six of them7,16-18,20,24 reported a statistically significant better survival among carriers.
On the basis of 189 cases of OvC, Boyd et al17 reported a 5-year survival of 47% compared with 22% in BRCA1/2 carriers and noncarriers, respectively (P = .004). An additional four reports also showed an advantage in survival among carriers,15,19,21,25 although the difference was not statistically significant. For example, Ramus et al15 who investigated 118 Ashkenazi patients with invasive OvC reported a median survival of 52 and 49 months among BRCA1 and BRCA2 mutation carriers, respectively, compared with 35 months in noncarriers (P = .5). On the basis of small number of carriers, Buller et al26 showed a similar survival between carriers and noncarriers, and Zwimmer et al27 reported a nonsignificantly better survival among the noncarrier group. Several methodologic issues may limit the assessment of differences in survival between carriers and noncarriers. In six of the aforementioned studies,15,16,18,20,26,27 the total sample size was less than 100 participants; three of them reported nonsignificant differences in survival between carriers and noncarriers. These nonsignificant results may be a result of insufficient statistical power of a small study population or may reflect a true similarity in survival between the groups. The inclusion of various populations in different studies might make the comparison of results between studies problematic. Some studies are based on carriers and noncarriers recruited from high-risk families,19-21,25,27 whereas others are based on a nonselective group of patients; some include all epithelial tumors whereas others exclude the borderline type.16 Another issue for consideration is a possible survival bias when studying only living OvC patients.16,18,20 Difference between studies may also be related to data analysis including the ability to control for possible confounders such as grade and stage, which are known to influence prognosis and are associated with mutation status. Among the advantages of our study is the fact that it is based on a relatively homogenous population of Jewish Ashkenazi women tested for the three founder mutations prevalent in this ethnic group. It includes consecutive OvC patients, reducing the possibility of survival bias. Data on clinical parameters were taken into consideration in the analyses. Most patients were treated similarly, diminishing the influence of the type of treatment on survival. Among the limitations of our study are that it is not certain to what extent these results may be generalized to non-Ashkenazi populations, the sample size does not allow a good differentiation between the influence of BRCA1 and BRCA2 on survival, and the lack of controlling for some possible confounders or modifiers such as other genes that may have an impact on prognosis. Relatively little data are available on the survival of women with BRCA2-associated OvC. Our results showed a better survival among BRCA2 carriers compared with noncarriers and a non–statistically significant difference between the survival of BRCA2 carriers compared with that of BRCA1 carriers. Pal et al7 reported an improved survival in BRCA2 carriers on the basis of 12 carriers in 232 incident cases of epithelial OvC. No statistically significant survival differences were seen in this study for BRCA1 carriers when compared with both BRCA2 carriers and noncarriers. It has been postulated that an advantage in life expectancy among carriers compared with noncarriers might be attributed to the biologic characteristics of the hereditary tumors, and/or to a better response to cancer treatment. BRCA1/2 gene products play a pivotal role in DNA repair mechanisms.17,28 It has been demonstrated that the deficiency of the BRCA proteins, confers substantial cellular sensitivity to the inhibition of Poly (ADP-Ribose) polymerase enzyme (PARP). This polymerase is a key enzyme in the repair of single strand DNA damage via the base excision repair pathway. The loss of PARP activity in BRCA mutant cells might lead to the persistence of DNA lesions normally repaired by homologous recombination with resultant increased chromosome instability and programmed cell death specifically in tumor cells.29,30 Therefore, because there is no functional protein within the tumor cells, they lose their capacity to repair DNA damage. This might be specifically pronounced for drugs acting through the induction of DNA damage such as cisplatin leading to cell death and to better therapeutic response. In support of this hypothesis, several in vitro studies showed increased sensitivity of some ovarian cell lines carrying a mutated BRCA1 allele to various chemotherapeutic agents. It has been found that human cells lacking BRCA1 may be particularly sensitive to cisplatinum and to other drugs that cause double-strand breaks in DNA.29,31-33 Furthermore, data demonstrate a greater cytotoxic effect of radiotherapy on OvC cell lines lacking the normal BRCA1/2 proteins than on those that have intact functional protein.34 The possible role of radiation treatment (which was more prevalent in the management of OvC patients in the past) should also be considered in the treatment of BRCA1/2 mutation carriers. Ovarian cancer is considered a high-fatality rate disease. If indeed, a better survival is seen in BRCA1/2 mutation carriers, some thought should be given to measures of second cancer risk reduction in women with BRCA1/2-associated OvC. Although extensive research has been conducted to investigate the effects of BRCA1/2 mutation status on the survival of breast cancer patients, no definitive conclusions can be drawn. BRCA-related breast cancers exhibit a number of clinicopathologic features typically associated with a poorer prognosis such as negative estrogen receptors.22 Therefore, even a similar survival between carriers and noncarriers might support the notion that response to chemotherapy is actually better for carriers compared with noncarriers. Whether it is the result of the tumor biology, or the tumor sensitivity to chemo- and radiation therapies, the differences in survival seen between OvC patients who are BRCA1/2 mutation carriers and noncarriers may suggest that the carrier OvC patients might benefit from a different therapeutic regimen, and thus might have practical implications.28 Tailoring a specific treatment regimen in the carrier patients based on chemosensitivity tests may even further improve their survival, compared with noncarriers. The current study confirms that, among Ashkenazi OvC patients, BRCA1/2 mutations are associated with improved long-term survival. This may be a result of distinct clinical behavior and/or of a better response to chemotherapy.
The author(s) indicated no potential conflicts of interest.
Conception and design: Angela Chetrit, Galit Hirsh-Yechezkel, Flora Lubin, Siegal Sadetzki Provision of study materials or patients: Yehuda Ben-David, Eitan Friedman Collection and assembly of data: Angela Chetrit, Galit Hirsh-Yechezkel, Flora Lubin Data analysis and interpretation: Angela Chetrit, Galit Hirsh-Yechezkel, Siegal Sadetzki Manuscript writing: Angela Chetrit, Galit Hirsh-Yechezkel, Yehuda Ben-David, Flora Lubin, Eitan Friedman, Siegal Sadetzki Final approval of manuscript: Angela Chetrit, Galit Hirsh-Yechezkel, Yehuda Ben-David, Flora Lubin, Eitan Friedman, Siegal Sadetzki
We dedicate this paper to the memory of the late Baruch Modan, MD, PhD, who was the principal investigator of the National Israeli Study of Ovarian Cancer.
Supported in part by Grant No. CA 61126-03 from the National Cancer Institute (National Institutes of Health, Bethesda, MD), and a grant from the Israel Cancer Association. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 55:10-30, 2005 2. Ries LAG, Harkins D, Krapcho M, et al (eds.): SEER Cancer Statistics Review, 1975-2003, National Cancer Institute Bethesda MD. http://seer.cancer.gov/csr/1975_2003/ 3. Claus EB, Schildkraut JM, Thompson WD, et al: The genetic attributable risk of breast and ovarian cancer. Cancer 77:2318-2324, 1996[CrossRef][Medline] 4. Risch HA, McLaughlin JR, Cole DE, 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 68:700-710, 2001[CrossRef][Medline] 5. Hirsh-Yechezkel G, Chetrit A, Lubin F, et al: Population attributes affecting the prevalence of BRCA mutation carriers in epithelial ovarian cancer cases in Israel. Gynecol Oncol 89:494-498, 2003[CrossRef][Medline] 6. Modan B, Hartge P, Hirsh-Yechezkel G, et al: Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med 345:235-240, 2001 7. Pal T, Permuth-Wey J, Kapoor R, et al: Improved survival in BRCA2 carriers with ovarian cancer. Fam Cancer 6:113-119, 2007[CrossRef][Medline] 8. Hartge P, Struewing JP, Wacholder S, et al: The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am J Hum Genet 64:963-970, 1999[CrossRef][Medline] 9. Bahar AY, Taylor PJ, Andrews L, et al: The frequency of founder mutations in the BRCA1, BRCA2, and APC genes in Australian Ashkenazi Jews: Implications for the generality of US population data. Cancer 92:440-445, 2001[CrossRef][Medline] 10. Moslehi R, Chu W, Karlan B, et al: BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am J Hum Genet 66:1259-1272, 2000[CrossRef][Medline] 11. Levy-Lahad E, Friedman E: Cancer risks among BRCA1 and BRCA2 mutation carriers. Br J Cancer 96:11-15, 2007[CrossRef][Medline] 12. Frank TS, Deffenbaugh AM, Reid JE, et al: Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 20:1480-1490, 2002 13. Struewing JP, Hartge P, Wacholder S, et al: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336:1401-1408, 1997 14. King MC, Marks JH, Mandell JB, et al: Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302:643-646, 2003 15. Ramus SJ, Fishman A, Pharoah PDP, et al: Ovarian cancer survival in Ashkenazi Jewish patients with BRCA1 and BRCA2 mutations. EJSO 27:278-281, 2001[CrossRef][Medline] 16. Rubin SC, Benjamin I, Behbakht K, et al: Clinical and pathologic features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med 335:1413-1416, 1996 17. Boyd J, Sonoda Y, Federici MG, et al: Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA 283:2260-2265, 2000 18. Cass I, Baldwin RL, Varkey T, et al: Improved survival in women with BRCA-Associated Ovarian Carcinoma. Cancer 97:2187-2195, 2003[CrossRef][Medline] 19. Pharoah PDP, Easton DF, Stockton DL, et al: Survival in familial, BRCA1-associated, and BRCA2-associated epithelial ovarian cancer. Cancer Res 59:868-871, 1999 20. Aida H, Takakuwa K, Nagata H, et al: Clinical features of ovarian cancer in Japanese women with germ-line mutations of BRCA1. Clin Cancer Res 4:235-240, 1998[Abstract] 21. Jóhannsson OT, Ranstam J, Borg A, et al: Survival of BRCA1 breast and ovarian cancer patients: A population-based study from southern Sweden. J Clin Oncol 16:397-404, 1998[Abstract] 22. Brekelmans CTM, Seynaeve C, Menke-Pluymers M, et al: Survival and prognostic factors in BRCA1-associated breast cancer. Ann Oncol 17:391-400, 2006 23. Rennert G, Bisland-Naggan S, Barnett-Griness O, et al: Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med 357:115-123, 2007 24. Ben David Y, Chetrit A, Hirsh-Yechezkel G, et al: Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol 20:463-466, 2002 25. Kringen P, Wang Y, Dumeaux V, et al: TP53 mutations in ovarian carcinomas from sporadic cases and carriers of two distinct BRCA1 founder mutations; relation to age at diagnosis and survival. BMC Cancer 5:134, 2005[CrossRef][Medline] 26. Buller RE, Shahin MS, Geisler JP, et al: Failure of BRCA1 dysfunction to alter ovarian cancer survival. Clin Cancer Res 8:1196-1202, 2002 27. Zweemer RP, Verheijen RH, Coebergh JW, et al: Survival analysis in familial ovarian cancer, a case control study. Eur J Obstet Gynecol Reprod Biol 98:219-223, 2001[CrossRef][Medline] 28. Foulkes WD: BRCA1 and BRCA2: chemosensitivity, treatment outcomes and prognosis. Fam Cancer 5:135-142, 2006[CrossRef][Medline] 29. McCabe N, Lord CJ, Tutt AN, et al: BRCA2-deficient CAPAN-1 cells are extremely sensitive to the inhibition of Poly (ADP-Ribose) polymerase: An issue of potency. Cancer Biol Ther 4:934-936, 2005[Medline] 30. Farmer H, McCabe N, Lord CJ, et al: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917-921, 2005[CrossRef][Medline] 31. D'Andrea AD. The Fanconi Anemia/BRCA signaling pathway: Disruption in cisplatin-sensitive ovarian cancers. Cell Cycle 2:290-292, 2003[Medline] 32. Kennedy RD, Quinn JE, Mullan PB, et al: The role of BRCA1 in the cellular response to chemotherapy. JNCI 96:1659-1668, 2004 33. Chen J, Silver DP, Walpita D, et al: Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Mol Cell 2:317-328, 1998[CrossRef][Medline] 34. Foray N, Randrianarison V, Marot D, et al: Gamma-rays-induced death of human cells carrying mutations of BRCA1 or BRCA2. Oncogene 18:7334-7342, 1999[CrossRef][Medline] Submitted March 15, 2007; accepted September 4, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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