Average Risks of Breast and Ovarian Cancer Associated with BRCA1 or BRCA2 Mutations Detected in Case Series Unselected for Family History: A Combined Analysis of 22 Studies
Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, wherea...
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| Published in | American journal of human genetics Vol. 72; no. 5; pp. 1117 - 1130 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Chicago, IL
Elsevier Inc
01.05.2003
University of Chicago Press The American Society of Human Genetics |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0002-9297 1537-6605 1537-6605 |
| DOI | 10.1086/375033 |
Cover
| Abstract | Germline mutations in
BRCA1 and
BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in
BRCA1 or
BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in
BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%–78%) for breast cancer and 39% (18%–54%) for ovarian cancer. The corresponding estimates for
BRCA2 were 45% (31%–56%) and 11% (2.4%–19%). Relative risks of breast cancer declined significantly with age for
BRCA1-mutation carriers (
P trend .0012) but not for
BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for
BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers. |
|---|---|
| AbstractList | Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers ( P trend .0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers. Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers. Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%–78%) for breast cancer and 39% (18%–54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%–56%) and 11% (2.4%–19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers ( P trend .0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers. Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1- mutation carriers by age 70 years were 65% (95% confidence interval 44%–78%) for breast cancer and 39% (18%–54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%–56%) and 11% (2.4%–19%). Relative risks of breast cancer declined significantly with age for BRCA1- mutation carriers ( P trend .0012) but not for BRCA2- mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers. |
| Author | Eyfjord, J.E. Thorlacius, S. Johannsson, O. Hopper, J.L. Loman, N. Evans, D.G. Pasini, B. Manoukian, S. Tulinius, H. Tang, N. Olah, E. Anton-Culver, H. Easton, D.F. Eerola, H. Nevanlinna, H. Syrjäkoski, K. Thompson, D. Pharoah, P.D.P. Antoniou, A. Warner, E. Kallioniemi, O.-P. Gronwald, J. Radice, P. Evans, C. Eccles, D.M. Lalloo, F. Gorski, B. Narod, S. Borg, Å. Lubinski, J. Risch, H.A. Peto, J. Olsson, H. |
| AuthorAffiliation | 1 Cancer Research U.K. Genetic Epidemiology Unit, Department of Public Health, and 2 Cancer Research U.K. Human Cancer Genetics Group, Department of Oncology, University of Cambridge, Cambridge, United Kingdom; 3 Centre for Research on Women’s Health, University of Toronto, Toronto; 4 Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT; 5 Icelandic Cancer Society and 6 University of Iceland, Reykjavík; 7 Centre for Genetic Epidemiology, Department of Public Health, The University of Melbourne, Melbourne; 8 Department of Oncology, Jubileum Institute, Lund University Hospital, Lund, Sweden; 9 National Cancer Institute and 10 FIRC Institute of Molecular Oncology, Milan; 11 Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom; 12 Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong; 13 National Institute of Oncology, Budapest; 14 Epidemiology Division, Department of Medicine, University |
| AuthorAffiliation_xml | – name: 1 Cancer Research U.K. Genetic Epidemiology Unit, Department of Public Health, and 2 Cancer Research U.K. Human Cancer Genetics Group, Department of Oncology, University of Cambridge, Cambridge, United Kingdom; 3 Centre for Research on Women’s Health, University of Toronto, Toronto; 4 Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT; 5 Icelandic Cancer Society and 6 University of Iceland, Reykjavík; 7 Centre for Genetic Epidemiology, Department of Public Health, The University of Melbourne, Melbourne; 8 Department of Oncology, Jubileum Institute, Lund University Hospital, Lund, Sweden; 9 National Cancer Institute and 10 FIRC Institute of Molecular Oncology, Milan; 11 Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom; 12 Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong; 13 National Institute of Oncology, Budapest; 14 Epidemiology Division, Department of Medicine, University of California, Irvine; 15 Hereditary Cancer Centre, Department of Genetics and Pathology, Pomeranian Academy of Medicine, Szczecin, Poland; Departments of 16 Obstetrics and Gynecology and 17 Oncology, Helsinki University Central Hospital, Helsinki; 18 Laboratory of Cancer Genetics, Institute of Medical Technology, Tampere University and Tampere University Hospital, Tampere, Finland; 19 Section of Epidemiology, Institute of Cancer Research, Sutton, United Kingdom; 20 London School of Hygiene and Tropical Medicine, London; and 21 Academic Unit of Medical Genetics and Regional Genetics Service, St. Mary’s Hospital, Manchester, United Kingdom |
| Author_xml | – sequence: 1 givenname: A. surname: Antoniou fullname: Antoniou, A. organization: Cancer Research U.K. Genetic Epidemiology Unit, Department of Public Health – sequence: 2 givenname: P.D.P. surname: Pharoah fullname: Pharoah, P.D.P. email: paul.pharoah@srl.cam.ac.uk organization: Cancer Research U.K. Human Cancer Genetics Group, Department of Oncology, University of Cambridge, Cambridge, United Kingdom – sequence: 3 givenname: S. surname: Narod fullname: Narod, S. organization: Centre for Research on Women’s Health, University of Toronto, Toronto – sequence: 4 givenname: H.A. surname: Risch fullname: Risch, H.A. organization: Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT – sequence: 5 givenname: J.E. surname: Eyfjord fullname: Eyfjord, J.E. organization: Icelandic Cancer Society and University of Iceland – sequence: 6 givenname: J.L. surname: Hopper fullname: Hopper, J.L. organization: Centre for Genetic Epidemiology, Department of Public Health, The University of Melbourne, Melbourne – sequence: 7 givenname: N. surname: Loman fullname: Loman, N. organization: Department of Oncology, Jubileum Institute, Lund University Hospital, Lund, Sweden – sequence: 8 givenname: H. surname: Olsson fullname: Olsson, H. organization: Department of Oncology, Jubileum Institute, Lund University Hospital, Lund, Sweden – sequence: 9 givenname: O. surname: Johannsson fullname: Johannsson, O. organization: Department of Oncology, Jubileum Institute, Lund University Hospital, Lund, Sweden – sequence: 10 givenname: Å. surname: Borg fullname: Borg, Å. organization: Department of Oncology, Jubileum Institute, Lund University Hospital, Lund, Sweden – sequence: 11 givenname: B. surname: Pasini fullname: Pasini, B. organization: National Cancer Institute – sequence: 12 givenname: P. surname: Radice fullname: Radice, P. organization: National Cancer Institute – sequence: 13 givenname: S. surname: Manoukian fullname: Manoukian, S. organization: National Cancer Institute – sequence: 14 givenname: D.M. surname: Eccles fullname: Eccles, D.M. organization: Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom – sequence: 15 givenname: N. surname: Tang fullname: Tang, N. organization: Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong – sequence: 16 givenname: E. surname: Olah fullname: Olah, E. organization: National Institute of Oncology, Budapest – sequence: 17 givenname: H. surname: Anton-Culver fullname: Anton-Culver, H. organization: Epidemiology Division, Department of Medicine, University of California, Irvine – sequence: 18 givenname: E. surname: Warner fullname: Warner, E. organization: Centre for Research on Women’s Health, University of Toronto, Toronto – sequence: 19 givenname: J. surname: Lubinski fullname: Lubinski, J. organization: Hereditary Cancer Centre, Department of Genetics and Pathology, Pomeranian Academy of Medicine, Szczecin, Poland – sequence: 20 givenname: J. surname: Gronwald fullname: Gronwald, J. organization: Hereditary Cancer Centre, Department of Genetics and Pathology, Pomeranian Academy of Medicine, Szczecin, Poland – sequence: 21 givenname: B. surname: Gorski fullname: Gorski, B. organization: Hereditary Cancer Centre, Department of Genetics and Pathology, Pomeranian Academy of Medicine, Szczecin, Poland – sequence: 22 givenname: H. surname: Tulinius fullname: Tulinius, H. organization: Icelandic Cancer Society and University of Iceland – sequence: 23 givenname: S. surname: Thorlacius fullname: Thorlacius, S. organization: Icelandic Cancer Society and University of Iceland – sequence: 24 givenname: H. surname: Eerola fullname: Eerola, H. organization: Departments of Obstetrics and – sequence: 25 givenname: H. surname: Nevanlinna fullname: Nevanlinna, H. organization: Departments of Obstetrics and – sequence: 26 givenname: K. surname: Syrjäkoski fullname: Syrjäkoski, K. organization: Laboratory of Cancer Genetics, Institute of Medical Technology, Tampere University and Tampere University Hospital, Tampere, Finland – sequence: 27 givenname: O.-P. surname: Kallioniemi fullname: Kallioniemi, O.-P. organization: Laboratory of Cancer Genetics, Institute of Medical Technology, Tampere University and Tampere University Hospital, Tampere, Finland – sequence: 28 givenname: D. surname: Thompson fullname: Thompson, D. organization: Cancer Research U.K. Genetic Epidemiology Unit, Department of Public Health – sequence: 29 givenname: C. surname: Evans fullname: Evans, C. organization: Cancer Research U.K. Genetic Epidemiology Unit, Department of Public Health – sequence: 30 givenname: J. surname: Peto fullname: Peto, J. organization: Section of Epidemiology, Institute of Cancer Research, Sutton, United Kingdom – sequence: 31 givenname: F. surname: Lalloo fullname: Lalloo, F. organization: Academic Unit of Medical Genetics and Regional Genetics Service, St. Mary’s Hospital, Manchester, United Kingdom – sequence: 32 givenname: D.G. surname: Evans fullname: Evans, D.G. organization: Academic Unit of Medical Genetics and Regional Genetics Service, St. Mary’s Hospital, Manchester, United Kingdom – sequence: 33 givenname: D.F. surname: Easton fullname: Easton, D.F. organization: Cancer Research U.K. Genetic Epidemiology Unit, Department of Public Health |
| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14804286$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/12677558$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | 2003 The American Society of Human Genetics 2003 INIST-CNRS 2003 by The American Society of Human Genetics. All rights reserved. 2003 |
| Copyright_xml | – notice: 2003 The American Society of Human Genetics – notice: 2003 INIST-CNRS – notice: 2003 by The American Society of Human Genetics. All rights reserved. 2003 |
| CorporateAuthor | Breastcancer-genetics Tumörmikromiljö Department of Clinical Sciences, Lund Section I Tumor microenvironment Faculty of Medicine Institutionen för kliniska vetenskaper, Lund Bröstcancer-genetik Lunds universitet Sektion I Medicinska fakulteten Lund University |
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| DocumentTitleAlternate | BRCA1/BRCA2 Breast and Ovarian Cancer Risks |
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| Keywords | Family study Pathogenesis Risk Breast cancer Malignant tumor Genetic determinism Female genital diseases Genetic disease Case study Mammary gland diseases Ovarian diseases Ovary Risk factor Mammary gland Mutation |
| Language | English |
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| Snippet | Germline mutations in
BRCA1 and
BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on... Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on... Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on... |
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| SubjectTerms | Adult Age Distribution Aged Basic Medicine Biological and medical sciences Breast Neoplasms - epidemiology Breast Neoplasms - genetics Cohort Studies Family Female Female genital diseases Genes, BRCA1 Genes, BRCA2 Genetic Testing - statistics & numerical data Global Health Gynecology. Andrology. Obstetrics Heterozygote Humans Incidence Male Medical and Health Sciences Medical Genetics and Genomics (including Gene Therapy) Medical sciences Medicin och hälsovetenskap Medicinsk genetik och genomik (Här ingår: Genterapi) Medicinska och farmaceutiska grundvetenskaper Middle Aged Mutation Ovarian Neoplasms - epidemiology Ovarian Neoplasms - genetics Pedigree Risk Risk Assessment Tumors |
| Title | Average Risks of Breast and Ovarian Cancer Associated with BRCA1 or BRCA2 Mutations Detected in Case Series Unselected for Family History: A Combined Analysis of 22 Studies |
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