Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families

D. Ford, D. F. Easton, M. Stratton, S. Narod, D. Goldgar, P. Devilee, D. T. Bishop, B. Weber, G. Lenoir, J. Chang-Claude, H. Sobol, M. D. Teare, J. Struewing, A. Arason, S. Scherneck, J. Peto, T. R. Rebbeck, P. Tonin, S. Neuhausen, R. Barkardottir & 18 others J. Eyfjord, Henry T. Lynch, B. A J Ponder, S. A. Gayther, J. M. Birch, A. Lindblom, D. Stoppa-Lyonnet, Y. Bignon, A. Borg, U. Hamann, N. Haites, R. J. Scott, C. M. Maugard, H. Vasen, S. Seitz, L. A. Cannon-Albright, A. Schofield, M. Zelada-Hedman

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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

Original languageEnglish
Pages (from-to)676-689
Number of pages14
JournalAmerican Journal of Human Genetics
Volume62
Issue number3
DOIs
StatePublished - Mar 1998

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BRCA2 Gene
BRCA1 Gene
Genetic Heterogeneity
Penetrance
Breast Neoplasms
Confidence Intervals
Mutation
Ovarian Neoplasms
Male Breast Neoplasms
Genes

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Ford, D., Easton, D. F., Stratton, M., Narod, S., Goldgar, D., Devilee, P., ... Zelada-Hedman, M. (1998). Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. American Journal of Human Genetics, 62(3), 676-689. https://doi.org/10.1086/301749

Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. / 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, Henry T.; 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.

In: American Journal of Human Genetics, Vol. 62, No. 3, 03.1998, p. 676-689.

Research output: Contribution to journalArticle

Ford, D, Easton, DF, Stratton, M, Narod, S, Goldgar, D, Devilee, P, Bishop, DT, Weber, B, Lenoir, G, Chang-Claude, J, Sobol, H, Teare, MD, Struewing, J, Arason, A, Scherneck, S, Peto, J, Rebbeck, TR, Tonin, P, Neuhausen, S, Barkardottir, R, Eyfjord, J, Lynch, HT, Ponder, BAJ, Gayther, SA, Birch, JM, Lindblom, A, Stoppa-Lyonnet, D, Bignon, Y, Borg, A, Hamann, U, Haites, N, Scott, RJ, Maugard, CM, Vasen, H, Seitz, S, Cannon-Albright, LA, Schofield, A & Zelada-Hedman, M 1998, 'Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families', American Journal of Human Genetics, vol. 62, no. 3, pp. 676-689. https://doi.org/10.1086/301749
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, Henry T. ; 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. / Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. In: American Journal of Human Genetics. 1998 ; Vol. 62, No. 3. pp. 676-689.
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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",
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T1 - Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families

AU - Ford, D.

AU - Easton, D. F.

AU - Stratton, M.

AU - Narod, S.

AU - Goldgar, D.

AU - Devilee, P.

AU - Bishop, D. T.

AU - Weber, B.

AU - Lenoir, G.

AU - Chang-Claude, J.

AU - Sobol, H.

AU - Teare, M. D.

AU - Struewing, J.

AU - Arason, A.

AU - Scherneck, S.

AU - Peto, J.

AU - Rebbeck, T. R.

AU - Tonin, P.

AU - Neuhausen, S.

AU - Barkardottir, R.

AU - Eyfjord, J.

AU - Lynch, Henry T.

AU - Ponder, B. A J

AU - Gayther, S. A.

AU - Birch, J. M.

AU - Lindblom, A.

AU - Stoppa-Lyonnet, D.

AU - Bignon, Y.

AU - Borg, A.

AU - Hamann, U.

AU - Haites, N.

AU - Scott, R. J.

AU - Maugard, C. M.

AU - Vasen, H.

AU - Seitz, S.

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AU - Zelada-Hedman, M.

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