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Genetic Heterogeneity and Penetrance Analysis of the BRCA1 and BRCA2 Genes in Breast Cancer Families

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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.J., Gayther, S.A., Birch, J.M., Lindblom, A., Stoppa-Lyonnet, D., Bignon, Y., Borg, A., Hamann, U., Haites, N., Scott, R.J., Maugard, C.M., Vasen, H., Seitz, S., Cannon-Albright, L.A., Schofield, A., Zelada-Hedman, M.·1998·The American Journal of Human Genetics
DOI 10.1086/301749
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Abstract

The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.

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Cites

  • Risks of cancer in BRCA1-mutation carriers

    FORD, D. (1994) · The Lancet · doi:10.1016/s0140-6736(94)91578-4 · Cited by 1,850 · cited 1×

    “The risks conferred by BRCA1 have been estimated both from linkage data (Easton et al. 1995) and from the study of cancer incidence in carriers within families with disease believed to be linked to the gene (Ford et al. 1994).”
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Metadata

Authors
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. J., Gayther, S. A., Birch, J. M., Lindblom, A., Stoppa-Lyonnet, D., Bignon, Y., Borg, A., Hamann, U., Haites, N., Scott, R. J., Maugard, C. M., Vasen, H., Seitz, S., Cannon-Albright, L. A., Schofield, A., & Zelada-Hedman, M.
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
1998-03
Volume
62
Issue
3
Pages
676-689
ISSN
0002-9297 (ISSN-L)
DOI
10.1086/301749
OpenAlex
W2103970959
Cited by
3,037
References
1
FWCI
77.75
Type
journal article
Language
en
Open access
hybrid
Licence

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