Clinical Cancer Research Bridging the Lab and the Clinic in Cancer Medicine Infection and Cancer: Biology, Therapeutics, and Prevention
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Satagopan, J. M.
Right arrow Articles by Offit, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Satagopan, J. M.
Right arrow Articles by Offit, K.
Clinical Cancer Research Vol. 8, 3776-3781, December 2002
© 2002 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Ovarian Cancer Risk in Ashkenazi Jewish Carriers of BRCA1 and BRCA2 Mutations

Jaya M. Satagopan1,2, Jeff Boyd, Noah D. Kauff, Mark Robson, Lauren Scheuer, Steven Narod and Kenneth Offit

Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [J. M. S., J. B., N. D. K., M. R., L. S., K. O.], and The Center for Research on Women’s Health, Toronto, Ontario, Canada [S. N.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 Appendix 1
 REFERENCES
 
Purpose: Several studies to date have reported ovarian cancer risk due to inherited BRCA1 and BRCA2 mutations using familial data or population-based series of probands. Familial aggregation associated with both of these methods may result in a substantial ascertainment bias. To address this, we have used a case-control design that does not involve familial aggregation to estimate the lifetime penetrance of ovarian cancer due to BRCA1 and BRCA2 mutations.

Experimental Design: A total of 382 ovarian cancer cases self-identified as being Jewish with no prior diagnosis of breast cancer were derived from two hospital-based series. In the first series, all 197 invasive epithelial ovarian cancer cases self-identified as Jewish and without a prior history of breast cancer, diagnosed and treated at Memorial Sloan-Kettering Cancer Center between 1986 and 2000, were identified. In the second series, 185 Jewish invasive epithelial ovarian cancer patients without prior breast cancer were identified in a study conducted at 11 centers in North America and Israel from 1995 to 1996. Controls were 3434 Jewish women without any prior history of breast or ovarian cancer from a large study of genotyped volunteers of Jewish origin in the Washington, D. C. area recruited by investigators at the National Cancer Institute. The cases and controls were genotyped for three Ashkenazi Jewish founder mutations, namely 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. The lifetime penetrances were estimated using the odds ratios, mutation prevalence in the controls, and ovarian cancer incidence rates in the general American population obtained from the Surveillance, Epidemiology and End Results database adjusted for the incidence of ovarian cancer following breast cancer.

Results: Mutations were identified in 147 cases and 62 controls. The estimated penetrances at age 70 years were 37% (95% confidence interval, 25–71%) for a BRCA1 mutation and 21% (95% CI, 13–41%) for a BRCA2 mutation.

Conclusions: The lifetime penetrances of BRCA1 mutations are lower than estimates obtained using familial data with multiple affected members but larger than estimates from some population-based proband series. The lifetime penetrance estimate of a BRCA2 mutation is in the range reported by some of the studies based on familial data. These results could have implications for clinical counseling, surgical interventions, and screening recommendations in women carrying these founder mutations.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 Appendix 1
 REFERENCES
 
Ovarian cancer is a leading cause of cancer-related mortality among women in the United States. The SEER3 lifetime risk of ovarian cancer is 1.71% (1) . It is well known that mutations in the BRCA1 and BRCA2 genes account for a large number, but not all, of familial ovarian cancers (2) . Inherited mutations commonly found in Ashkenazi Jewish individuals (namely, 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2) have been of particular interest. Several studies to date have reported lifetime risk of ovarian cancer due to inherited BRCA1 and BRCA2 mutations using familial data and population series of ovarian cancer probands. The lifetime risks are estimated in the range of 28–66% for a BRCA1 mutation (2, 3, 4, 5, 6, 7, 8) and 16–27% for a BRCA2 mutation (5 , 9) .

In studies involving family-based ascertainment, families with a high cancer incidence are more likely to be identified than families with no or fewer cancers among the relatives of probands. As a result, this can lead to a substantial positive bias in the risk estimates. Even population-based studies that rely on occurrences of cancer in relatives of probands to estimate penetrance can be biased if incident cases are used as probands (10) . We recently used a case-control design to estimate the lifetime risk of breast cancer conferred by inherited BRCA1 and BRCA2 mutations among Ashkenazi Jewish women (11) . In this design familial aggregation is not used, eliminating ascertainment bias. We showed that the lifetime risk of breast cancer due to an inherited mutation is substantially lower than the estimates reported in family-based studies. The goal of this study is to investigate the lifetime risk of ovarian cancer due to an inherited BRCA1 or BRCA2 mutation among Ashkenazi Jewish women ascertained using the same case-control approach and compare the estimates with those obtained by family-based and population-based studies.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 Appendix 1
 REFERENCES
 
Cases.
Cases were derived from two hospital-based ascertainment series: the first series was from MSKCC, New York (12) ; and the second series was from 11 centers in North America and Israel (13) . The first series comprised of 1150 consecutive ovarian cancer cases diagnosed and treated at MSKCC between 1986 and 2000. A subset of this series has been reported previously (12) . Review of patient records identified a total of 228 patients with ovarian cancer who identified themselves as being Ashkenazi Jewish. Of these, 31 patients had a prior history of breast cancer. Archival pathological tissue specimens were obtained from the hospital tissue bank for each of these participants. Once the ethnicity of the participants, overall survival time, and other clinical factors were determined, the samples were anonymized following published guidelines (14) . Samples were then analyzed to determine the presence of 185delAG and 5382insC BRCA1 or 6174delT BRCA2 mutations using previously published methods (12) .

The second series comprised of ovarian cancer cases from 11 centers in North America and Israel, as reported by Moslehi et al. (13) . Ovarian cancer patients, self-reported as Jewish, were contacted to participate in a study of mutation analysis of BRCA1 and BRCA2 genes. A total of 465 ovarian cancer cases of Jewish origin were identified, of whom 208 cases were alive. These 208 individuals were pathologically confirmed to have invasive epithelial ovarian cancer, agreed to participate in the mutation analysis study, and provided blood samples. Twenty-three of these 208 ovarian cancer patients had a prior history of breast cancer.

Aggregating data from these two series gave a total of 436 Ashkenazi Jewish ovarian cancer patients, of whom 382 cases did not have a prior history of breast cancer.

Controls.
The controls required for this study were obtained from a study of genotyped volunteers in the Washington, D. C. area (15) , providing a large series of Jewish individuals without a history of breast or ovarian cancer at the time of ascertainment. Jewish volunteers, both men and women, were recruited through advertisements. Breast and ovarian cancer history of the volunteers and their families was obtained. Furthermore, blood samples were obtained from all of the volunteers. A total of 3434 women without a personal history of breast or ovarian cancer at the time of data collection were identified for this study. The presence or absence of the three founder mutations was determined for every individual using previously published methods (15) . Of these 3434 volunteers, a total of 1606 women (47%) had a first- or second-degree relative affected with breast or ovarian cancer.

Statistical Methods.
All analyses were stratified by age. Because breast cancer can be a competing cause of risk for ovarian cancer incidence, inclusion of the 54 ovarian cancer patients with a prior diagnosis of breast cancer may result in biased penetrance estimates. Therefore, penetrance estimates were calculated by restricting the cases to the 382 patients without a prior history of breast cancer. All 3434 controls were included in the analysis. Penetrance estimation calculations are provided in the "Appendix ." This approach is similar to the estimation method described in our breast cancer penetrance study (11) . Briefly, the lifetime risk in a given age group can be estimated as a function of the following three quantities: (a) SEER ovarian cancer incidence rate after adjusting for the SEER incidence of ovarian cancer in patients with a prior diagnosis of breast cancer in that age group, and the SEER breast cancer incidence in that age group; (b) the age-specific relative risk of the mutation; and (c) the age-specific carrier prevalence of the mutation. This calculation involves the following three assumptions: (a) the hospital-based series of Jewish ovarian cancer cases are representative of the general population series of Jewish cases; (b) the controls are representative of the general Jewish population; and (c) the breast and ovarian cancer incidence rates among the Jewish population without BRCA mutation is similar to the SEER breast and ovarian cancer incidence rate. The CIs of the lifetime risk estimates were calculated using the bootstrap method (16) . This involves repeatedly calculating penetrance estimates by sampling cases and controls with replacement from the observed data and deriving the CIs from the empirical distribution of the penetrance estimates.

The risk conferred by BRCA1 versus BRCA2 mutations and the risk conferred by 185delAG versus 5382insC BRCA1 mutations were compared using a logistic regression model restricted to mutation carriers (11) . The outcome was case-control status. The variables entered into the model were the mutation BRCA1 versus BRCA2 (or 185delAG versus 5382insC) and age. A likelihood ratio test was then used to test the hypothesis of no difference in the risk conferred by the two mutations.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 Appendix 1
 REFERENCES
 
Aggregating the two case series and restricting to only cases without a prior diagnosis of breast cancer provided a total of 382 incident ovarian cancer cases. A BRCA1 mutation was observed in 103 (27%) cases, and 44 (12%) cases had a BRCA2 mutation. Table 1Citation gives the age-specific frequencies of cases and controls and the corresponding mutation rates. The age-specific relative risks of BRCA1 and BRCA2 mutations are given in Table 2Citation . The relative risks corresponding to an inherited BRCA1 mutation were estimated to be 42.4 in the <40 age group, 90.8 in age group 40–49, and 53.0 in the >=50 age group. The corresponding relative risks due to an inherited BRCA2 mutation were estimated as 6.5, 14.9, and 29.7, respectively.


View this table:
[in this window]
[in a new window]
  		Table 1 Mutations in cases and controls

 

View this table:
[in this window]
[in a new window]
  		Table 2 Odds ratios

 
Table 3Citation gives the age-specific SEER ovarian cancer incidence rates in the general population, adjusted for the incidence of breast cancer in the corresponding age groups. These adjusted rates, the age-specific relative risks, and carrier mutation prevalence were used to derive the age-specific lifetime risk estimates given in Table 4Citation . The estimated lifetime risk of ovarian cancer at age 70 was 37% (95% CI, 25–71%) due to an inherited BRCA1 mutation and 21% (95% CI, 13–41%) due to an inherited BRCA2 mutation. Based on the likelihood ratio test, the risk conferred by a BRCA1 mutation is significantly higher than the risk conferred by a BRCA2 mutation (P = 0.01).


View this table:
[in this window]
[in a new window]
  		Table 3 SEER incidence rates

SEER ovarian (Ia*) and breast (Fa*) cancer incidence rates expressed as the probability of developing ovarian or breast cancer over the corresponding 10-year range. For example, the SEER rate of ovarian cancer for women in the age group 20–29 is 4 per 10,000 person-years or 0.0004 when expressed as a probability and similarly for breast cancer. The standardized incidence ratio (SIR) SIRa is the incidence of a primary ovarian cancer in breast cancer patients in a given age group, relative to the general population incidence of ovarian cancer for the same age group. This is calculated using the SEER database. For example, the incidence of ovarian cancer among breast cancer patients in the age group 20–29 is 11.42 times higher than the incidence of ovarian cancer in the general population for the same age group. The adjusted incidence is given by Ra* = (Ia* - SIRa x Ia* x Fa*)/(1 - Fa*).

 

View this table:
[in this window]
[in a new window]
  		Table 4 Age-stratified analysis of lifetime risk of ovarian cancer

 
These analyses were repeated for 185delAG and 5382insC BRCA1 mutations (Table 5)Citation . However, it must be noted that very few cases and controls carry a 5382insC mutation. The estimated lifetime risks were 66% (95% CI, 37–100%) due to a 185delAG mutation and 29% (95% CI, 16–69%) due to a 5382insC mutation. There was no significant difference between the risks conferred by these BRCA1 mutations (P = 0.38).


View this table:
[in this window]
[in a new window]
  		Table 5 Age-stratified analysis of lifetime risk of ovarian cancer associated with BRCA1 mutations

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
Appendix 1
 REFERENCES
 
The lifetime risk estimate for BRCA1 was lower than estimates from familial studies (3 , 4) but larger than estimates from some of the population-based studies (6 , 9) . The lifetime risk of BRCA2 mutation was in the range of 16–27% reported in two family studies (4 , 5) . The penetrance estimates reported here represent the risk of ovarian cancer in the absence of any risk of prior breast cancer. A total of 54 ovarian cancer cases with a prior diagnosis of breast cancer were excluded from our analysis. Of the 54 cases, 25 had a 185delAG mutation, 5 had a 5382insC mutation, and 9 had a 6174delT BRCA2 mutation. The remaining 15 cases did not carry any of these three mutations.

The lifetime risks were estimated based on three major assumptions: (a) the hospital-based cases are representative of the population of ovarian cancer cases; (b) the volunteer controls are representative of the general Ashkenazi Jewish population; and (c) the cancer incidence in the general Ashkenazi Jewish population without BRCA mutations is similar to the SEER rate. The cases were derived from a hospital-based series of ovarian cancer patients. Because initial management of ovarian cancer in the United States is predominantly surgical, cases from the MSKCC series are likely to be similar to the general ovarian cancer case population in the United States. Furthermore, previous analysis showed that the clinicopathological features of high-risk (i.e., BRCA-linked) cancer patients diagnosed and treated at MSKCC were similar to those of sporadic ovarian cancer cases (12) . The controls were derived from a series of volunteers recruited via both general and Jewish-targeted media outlets. It is likely that individuals with a strong family history were more likely to participate in a study analyzing genetic influence on cancer risk. If the control group contained an enriched proportion of mutation carriers, then the odds ratios derived in our analysis would be underestimates, and the true penetrance figures would actually be higher. A total of 62 (1.8%) controls had a BRCA1 or BRCA2 mutation. This mutation frequency is similar to the 2.2% reported in the study of general Ashkenazi Jewish population (17) , suggesting that the mutation prevalence is not inflated among these controls. The SEER ovarian cancer incidence rates were assumed to the represent ovarian cancer incidence among the general Jewish population and the incidence of second primary ovarian cancer following a first primary breast cancer. Violation of this assumption would lead to biased risk estimates. Therefore, a sensitivity analysis was performed to determine lifetime risk when the Jewish population had 10% higher risk than the SEER population. The lifetime risk at age 70 years increased to 40% for a BRCA1 mutation and to 23% for a BRCA2 mutation.

Gayther et al. (18) reported a correlation between the location of a truncating mutation in the BRCA1 coding region and the chances of developing breast or ovarian cancer using data from 60 families. Mutations near the 5' end of the coding region are thought to confer a higher risk than mutations near the 3' end. The 185delAG mutation is located near the 5' end, and the 5382insC mutation is located near the 3' end of the BRCA1 coding region. Our estimate of a higher penetrance associated with a 185delAG mutation than a 5382insC mutation, although not statistically significant, is consistent with these findings.

The penetrance of BRCA2 mutation has not been widely reported. Our results show that a BRCA2 mutation is not a significant risk factor in younger women (age <40 years; odds ratio, 6.5; 95% CI, 0.8–55.6). The odds ratio increases as the population ages, suggesting BRCA2 to be a risk factor only in older women. The 6174delT mutation is located in the OCCR (19) , in the region of exon 11 extending from nucleotide 3035 to 6629. Truncating mutations in OCCR are known to be associated with an increased risk of breast and ovarian cancer (5 , 19) . Furthermore, founder mutations in BRCA1 are believed to have a significantly higher penetrance than a founder mutation in BRCA2 (20) . Our results are consistent with the findings of these published studies. Recent studies have reported associations between other cancers such as colorectal, stomach, pancreatic, and prostate cancers and mutations in BRCA1 and OCCR BRCA2 mutations (2 , 5 , 9 , 13 , 21 , 22) .

Our penetrance estimates can have implications for the management of ovarian cancer in germ-line mutation carriers. Prophylactic mastectomy and oophorectomy may be reasonable options for germ-line BRCA1 and BRCA2 mutation carriers. Their advantages have been reported in recent literature (23, 24, 25, 26) . The penetrance estimates derived in this study can be used in decisions regarding such preventive measures (i.e., risk-reducing oophorectomy might safely be delayed until after menopause in carriers of the 6174delT BRCA2 mutation). Surgical removal of the ovaries is increasingly offered to BRCA mutation carriers, given the variable sensitivity of ovarian cancer screening strategies and the finding of early stage tumors in "prophylactic" oophorectomy specimens (27) . In the absence of more sensitive means of detecting ovarian cancer, penetrance estimates such as those provided here will continue to be used to inform surgical as well as medical interventions in populations at greatest hereditary risk for ovarian cancer.


   Appendix 1
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 Appendix 1
REFERENCES
 
Penetrance Estimate.
The penetrance of ovarian cancer in mutation carriers at a given age is the probability of developing ovarian cancer by that age in a randomly selected individual, assuming that the individual does not die of competing causes of risk before that age. Denote I10, I20, ... as the age-specific incidence of ovarian cancer among carriers without a prior history of breast cancer in age groups 1, 2, ... The penetrance (Pa) at the end of the ath age interval can be written as shown below.

The age-specific carrier incidence in the ath age group, Ia0, can be calculated as a function of the following three quantities: (a) the general population incidence rate of ovarian cancer without a prior history of breast cancer in the ath age group, denoted Ra* (referred to as the age-specific adjusted ovarian cancer incidence rate); (b) the age-specific mutation prevalence, denoted {pi}a; and (c) the age-specific relative risk of the mutation, denoted {phi}a.

The overall incidence of ovarian cancer for a given age group in the general population is the weighted average of ovarian cancer incidence with and without a prior history of breast cancer, weighted by the (competing risk of) breast cancer incidence in the general population in that age group. Furthermore, the ovarian cancer incidence among those without a prior history of breast cancer in the general population is a weighted average of the incidence among carriers and noncarriers without breast cancer, weighted by the mutation prevalence. For the ath age group, denote Ia* as the general population incidence of ovarian cancer, Sa* as the incidence of (second primary) ovarian cancer among (first primary) breast cancer cases, and Fa* as the incidence of breast cancer in the general population. Then, the age-specific adjusted ovarian cancer incidence rate is given by:

The age-specific carrier incidence rate Ia0 can then be written as:

In practice, the quantity Sa* can be obtained as a product of the age-specific standardized incidence ratio of ovarian cancer in breast cancer cases and the age-specific incidence of ovarian cancer in the general population.


   ACKNOWLEDGMENTS
 
We thank Dr. Colin Begg for providing the standardized incidence ratios and insightful comments. The control data were obtained from Dr. Jeff Struewing and colleagues from the National Cancer Institute.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by NIH Grant GM60457. Back

2 To whom requests for reprints should be addressed, at Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: (212) 639-2467; Fax: (212) 717-3137; E-mail: satagopj{at}mskcc.org Back

3 The abbreviations used are: SEER, Surveillance, Epidemiology and End Results; CI, confidence interval; MSKCC, Memorial Sloan-Kettering Cancer Center; OCCR, ovarian cancer cluster region. Back

Received 3/12/02; revised 7/10/02; accepted 7/16/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 Appendix 1
 REFERENCES
 

  1. Ries L.A.G. Eisner M. P. Kosary C. L. Hankey B. F. Miller B. A. Clegg L. Edwards B. K. eds. . SEER Cancer Statistics Review, 1973–1999, National Cancer Institute Bethesda, MD (http://seer.cancer.gov/Publications/CSR1973_1999/) 2002.
  2. Ford D., Easton D. F., Stratton M., Narod S., Goldgar D., Devilee P., Bishop D. T., Weber B., Lenoir G., Chang-Claude J., Sobol H., Teare M. D., Struewing J., Arason A., Scherneck S., Peto J., Rebbeck T. R., Tonin P., Neuhausen S., Barkardottir R., Eyfjord J., Lynch H., Ponder B. A., Gayther S. A., Zelada-Hedman M. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am. J. Hum. Genet., 62: 676-698, 1998.[CrossRef][Medline]
  3. Ford D., Easton D. F., Bishop D. T., Narod S. A., Goldgar D. E. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet, 343: 692-695, 1994.[CrossRef][Medline]
  4. Easton D. F., Ford D., Bishop D. T., the Breast Cancer Linkage Consortium. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Am. J. Hum. Genet., 56: 265-271, 1995.[Medline]
  5. The Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J. Natl. Cancer Inst. (Bethesda), 91: 1310-1316, 1999.[Abstract/Free Full Text]
  6. Whittemore A. S., Gong G., Intypre J. Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: results from three U. S. population-based case-control studies of ovarian cancer. Am. J. Hum. Genet., 60: 496-504, 1997.[Medline]
  7. Wacholder S., Hartge P., Struewing J. P., Pee D., McAdams M., Brody L., Tucker M. The kin-cohort study for estimating penetrance. Am. J. Epidemiol., 148: 623-630, 1998.[Abstract/Free Full Text]
  8. Antoniou A. C., Gayther S. A., Stratton J. F., Ponder B. A-J., Easton D. F. Risk models for familial ovarian and breast cancer. Gen. Epi., 18: 183-190, 2000.
  9. Risch H. A., McLaughlin J. R., Cole D. E. C., Rosen B., Bradley L., Kwan E., Jack E., Vesprini D. J., Kuperstein G., Abrahamson J. L-A., Fan I., Wong B., Narod S. A. 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]
  10. Begg C. B. On the use of familial aggregation in population-based case probands for calculating penetrance. J. Natl. Cancer Inst. (Bethesda), 94: 1221-1226, 2002.[Abstract/Free Full Text]
  11. Satagopan J. M., Offit K., Foulkes W., Robson M. E., Wacholder S., Eng C. M., Karp S. E., Begg C. B. The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol. Biomark. Prev., 10: 467-473, 2001.[Abstract/Free Full Text]
  12. Boyd J., Sonada Y., Federici M. G., Bogomolniy F., Rhei E., Maresco D. L., Saigo P. E., Almadrones L. A., Barakat R. R., Brown C. L., Chi D. S., Curtin J. P., Poynor E. A., Hoskins W. J. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. J. Am. Med. Assoc., 283: 2260-2265, 2000.[Abstract/Free Full Text]
  13. Moslehi R., Chu W., Karlan B., Fishman D., Risch H., Fields A., Smotkin D., Ben-David Y., Rosenblatt J., Russo D., Schwartz P., Tung N., Warner E., Rosen B., Friedman J., Brunet J., Narod S. A. BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am. J. Hum. Genet., 66: 1259-1272, 2000.[CrossRef][Medline]
  14. American Society of Human Genetics Report. Statement on informed consent for genetic research. The American Society of Human Genetics. Am. J. Hum. Genet., 59: 471-474, 1996.[Medline]
  15. Struewing J. P., Hargate P., Wacholder S., Baker S. M., Berlin M., McAdams M., Timmerman M. M., Brody L. C., Tucker M. A. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N. Engl. J. Med., 336: 1401-1408, 1997.[Abstract/Free Full Text]
  16. Efron B., Tibshirani R. J. . An Introduction to the Bootstrap, Chapman and Hall New York 1993.
  17. Roa B. B., Boyd A. A., Volick K., Richards C. S. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and. BRCA2. Nat Genet., 14: 185-187, 1996.[CrossRef][Medline]
  18. Gayther S. A., Warren W., Mazoyer S., Russell P. A., Harrington P. A., Chiano M., Seal S., Hamoudi R., van Rensburg E. J., Dunning A. M., Love R., Evans G., Easton D., Clayton D., Stratton M. R., Ponder B. A. J. Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation. Nat. Genet., 11: 428-433, 1997.
  19. Gayther S. A., Mangion J., Russell P., Seal S., Barfoot R., Ponder B. A. J., Stratton M. R., Easton D. Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat. Genet., 15: 103-105, 1997.[CrossRef][Medline]
  20. Levy-Lahad E., Catane R., Eisenberg S., Kaufman B., Hornreich G., Lishinsky E., Shohat M., Weber B. L., Beller U., Lahad A., Halle D. 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., 60: 1059-1067, 1997.[CrossRef][Medline]
  21. Warner E., Foulkes W., Goodwin P., Meschino W., Blondal J., Paterson C., Ozcelik H., Goss P., Allingham-Hawkins D., Hamel N., Di Prospero L., Contiga V., Serruya C., Klein M., Moslehi R., Honeyford J., Liede A., Glendon G., Brunet J. S., Narod S. Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J. Natl. Cancer Inst. (Bethesda), 91: 1241-1247, 1999.[Abstract/Free Full Text]
  22. Thompson D., Easton D., Breast Cancer Linkage Consortium. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am. J. Hum. Genet., 68: 410-419, 2001.[CrossRef][Medline]
  23. Meijers-Heijboer H., van Geel B., van Putten W. L., Henzen-Logmans S. C., Seynaeve C., Menke-Pluymers M. B., Bartels C. C., Verhoog L. C., van den Ouweland A. M., Niermeijer M. F., Berkelmans C. T., Klijn J. G. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N. Engl. J. Med., 354: 154-164, 2001.
  24. Rebbeck T. R., Levin A. M., Eisen A., Snyder C., Watson P., Cannon-Albright L., Isaacs C., Olopade O., Garber J. E., Godwin A. K., Daly M. B., Narod S. A., Neuhausen S. L., Lynch H. T., Weber B. L. Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J. Natl. Cancer Inst., 91: 1475-1479, 1999.[Abstract/Free Full Text]
  25. Kauff N. D., Satagopan J. M., Robson M. E., Scheuer L., Hensley M., Hudis C. A., Ellis N. A., Boyd J., Borgen P. I., Barakat R. R., Norton L., Castiel M., Nafa K., Offit K. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N. Engl. J. Med., 346: 1609-1615, 2002.[Abstract/Free Full Text]
  26. Rebbeck T. R., Lynch H. T., Neuhausen S. L., Narod S. A., Van’t Veer L., Garber J. E., Evans G., Isaacs C., Daly M. B., Matloff E., Olopade O. I., Weber B. I. The Prevention and Observation of Surgical End Points Study Group. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N. Engl. J. Med., 346: 1616-1622, 2002.[Abstract/Free Full Text]
  27. Scheuer L., Kauff N., Robson M., Kelly B., Barakat R., Satagopan J., Ellis N., Hensley M., Boyd J., Borgen P., Norton L., Offit K. Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J. Clin. Oncol., 20: 1260-1268, 2002.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 JCOHome page
N. D. Kauff, S. M. Domchek, T. M. Friebel, M. E. Robson, J. Lee, J. E. Garber, C. Isaacs, D. G. Evans, H. Lynch, R. A. Eeles, et al.
Risk-Reducing Salpingo-Oophorectomy for the Prevention of BRCA1- and BRCA2-Associated Breast and Gynecologic Cancer: A Multicenter, Prospective Study
J. Clin. Oncol., March 10, 2008; 26(8): 1331 - 1337.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
N. D. Kauff and R. R. Barakat
Risk-Reducing Salpingo-Oophorectomy in Patients With Germline Mutations in BRCA1 or BRCA2
J. Clin. Oncol., July 10, 2007; 25(20): 2921 - 2927.
[Abstract] [Full Text] [PDF]

Home page
 JAMAHome page
J. N. Weitzel, V. I. Lagos, C. A. Cullinane, P. J. Gambol, J. O. Culver, K. R. Blazer, M. R. Palomares, K. J. Lowstuter, and D. J. MacDonald
Limited Family Structure and BRCA Gene Mutation Status in Single Cases of Breast Cancer
JAMA, June 20, 2007; 297(23): 2587 - 2595.
[Abstract] [Full Text] [PDF]

Home page
 JAMAHome page
N. D. Kauff and K. Offit
Modeling Genetic Risk of Breast Cancer
JAMA, June 20, 2007; 297(23): 2637 - 2639.
[Full Text] [PDF]

Home page
 JCOHome page
S. Chen and G. Parmigiani
Meta-Analysis of BRCA1 and BRCA2 Penetrance
J. Clin. Oncol., April 10, 2007; 25(11): 1329 - 1333.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
H. A. Risch, J. R. McLaughlin, D. E. C. Cole, B. Rosen, L. Bradley, I. Fan, J. Tang, S. Li, S. Zhang, P. A. Shaw, et al.
Population BRCA1 and BRCA2 Mutation Frequencies and Cancer Penetrances: A Kin-Cohort Study in Ontario, Canada
J Natl Cancer Inst, December 6, 2006; 98(23): 1694 - 1706.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
S. Chen, E. S. Iversen Jr, and G. Parmigiani
In Reply
J. Clin. Oncol., July 10, 2006; 24(20): 3313 - 3314.
[Full Text] [PDF]

Home page
 JCOHome page
S. Chen, E. S. Iversen, T. Friebel, D. Finkelstein, B. L. Weber, A. Eisen, L. E. Peterson, J. M. Schildkraut, C. Isaacs, B. N. Peshkin, et al.
Characterization of BRCA1 and BRCA2 Mutations in a Large United States Sample
J. Clin. Oncol., February 20, 2006; 24(6): 863 - 871.
[Abstract] [Full Text] [PDF]

Home page
 ANN INTERN MEDHome page
U.S. Preventive Services Task Force*
Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility: Recommendation Statement
Ann Intern Med, September 6, 2005; 143(5): 355 - 361.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
A C Antoniou, P D P Pharoah, S Narod, H A Risch, J E Eyfjord, J L Hopper, H Olsson, O Johannsson, A Borg, B Pasini, et al.
Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies
J. Med. Genet., July 1, 2005; 42(7): 602 - 603.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
M. M. Bertagnolli
Surgical Prevention of Cancer
J. Clin. Oncol., January 10, 2005; 23(2): 324 - 332.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
D. A. Levine, P. A. Argenta, C. J. Yee, D. S. Marshall, N. Olvera, F. Bogomolniy, J. A. Rahaman, M. E. Robson, K. Offit, R. R. Barakat, et al.
Fallopian Tube and Primary Peritoneal Carcinomas Associated With BRCA Mutations
J. Clin. Oncol., November 15, 2003; 21(22): 4222 - 4227.
[Abstract] [Full Text] [PDF]

Home page
 ScienceHome page
M.-C. King, J. H. Marks, and J. B. Mandell
Breast and Ovarian Cancer Risks Due to Inherited Mutations in BRCA1 and BRCA2
Science, October 24, 2003; 302(5645): 643 - 646.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Satagopan, J. M.
Right arrow Articles by Offit, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Satagopan, J. M.
Right arrow Articles by Offit, K.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online