- Email: [email protected]
The genetic epidemiology of BRCA1
during the whole period 1960-84. In a multivariate analysis with adjustments for year of diagnosis, follow-up years, age, and for the number of cancers of the stomach, lung, and uterine cervix, the hazard rate was 12% lower (95% CI 10-13%) in women than in men. Moreover, in more detailed analyses of cutaneous malignant melanoma, women had a 33% lower hazard rate even after adjustment for a larger number of prognostic factors, both clinical and 4
histopathological.
As a corollary, we examined outlook by sex in young individuals with cancer. 5* The hazard rate was similar before age 11 years, but 55-65% lower at ages 11-19. Interestingly, this survival advantage for girls after the age of menarche was confined to epithelial cancers and sarcomas, whereas no difference by sex was seen for malignant diseases in which prognosis is determined by factors other than tumour cell dissemination and distant metastases (ie, brain tumours and
haemopoietic malignant diseases). Do these apparently disparate findings fit into a common hypothesis? We think they do. The observed pattern would be expected if female sex hormones were modifiers of the complex process when disseminated tumour cells form distant metastases-eg, by affecting host immune function or angiogenesis. *A complete reference list is available The Lancet.
on
request from the authors
or
Hans-Olov Adami, Lars Holmberg, Ingemar Persson Department of Cancer Epidemiology, University Hospital, S-751 85 Uppsala, Sweden
1 Adami HO, Malker B, Holmberg L, Persson I, Stone B. The relation between survival and age at diagnosis in breast cancer. N Engl J Med 1986; 315: 559-63. 2 Bergkvist L, Adami HO, Persson I, Bergström R, Krusemo UB. Prognosis after breast cancer diagnosed in women exposed to estrogen and estrogen-progestogen replacement therapy. Am J Epidemiol 1989; 130: 221-28. 3 Adami HO, Sparén P, Bergstrom R, Holmberg L, Krusemo UB, Pontén J. Increasing survival trend after cancer diagnosis in Sweden 1960-1984. J Natl Cancer Inst 1989; 81: 1640-47. 4 Thorn M, Pontén F, Bergström R, Sparén P, Adami HO. Clinical and histopathological predictors of survival in patients with malignant melanoma: a population-based study in Sweden. J Natl Cancer Inst 1994; 86: 761-69. 5 Adami HO, Bergström R, Holmberg L, Klareskog L, Persson I, Pontén J. The effect of female sex hormones on cancer survival: a register-based study in patients younger than 20 years at diagnosis. JAMA 1990; 263: 2189-93.
The
genetic epidemiology of BRCA1
SiR-There are several families with a high risk of early onset breast cancer or ovarian cancer that is caused by inherited mutations in a gene on chromosome 17q known as BRCA 1. The localisation of this gene, and the possibility of its imminent cloning, has generated widespread interest among breast cancer researchers and in the popular press. Unfortunately, there appears to be some confusion surrounding certain aspects of the epidemiology of BRCA1, including the probable frequency of mutations in the general population and the cancer risks they confer. The following points summarise what we believe to be the current state of knowledge of the genetic epidemiology of BJRCL47. These notes were compiled following discussions that took place at a meeting of the Breast Cancer Linkage Consortium held in Paris on May 6 and 7, under the auspices of the European Community Concerted Action on Hereditary Breast Cancer. Constitutional mutations of BRCA account for a very high proportion (over 80%) of families with multiple cases of early onset breast cancer plus ovarian cancer (breast-ovarian
cancer
breast
only
a
families) or multiple cases of ovarian cancer without (ovarian cancer only families). By contrast, minority of families with early onset breast cancer but cancer
no ovarian cancer seem to be linked to BRCA 1.2 In particular, few large site-specific breast cancer families (with for example six or more early onset cases) are linked to BRCA1. Only invasive epithelial ovarian cancers have been shown to occur in RRC/17 families; there is no evidence that borderline or non-epithelial tumours are caused by BRCA1. Breast cancer in males is sometimes hereditary but does not seem to be a feature of BRCA1 families. Most if not all families with both early-onset breast cancer and male breast cancer cases are due to genes other than BRCA1.3 Germline BRCA1 mutations confer a substantial lifetime risk of both breast and ovarian cancer. Based on a study by the Breast Cancer Linkage Consortium, the breast cancer risk has been estimated to be 51% by age 50 and 85% by age 70, and the ovarian cancer risk to be 23% by age 50 and 63% by age 70.4 There are data to suggest that the ovarian cancer risks may vary between families. These risk estimates are derived from studies in families with a striking incidence of cancer and it is possible that BRCA1 mutations that confer substantially lower overall risks may be discovered after BRCA has been identified. Women in BRCA families who have breast cancer are at high risk of both a second primary breast cancer and of ovarian cancer.’ The screening and therapeutic options offered to these women should reflect these high risks. There is evidence that males in BRCA1 families are at increased risk of prostate cancer, and that males and female carriers are at an increased risk of colon cancer. However, these risks are much lower than the breast and ovarian risks; the absolute risks by age 70 have been estimated to be 6% for prostate cancer and 8% for colon cancer.’ BRCA1 mutations explain only a small proportion of all breast and ovarian cancer cases, probably between 1 % and 5% for each site. A higher proportion of breast cancer cases diagnosed below age 40 will be due to RRC/47. The proportion of individuals in the general population who carry BRCA1 mutations is probably between 1 in 2000 and 1 in 500. The proportion of the population who carry a mutation in any breast cancer causing gene is likely to be much higher. At present (and until BRCA1 has been cloned) the only method for detecting BRCA carriers is by linkage analysis, by use of polymorphic genetic markers on chromosome 17. This can only be performed reliably in large breast-ovarian cancer families.
Douglas F Easton, Steven A Narod, Deborah Ford, Michael Steel, on behalf of the Breast Cancer Linkage Consortium Section of Epidemiology, Institute of Cancer Research, Belmont, Surrey SM2 5NG, UK; Division of Medical Genetics, Montreal General Hospital, Montreal, Canada; and School of Biological Sciences, University of St Andrews, St Andrews, UK
1
2
3 4
5
Hall JM, Lee MK, Morrow J, et al. Linkage analysis of early onset familial breast cancer to chromosome 17q21. Science 1990; 250: 1684-89. Easton DF, Bishop DT, Ford D, Crockford GP, and the Breast Cancer Linkage Consortium. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. Am J Hum Genet 1993; 52: 678-701. Stratton MR, Ford D, Neuhausen S, et al. Familial male breast cancer is not linked to BRCA1. Nat Genet (in press). Easton DF, Ford D, Bishop DT, and the Breast Cancer Linkage Consortium. Breast and ovarian cancer incidence in BRCA1 mutation carriers. Am J Hum Genet (in press). Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE, and the Breast Cancer Linkage Consortium. Risks of cancer in BRCA1mutation carriers. Lancet 1994; 343: 692-95.
761
histopathological.
As a corollary, we examined outlook by sex in young individuals with cancer. 5* The hazard rate was similar before age 11 years, but 55-65% lower at ages 11-19. Interestingly, this survival advantage for girls after the age of menarche was confined to epithelial cancers and sarcomas, whereas no difference by sex was seen for malignant diseases in which prognosis is determined by factors other than tumour cell dissemination and distant metastases (ie, brain tumours and
haemopoietic malignant diseases). Do these apparently disparate findings fit into a common hypothesis? We think they do. The observed pattern would be expected if female sex hormones were modifiers of the complex process when disseminated tumour cells form distant metastases-eg, by affecting host immune function or angiogenesis. *A complete reference list is available The Lancet.
on
request from the authors
or
Hans-Olov Adami, Lars Holmberg, Ingemar Persson Department of Cancer Epidemiology, University Hospital, S-751 85 Uppsala, Sweden
1 Adami HO, Malker B, Holmberg L, Persson I, Stone B. The relation between survival and age at diagnosis in breast cancer. N Engl J Med 1986; 315: 559-63. 2 Bergkvist L, Adami HO, Persson I, Bergström R, Krusemo UB. Prognosis after breast cancer diagnosed in women exposed to estrogen and estrogen-progestogen replacement therapy. Am J Epidemiol 1989; 130: 221-28. 3 Adami HO, Sparén P, Bergstrom R, Holmberg L, Krusemo UB, Pontén J. Increasing survival trend after cancer diagnosis in Sweden 1960-1984. J Natl Cancer Inst 1989; 81: 1640-47. 4 Thorn M, Pontén F, Bergström R, Sparén P, Adami HO. Clinical and histopathological predictors of survival in patients with malignant melanoma: a population-based study in Sweden. J Natl Cancer Inst 1994; 86: 761-69. 5 Adami HO, Bergström R, Holmberg L, Klareskog L, Persson I, Pontén J. The effect of female sex hormones on cancer survival: a register-based study in patients younger than 20 years at diagnosis. JAMA 1990; 263: 2189-93.
The
genetic epidemiology of BRCA1
SiR-There are several families with a high risk of early onset breast cancer or ovarian cancer that is caused by inherited mutations in a gene on chromosome 17q known as BRCA 1. The localisation of this gene, and the possibility of its imminent cloning, has generated widespread interest among breast cancer researchers and in the popular press. Unfortunately, there appears to be some confusion surrounding certain aspects of the epidemiology of BRCA1, including the probable frequency of mutations in the general population and the cancer risks they confer. The following points summarise what we believe to be the current state of knowledge of the genetic epidemiology of BJRCL47. These notes were compiled following discussions that took place at a meeting of the Breast Cancer Linkage Consortium held in Paris on May 6 and 7, under the auspices of the European Community Concerted Action on Hereditary Breast Cancer. Constitutional mutations of BRCA account for a very high proportion (over 80%) of families with multiple cases of early onset breast cancer plus ovarian cancer (breast-ovarian
cancer
breast
only
a
families) or multiple cases of ovarian cancer without (ovarian cancer only families). By contrast, minority of families with early onset breast cancer but cancer
no ovarian cancer seem to be linked to BRCA 1.2 In particular, few large site-specific breast cancer families (with for example six or more early onset cases) are linked to BRCA1. Only invasive epithelial ovarian cancers have been shown to occur in RRC/17 families; there is no evidence that borderline or non-epithelial tumours are caused by BRCA1. Breast cancer in males is sometimes hereditary but does not seem to be a feature of BRCA1 families. Most if not all families with both early-onset breast cancer and male breast cancer cases are due to genes other than BRCA1.3 Germline BRCA1 mutations confer a substantial lifetime risk of both breast and ovarian cancer. Based on a study by the Breast Cancer Linkage Consortium, the breast cancer risk has been estimated to be 51% by age 50 and 85% by age 70, and the ovarian cancer risk to be 23% by age 50 and 63% by age 70.4 There are data to suggest that the ovarian cancer risks may vary between families. These risk estimates are derived from studies in families with a striking incidence of cancer and it is possible that BRCA1 mutations that confer substantially lower overall risks may be discovered after BRCA has been identified. Women in BRCA families who have breast cancer are at high risk of both a second primary breast cancer and of ovarian cancer.’ The screening and therapeutic options offered to these women should reflect these high risks. There is evidence that males in BRCA1 families are at increased risk of prostate cancer, and that males and female carriers are at an increased risk of colon cancer. However, these risks are much lower than the breast and ovarian risks; the absolute risks by age 70 have been estimated to be 6% for prostate cancer and 8% for colon cancer.’ BRCA1 mutations explain only a small proportion of all breast and ovarian cancer cases, probably between 1 % and 5% for each site. A higher proportion of breast cancer cases diagnosed below age 40 will be due to RRC/47. The proportion of individuals in the general population who carry BRCA1 mutations is probably between 1 in 2000 and 1 in 500. The proportion of the population who carry a mutation in any breast cancer causing gene is likely to be much higher. At present (and until BRCA1 has been cloned) the only method for detecting BRCA carriers is by linkage analysis, by use of polymorphic genetic markers on chromosome 17. This can only be performed reliably in large breast-ovarian cancer families.
Douglas F Easton, Steven A Narod, Deborah Ford, Michael Steel, on behalf of the Breast Cancer Linkage Consortium Section of Epidemiology, Institute of Cancer Research, Belmont, Surrey SM2 5NG, UK; Division of Medical Genetics, Montreal General Hospital, Montreal, Canada; and School of Biological Sciences, University of St Andrews, St Andrews, UK
1
2
3 4
5
Hall JM, Lee MK, Morrow J, et al. Linkage analysis of early onset familial breast cancer to chromosome 17q21. Science 1990; 250: 1684-89. Easton DF, Bishop DT, Ford D, Crockford GP, and the Breast Cancer Linkage Consortium. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. Am J Hum Genet 1993; 52: 678-701. Stratton MR, Ford D, Neuhausen S, et al. Familial male breast cancer is not linked to BRCA1. Nat Genet (in press). Easton DF, Ford D, Bishop DT, and the Breast Cancer Linkage Consortium. Breast and ovarian cancer incidence in BRCA1 mutation carriers. Am J Hum Genet (in press). Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE, and the Breast Cancer Linkage Consortium. Risks of cancer in BRCA1mutation carriers. Lancet 1994; 343: 692-95.
761