Affiliations of authors: D. Thompson, D. F. Easton, Cancer Research U.K., Genetic Epidemiology Unit, University of Cambridge, United Kingdom.
Correspondence to: Douglas Easton, Ph.D., Cancer Research U.K., Genetic Epidemiology Unit, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK (e-mail: douglas{at}srl.cam.ac.uk).
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
One study (3), based on 33 breast and/or ovarian cancer families in which the disease was linked to the BRCA1 locus, found a statistically significant elevation in the risk of cancers other than breast or ovarian cancer, with particular increases in the risks for prostate cancer and colon cancer. Subsequent studies [e.g., see (810)] attempted to identify associations with other cancer types or to replicate these results, particularly for prostate cancer, but no consensus has emerged. To provide more precise estimates of the risks of other cancers in BRCA1 carriers, we have performed a much larger study, based on 11 847 individuals in 699 families, ascertained from 30 centers across Europe and North America.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
For all men and for women without a breast or ovarian cancer, follow-up started at the date of birth or on January 1, 1960, whichever occurred later, and continued until the date of cancer diagnosis, death, their 80th birthday, or the date of last contact, whichever occurred first. We truncated all observation before January 1, 1960, because earlier population cancer incidence rates are not generally available. For individuals with a breast or ovarian cancer, entry into the cohort was assumed to begin at the first diagnosis of breast or ovarian cancer or on January 1, 1960, whichever occurred later. Exit was as for the rest of the cohort, but with a cancer diagnosis being the first cancer subsequent to the initial breast or ovarian cancer. Thus, women with a non-breast/ovarian cancer before their first breast/ovarian cancer were excluded, because they did not contribute to follow-up. During the follow-up period, 300 individuals were diagnosed with breast cancer, 145 with ovarian cancer, and 744 (392 men, 352 women) with another cancer type; 10 136 (4338 men, 5798 women) individuals died or were censored without a diagnosis of cancer. The total number of person-years of follow-up was 295 850 (26.12 per individual).
Risks to mutation carriers relative to the general population (i.e., relative risks [RRs]) were evaluated with the standardized incidence ratio, which is simply the ratio of observed cases to expected cases in the cohort. The expected number of cases was calculated with the program PYRS (version 1.21) (12). Population rates were from the "Cancer Incidence in Five Continents" publications (1317) and from information provided by the International Agency for Research on Cancer and were specific to country, calendar period, sex, and 5-year age group.
To optimize the amount of information available for analysis and to avoid the bias that would have been incurred by studying only those individuals who had undergone a mutation test, untested individuals were included, weighted by their estimated probability of carrying a mutation. These probabilities were estimated with the program MENDEL (http://www.biomath.medsch.ucla.edu/faculty/klange/software.html) (18), based on an individual's history of breast and/or ovarian cancer, his or her family history of breast and/or ovarian cancer, and the mutation status of their relatives, as we previously described (19). The age-specific incidences of breast and ovarian cancer for carriers were fixed at those previously estimated with a subset of the same dataset (20). Incidence rates for noncarriers were taken from the most recent edition of "Cancer Incidence in Five Continents" (17), averaged over all countries represented in the study. The weighted RR, , took the form:
![]() | [1] |
where Oi is the observed number of cancers in individual i (i.e., 1 if individual i is affected and 0 if individual i is unaffected), Ei is the expected number of cancers (in person-years) in individual i under the null hypothesis, and wi is the estimated carrier probability for individual i. For tested carriers, wi is 1 and for tested noncarriers, wi is 0. RRs were computed, by sex, for each of 28 cancer sites. The RR to noncarriers in the cohort, , was also computed by replacing the wi by (1 wi), the probability of an individual not carrying a mutation, in equation 1
.
Two-sided statistical significance levels for the RRs were estimated by simulation that was performed with Splus (version 3.4; http://www.insightful.com). The simulated number of cases in individual i was drawn from the Poisson distribution with a mean of Ei, under the null hypothesis of no increased risk to carriers. This process was repeated 1000 times to obtain the proportion of simulations resulting in an RR more extreme than that observed.
The RR to carriers and noncarriers were estimated, jointly, in two ways. First, we derived pseudo-maximum likelihood estimates by ignoring the dependence between individuals within the same family. (This procedure provides estimates that are consistent but not fully efficient.) These estimates were obtained iteratively with the EM algorithm (21). The estimated carrier probability for each untested individual was iteratively updated in light of his/her own cancer incidence at the given site and the current RR estimate, and the updated carrier probabilities were then used to produce the revised RR estimates with equation 1. Asymptotic 95% confidence intervals (CIs) were obtained from the variancecovariance matrix, as described previously (19). In most cases, joint estimation of
and
, the RR to noncarriers, led to estimates of
that were not statistically significantly different from 1. To simplify the analyses (and to gain some precision), the estimates of
presented in the "Results" section were derived under the restriction that
was fixed at 1, unless otherwise specified.
For those cancers with some evidence of an elevated risk in mutation carriers, we also computed full maximum likelihood estimates and used MENDEL (18) to perform the pedigree analysis. For each family, the likelihood was computed from the observed and expected number of cancers at the site of interest in each family member, along with the occurrence of breast and ovarian cancer within the family and each individual's carrier status. The incidence rates for breast and ovarian cancer were fixed, as in the previous analysis, and the noncarrier RR was fixed at 1. In practice, the estimates from the two methods were very similar; we have therefore presented only the results from the pseudo-maximum likelihood method.
Separate analyses were also performed stratified by age group (<65 years or 65 years), region (Europe or North America), and the number of patients with breast and/or ovarian cancer in the family (families with three or more patients were compared with smaller families). The 25 families that had been included in the previous BCLC study (3) were analyzed separately to see if they were typical of BRCA1 families.
The cumulative risks of cancer by age t (in the absence of other causes of death), F(t), were estimated with the standard formula (based on the usual assumption that the number of cancers in an individual carrier at age t follows a Poisson distribution):
![]() | [2] |
where j is the RR in age group j in carriers relative to the general population, and µj is the corresponding population incidence rate. Separate RR estimates were used for those carriers aged younger than 65 years and 65 years old or older. Population incidence rates, µj, were those for England and Wales from 1988 through 1992, except for prostate cancer, where separate population rates (and RR estimates) were used for North America and Europe. For cervical cancer, the risks to carriers aged 65 years or older were taken to be the same as those in the general population, because the RR estimate did not converge for the older age group. All statistical tests were two-sided.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
The cohort included 65 people with cancers that were assigned to the category of "other cancers" in tested carriers (12 cases) or untested relatives (53 cases) (there was one more case in a noncarrier). Forty-seven of these 65 cases occurred in women (23 of which were confirmed diagnoses) compared with 8.6 cases expected (female carrier RR = 9.64, 95% CI = 6.36 to 14.61, P<.001; noncarrier RR = 2.60, 95% CI = 1.55 to 4.35, P<.001). The most frequent "other cancer" sites in women were peritoneal (13 cases), "abdomen not otherwise specified" (10 cases), "unspecified intestinal tract" (nine cases), "other female genital organ" (four cases), vagina (two cases), vulva (two cases), unspecified site (two cases), and "secondary and unspecified malignant neoplasm of the lymph nodes" (three cases). RRs for these "other cancers" were similar for women younger than 65 years and for women 65 years old or older (for women aged <65 years, RR = 10.12, 95% CI = 6.35 to 16.12; for women aged 65 years, RR = 8.25, 95% CI = 3.29 to 20.67). In contrast, there was no evidence of an increased risk of other cancers in men (carrier RR = 2.10, 95% CI = 0.74 to 5.90; noncarrier RR = 3.36, 95% CI = 1.27 to 8.90).
Incidence rates for peritoneal cancers were not available for all the populations in this study. However, we derived an RR estimate for this site that was based on rates from 1983 through 1987 for Caucasians from the SEER (Surveillance, Epidemiology and End Results)1 Program (16) (RR = 44.64, 95% CI = 24.86 to 80.15, P<.001).
In addition to the cancer sites summarized in Table 1, seven cancers of the fallopian tube (ICD 183.2) were reported in the cohort, of which six were confirmed. Cancer of the fallopian tube is usually combined with ovarian cancer in published incidence rates, but an approximate RR was obtained by use of incidence rates provided by the East Anglian Cancer Registry (U.K.) for 1995 through 1998 (RR = 49.94, 95% CI = 22.48 to 110.94, P<.001).
The estimated RR to mutation carriers was greater for those younger than 65 years than for those 65 years old or older (Table 2). The RR estimates for those 65 years old or older were not statistically significantly different from 1.0 (for both sexes combined, RR = 0.99, 95% CI = 0.81 to 1.20). The cancer risks in men younger than 65 years old were also very similar to those expected (RR = 1.05, 95% CI = 0.85 to 1.31, P = .64), so that the only marked overall increased risk was in women younger than 65 years (RR = 2.62, 95% CI = 2.15 to 3.18, P<.001). RRs were higher for those younger than 65 years for pancreatic cancer (RR = 3.10, 95% CI = 1.43 to 6.70, P = .008), cervical cancer (RR = 3.84, 95% CI = 2.33 to 6.33, P<.001), and uterine cancer (RR = 3.40, 95% CI = 2.13 to 5.44, P<.001). We also observed some evidence of an increased risk of prostate cancer for those for men younger than 65 years (RR = 1.82, 95% CI = 1.01 to 3.29, P = .05) but not for those 65 years old or older (RR = 0.84, 95% CI = 0.53 to 1.33, P = .45).
|
Estimated cumulative cancer risks (based on the RR estimates) are shown in Table 3 for all cancers and for each cancer site for which there was evidence of a greater than expected risk. Cumulative risks were calculated in the absence of other causes of death and were based on population rates for England and Wales. By the age of 50 years, the estimated cumulative risk of any cancer other than breast or ovarian was 6.16% in female carriers and 2.65% in male carriers. These risks increased to 23.27% and 16.89%, respectively, by the age of 70 years. The estimated cumulative risks of cervical cancer and of other uterine cancers in female carriers were approximately 4% and 2%, respectively, by the age of 70 years, and the risk of pancreatic cancer was approximately 1% for both sexes. The absolute risk of prostate cancer by the age of 70 years was approximately 3%, based on European RRs and population rates for England and Wales, but nearly 8%, based on North American RRs and U.S. population rates.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A critical assumption in this study is that families were ascertained independently of the occurrence of any cancer type other than breast or ovarian. Although these criteria were strictly adhered to by each center, it is of course possible that other cancers may have led to a family's being referred for counseling. Overall, no increased risk to noncarriers was observed (RR = 0.83, 95% CI = 0.72 to 0.95), indicating that any ascertainment bias is likely to be small, although there was a slightly elevated risk to women from European centers (RR = 1.36, 95% CI = 1.09 to 1.69). As a further check on the validity of this assumption, we performed analyses subdivided by numbers of breast or ovarian cancers in the family. The rationale for these analyses is that any referral bias would be more likely in families with few breast and/or ovarian cancers. Families with three or more women with ovarian cancer or with breast cancer diagnosed before the age of 60 years were referred to as large (499 large families), whereas those with fewer than three such women were referred to as small (200 small families). For men, there was no difference in the risk between the groups (P = .5), but for women the RR was somewhat higher in the small families (RR for small families = 3.37, 95% CI = 2.10 to 5.43; RR for large families = 2.17, 95% CI = 1.79 to 2.62; P = .09 for the difference). However, the RR for the large families (for whom referral bias is unlikely to have been a major factor) was very close to that for the whole dataset (RR = 2.30, 95% CI = 1.93 to 2.75; Table 1), confirming that any ascertainment bias is likely to be small.
The increased risks for brain and liver cancer may well be explicable as misreported metastases from other sites, given that the proportion of cancers confirmed is low (21% [5 of 24] brain cancers and 11% [2 of 17] liver cancers compared with 34.3% [255 of 744] overall). In the analysis in which RRs to both carriers and noncarriers are estimated, the estimated RRs for stomach cancer were similar in carriers (1.37) and noncarriers (1.35), suggesting that the observed excess may be a consequence of overreporting, independent of BRCA1 status.
We found a twofold increased RR for pancreatic cancer. This RR was similar in men and women but declined with age. This increased risk is interesting in light of the well established increase in risk of pancreatic cancer in BRCA2 mutation carriers (2225). However, the risk for pancreatic cancer in BRCA1 carriers appears to be more moderate than the risk in BRCA2 carriers; the BCLC study (19) estimated an RR of 3.5 for BRCA2 carriers. Tonin et al. (26) reported that 11 of 91 Ashkenazi Jewish breast cancer families with a founder BRCA1 mutation contained a member with pancreatic cancer, compared with five of 120 Ashkenazi Jewish families without a founder BRCA1 or BRCA2 mutation. In addition, there have been several other anecdotal reports of pancreatic cancers in BRCA1 families [e.g., see (4,27,28)].
The interpretation of the twofold increased RR of colon cancer is more problematic. The increased risk was still statistically significant after adjustment for an increased risk in noncarriers. However, there was a marked deficit in the number of rectal cancers, and when the two sites were considered together, the observed risk was much closer to the expected risk (RR = 1.25, 95% CI = 0.91 to 1.72, P = .16), suggesting that some rectal cancers may have been inaccurately reported as colon cancers. In addition, no excess risk of colorectal cancer was observed in men (RR = 0.93, 95% CI = 0.60 to 1.44, P = .8), but a statistically significantly increased risk was found in women, even for the two sites combined (RR = 1.94, 95% CI = 1.21 to 3.10, P = .006), suggesting that some of this increased risk may be from ovarian cancers misdiagnosed as colon cancers. The earlier BCLC study (3) reported a fourfold increased RR for colon cancer in BRCA1 carriers. Since then, one BRCA1 family with seven cases of breast cancer, one case of ovarian cancer, and seven cases of colon cancer has been reported (29), but there has been no further strong evidence that colon cancer is part of the BRCA1 phenotype (30).
The analysis of this cohort provides weak evidence for a modestly elevated risk for prostate cancer at younger ages in BRCA1 mutation carriers (RR = 1.82 for those younger than 65 years, 95% CI = 1.01 to 3.29, P = .05) but no evidence of an elevated risk in those 65 years old or older. When the analysis was restricted to the European centers, where the effects of screening would be much less important, the estimated RR for prostate cancer in those younger than 65 years was somewhat larger (RR = 2.53, 95% CI = 1.10 to 5.82, P = .026). However, this risk is still modest in comparison with the risk in BRCA2 carriers; the BCLC study (19) estimated an RR of approximately 5 overall, increasing to more than 7 in men younger than 65 years.
The original BCLC BRCA1 analysis (3) of 33 families reported an RR for prostate cancer of 3.33, but the results of more recent studies have been conflicting. Some studies in Ashkenzi Jewish populations found modest evidence for BRCA1's involvement in prostate cancer (4,9,31,32), but others found no evidence (3335). Studies in non-Jewish populations have found little or no evidence of an increased risk for prostate cancer in BRCA1 mutation carriers (8,10,36).
We observed statistically significantly increased risks of cervical and other uterine cancers in BRCA1 mutation carriers. Again, it is possible that some of these cancers may result from the misreporting of ovarian cancer. Another possibility is that the increased number of endometrial cancers may be associated with tamoxifen use, which may increase the risk of endometrial cancer (3739). Tamoxifen is a widely prescribed treatment for breast cancer, but its use in unaffected women has largely been restricted to recent chemoprevention trials. Comprehensive information on tamoxifen use was not available in this study, but the large majority of endometrial cancer cases occurred before 1990 and, hence, predate the chemoprevention trials. Restricting the analysis to women unaffected with breast cancer did not materially change the results (RR = 3.13, 95% CI = 1.73 to 5.67, P<.001), suggesting that the use of tamoxifen is unlikely to have been a major confounder.
Several groups have pursued a possible association between BRCA1 mutations and uterine papillary serous carcinoma (UPSC), a particularly virulent form of uterine cancer that accounts for 5%10% of uterine cancer cases. UPSC is histologically similar to papillary serous carcinoma of the peritoneum and to papillary serous ovarian cancer, the most common histologic form of ovarian cancer in BRCA1 mutation carriers (31). An Israeli study (40) found that two of nine Ashkenazi Jewish women with UPSC carried a BRCA1 mutation, but other studies [e.g., see (41)] have not replicated this observation.
The greater than expected risk of cervical cancer in mutation carriers was observed in the European centers and in the North American centers. No statistically significantly increased risk was observed in European noncarriers, but the North American centers did show an increased risk in noncarriers. The rate of pathologic confirmation was markedly higher in the European centers (62.5% [10 of 16] versus 25.0% [5 of 20]), suggesting that some of the increased risk in North America may result from misspecifying screening-detected cervical intraepithelial neoplasia as invasive cancer.
The highly statistically significantly increased risk of cancer of the fallopian tube is consistent with previous case reports [e.g., see (26,4244)]. The estimated RR was comparable to that for ovarian cancer and is equivalent to an absolute risk of 1.6% by the age of 80 years. It can be difficult to distinguish fallopian tube cancer from ovarian cancer, particularly at advanced stages, and because it is more likely that an ambiguous tumor would be described as ovarian cancer, it is possible that the risk for fallopian tube cancer is underestimated. Clearly, this risk for fallopian tube cancer needs to be borne in mind when prophylactic surgery is considered.
The RR estimate for peritoneal cancer was also comparable to that for ovarian cancer. Peritoneal cancers are thought to develop from the peritoneal surfaces of the abdomen and pelvis and have the same histologic appearance as papillary serous ovarian carcinomas. BRCA1 mutations have been reported specifically in women with papillary serous carcinoma of the peritoneum (45,46). There have also been several reports of peritoneal cancers occurring in women after they have had an oophorectomy, including those with a family history of ovarian cancer [e.g., see (47,48)]. Of the 13 female patients in our cohort, one had had a prophylactic oophorectomy a year before her peritoneal cancer was diagnosed.
In conclusion, these results establish important differences in the site-specific cancer risks associated with BRCA1 and BRCA2 mutations that may reflect essential functional differences. BRCA2 mutations are associated with increased risks for male breast cancer, prostate cancer, and pancreatic cancer and are associated with possible increased risks for gallbladder cancer, stomach cancer, and melanoma (19). Thus, there are important management implications for male BRCA2 carriers. In contrast, the major increased risks in BRCA1 carriers, aside from that for breast cancer, are for ovarian cancer and other gynecologic or abdominal cancers in women. The overall cancer risk and associated mortality to women who carry a BRCA1 mutation is considerably increased, but there is little increased risk to men who carry a BRCA1 mutation. Such risk estimates can guide the future management of BRCA1 carriers.
![]() |
APPENDIX |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Cancer Research U.K. Genetic Epidemiology Unit, Cambridge, U.K. (coordinating center): D. Easton, D. Thompson, L. McGuffog; University of Pennsylvania, Philadelphia: B. Weber [97]; Institut Curie, Paris, France: S. Gad, D. Stoppa-Lyonnet [76]; University of Vienna, Vienna, Austria: V. Korn, R. Kroiss, G. Langbauer, D. Muhr, T. Wagner [48]; Creighton University, Omaha, NE, and International Agency for Research on Cancer, Lyon, France: D. Goldgar, G. Lenoir, H. T. Lynch, S. Narod, O. Sinilnikova [46]; Cancer Research U.K. Human Cancer Genetics Research Group, Cambridge: S. Gayther, B. Ponder, A. Taylor [43]; Erasmus Medical Centre and Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands: J. G. M. Klijn, H. Meijers-Heijboer [42]; National Institute of Oncology, Budapest, Hungary: E. Olah [35]; Institut Paoli Calmettes, Marseille, France: H. Sobol, F. Eisinger [34]; University of Lund, Sweden: A. Borg, O. Johannsson, N. Loman, H. Olsson [32]; Deutsches Krebsforschungszentrum, Heidelberg, Germany, and University of Würzburg, Würzburg, Germany: J. Chang-Claude, U. Hamann, B. H. F. Weber [31]; Karolinska Hospital, Department of Molecular Medicine, Stockholm, Sweden: B. Arver, A. Lindblom [31]; Institute of Cancer Research, Sutton, U.K.: R. Eeles, D. Ford, J. Peto, M. Stratton, [25]; University of Utah, Salt Lake City: L. Cannon-Albright, S. L. Neuhausen [23]; Helsinki University Central Hospital, Helsinki, Finland: H. Eerola, H. Nevanlinna [20]; Centre Jean Perrin, Clermont-Ferrand: Y. Bignon [17]; National Cancer Institute, Milan, Italy: S. Manoukian, B. Pasini, M. A. Pierotti, P. Radice [15]; Duke University Medical Center Comprehensive Cancer Center, Durham, NC: A. Futreal [15]; University of Leiden and Foundation for the Detection of Hereditary Tumours, Leiden, The Netherlands: C. J. Cornelisse, P. Devilee, H. Vasen [13]; Centre René Gauducheau, Nantes, France: C. M. Maugard [9]; Lothian Breast Cancer Family Clinic, Edinburgh and Tayside Breast Cancer Family Clinic, Dundee, Scotland: J. Campbell, L. McCleish, M. Stell [8]; Max-Delbrück-Centrum für Molekulare Medizin, Tumorgenetik, Berlin, Germany: S. Scherneck, S. Seitz [8]; Imperial Cancer Research Fund, Leeds, U.K.: D. T. Bishop, G. Crockford [7]; Fundación Jiménez Diaz, Madrid, Spain: J. Benitez, A. Osorio [6]; McGill University, Montreal, Canada: S. Narod (currently at University of Toronto) [6]; National Cancer Institute, Bethesda, MD: J. Struewing [6]; Heinrich-Heine Universität, Düsseldorf, Germany: M. W. Beckmann, B. Kuschel [5]; University of Aberdeen, Aberdeen, U.K.: N. Haites, A. Schofield [1]; Centre for Cancer Epidemiology, Manchester, U.K.: G. Evans [1].
![]() |
NOTES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
See "Appendix" for list of consortium members who contributed to this study.
The coordination and analysis of this study have been supported by Cancer Research U.K. and by a Concerted Action from the European Union. Data collection has been supported by Cancer Research U.K., the Imperial Cancer Research Fund, The Swedish Cancer Society, Fondation de France, European Union grants Biomed2 BMH4-CT96-1133 and SAF 96/0192, the Nordic Cancer Union, The Cancer Society and Cancer Registry of Finland, the Canadian Breast Cancer Research Initiative, the Ministry of Education Szechenyi project NFKP1/48/2001 (to E. Olah), the Italian Association for Cancer Research, the Italian Foundation for Cancer Research, Public Health Service grants 1R01CA81203-01A1 and RO1CA77415 (from the National Cancer Institute [NCI], National Institutes of Health [NIH], Department of Health and Human Services [DHHS] to D. E. Goldgar and S. L. Neuhausen, respectively), and American Cancer Society (ACS) grant RPG-99-181-01-CCE, with partial support by a generous contribution to the ACS from the Kirby Foundation (to S. L. Neuhausen), and the Utah Cancer Registry (supported by grant PC-67000 from the NCI, NIH, DHHS), with additional support from the Utah State Department of Health and the University of Utah). D. F. Easton is a Principal Research Fellow of Cancer Research U.K.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1 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]
2 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]
3 Ford D, Easton DF, Bishop DT, Narod SA, Goldgar D. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 1994;343:6925.[Medline]
4 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.
5 Antoniou AC, Gayther SA, Stratton JF, Ponder BA, Easton DF. Risk models for familial ovarian and breast cancer. Genet Epidemiol 2000;18:17390.[Medline]
6 Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group. Br J Cancer 2000;83:13018.[Medline]
7 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.
8 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]
9 Vazina A, Baniel J, Yaacobi Y, Shtriker A, Engelstein D, Leibovitz I, et al. The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel. Br J Cancer 2000;83:4636.[Medline]
10 Gayther SA, de Foy KA, Harrington P, Pharoah P, Dunsmuir WD, Edwards SM, et al. The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. Cancer Res 2000;60:45138.
11 World Health Organization International Classification of Diseases: manual of the international statistical classification of diseases, injuries and causes of death. Geneva (Switzerland): World Health Organization; 1977.
12 Coleman MP, Hermon C, Douglas A. Person-years (PYRS)a Fortran program for cohort study analysis. IARC Internal Report No. 89/006. Lyon (France): IARC; 1989.
13 Waterhouse JA, Muir C, Correa P, Powell J, editors. Cancer incidence in five continents. Vol III. IARC Sci Publ 15. Lyon (France): IARC; 1976.
14 Waterhouse J, Muir C, Shanmugaratnam K, Powell J, editors. Cancer incidence in five continents. Vol IV. IARC Sci Publ 42. Lyon (France): IARC; 1982.
15 Muir C, Waterhouse J, Mack T, Powell J, Whelan S, editors. Cancer incidence in five continents. Vol V. IARC Sci Publ 88. Lyon (France): IARC; 1987.
16 Parkin DM, Muir CS, Whelan SL, Gao YT, Ferlay J, Powell J, editors. Cancer incidence in five continents. Vol VI. IARC Sci Publ 120. Lyon (France): IARC; 1992.
17 Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J, editors. Cancer incidence in five continents. Vol VII. IARC Sci Publ 143. Lyon (France): IARC; 1997.
18 Lange K, Weeks D. Programs for pedigree analysis: MENDEL, FISHER and dGENE. Genet Epidemiol 1988;5:4712.[Medline]
19 Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 1999;91:13106.
20 Thompson D, Easton D. Variation in BRCA1 cancer risks by mutation position. Cancer Epidemiol Biomarkers Prev 2002,11:32936.
21 Dempster AP, Laird NM, Rubin DB. Maximum likelihood from incomplete data via the EM algorithm (with discussion). J Roy Stat Soc Series B 1977;39:138.
22 Schutte M, da Costa LT, Hahn SA, Moskaluk C, Hoque AT, Rozenblum E, et al. Identification by representational difference analysis of a homozygous deletion in pancreatic carcinoma that lies within the BRCA2 region. Proc Natl Acad Sci U S A 1995;92:59504.
23 Phelan CM, Lancaster JM, Tonin P, Gumbs C, Cochran C, Carter R, et al. Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families. Nat Genet 1996;13:1202.[Medline]
24 Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, et al. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 1996;56:53604.[Abstract]
25 Ozcelik H, Schocker B, Di Nicola N, Shi XH, Langer B, Moore M, et al. Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet 1997;16:178.[Medline]
26 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]
27 Lal G, Liu G, Schmocker B, Kaurah P, Ozcelik H, Narod SA, et al. Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations. Cancer Res 2000;60:40916.
28 Simard J, Tonin P, Durocher F, Morgan K, Rommens J, Gingras S, et al. Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. Nat Genet 1994;8:3928.[Medline]
29 Peelen T, de Leeuw W, van Lent K, Morreau H, van Eijk R, van Vliet M, et al. Genetic analysis of a breast-ovarian cancer family, with 7 cases of colorectal cancer linked to BRCA1, fails to support a role for BRCA1 in colorectal tumorigenesis. Int J Cancer 2000;88:77882.[Medline]
30 Chen-Shtoyerman R, Figer A, Rath P, Yeremin L, Bar Meir S, Friedman E, et al. The frequency of the predominant Jewish mutations in BRCA1 and BRCA2 in unselected Ashkenazi colorectal cancer patients. Br J Cancer 2001;84:4757.[Medline]
31 Moslehi R, Chu W, Karlan B, Fishman D, Risch H, Fields A, et al. BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am J Hum Genet 2000;66:125972.[Medline]
32 Warner E, Foulkes W, Goodwin P, Meschino W, Blondal J, Paterson C, et al. Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst 1999;91:12417.
33 Wilkens EP, Freije D, Xu J, Nusskern DR, Suzuki H, Isaacs SD, et al. No evidence for a role of BRCA1 or BRCA2 mutations in Ashkenazi Jewish families with hereditary prostate cancer. Prostate 1999;39:2804.[Medline]
34 Hubert A, Peretz T, Manor O, Kaduri L, Wienberg N, Lerer I, et al. The Jewish Ashkenazi founder mutations in the BRCA1/BRCA2 genes are not found at an increased frequency in Ashkenazi patients with prostate cancer. Am J Hum Genet 1999;65:9214.[Medline]
35 Nastiuk KL, Mansukhani M, Terry MB, Kularatne P, Rubin MA, Melamed J, et al. Common mutations in BRCA1 and BRCA2 do not contribute to early prostate cancer in Jewish men. Prostate 1999;40:1727.[Medline]
36 Langston AA, Stanford JL, Wicklund KG, Thompson JD, Blazej RG, Ostrander EA, et al. Germ-line BRCA1 mutations in selected men with prostate cancer. Am J Hum Genet 1996;58:8814.[Medline]
37 Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project B-14. J Natl Cancer Inst 1994;86:52737.[Abstract]
38 Rutqvist LE, Johansson H, Signomklao T, Johansson U, Fornander T, Wilking N. Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. J Natl Cancer Inst 1995;87:64551.[Abstract]
39 Katase K, Sugiyama Y, Hasumi K, Yoshimoto M, Kasumi F. The incidence of subsequent endometrial carcinoma with tamoxifen use in patients with primary breast carcinoma. Cancer 1998;82:1698703.[Medline]
40 Lavie O, Hornreich G, Ben Arie A, Renbaum P, Levy-Lahad E, Beller U. BRCA1 germline mutations in women with uterine serous papillary carcinoma. Obstet Gynecol 2000;96:2832.
41 Goshen R, Chu W, Elit L, Pal T, Hakimi J, Ackerman I, et al. Is uterine papillary serous adenocarcinoma a manifestation of the hereditary breast-ovarian cancer syndrome? Gynecol Oncol 2000;79:47781.[Medline]
42 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]
43 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]
44 Aziz S, Kuperstein G, Rosen B, Cole D, Nedelcu R, McLaughlin J, et al. A genetic epidemiological study of carcinoma of the fallopian tube. Gynecol Oncol 2001;80:3415.[Medline]
45 Bandera CA, Muto MG, Schorge JO, Berkowitz RS, Rubin SC, Mok SC. BRCA1 gene mutations in women with papillary serous carcinoma of the peritoneum. Obstet Gynecol 1998;92:596600.
46 Schorge JO, Muto MG, Welch WR, Bandera CA, Rubin SC, Bell DA, et al. Molecular evidence for multifocal papillary serous carcinoma of the peritoneum in patients with germline BRCA1 mutations. J Natl Cancer Inst 1998;90:8415.
47 Tobacman JK, Greene MH, Tucker MA, Costa J, Kase R, Fraumeni JF Jr. Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian-cancer-prone families. Lancet 1982;2:7957.[Medline]
48 Piver MS, Jishi MF, Tsukada Y, Nava G. Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer. Cancer 1993;71:27515.[Medline]
Manuscript received January 11, 2002; revised June 27, 2002; accepted July 2, 2002.
This article has been cited by other articles in HighWire Press-hosted journals:
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |