Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium

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, H Lynch, B A Ponder, S A Gayther, JM Birch, A Lindblom, D Stoppa-Lyonnet, Y Bignon, A Borg, U Hamann, Neva Elizabeth Haites, RJ Scott, CM Maugard, H Vasen, S Seitz, LA Cannon-Albright, Andrew Craig Schofield, M Zelada-Hedman

Research output: Contribution to journalArticle

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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
Publication statusPublished - 1 Mar 1998

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

Keywords

  • Adult
  • Aged
  • BRCA2 Protein
  • Breast Neoplasms
  • Female
  • Genes, BRCA1
  • Genetic Heterogeneity
  • Genetic Predisposition to Disease
  • Heterozygote Detection
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Proteins
  • Transcription Factors
  • BRCA1
  • BRCA2
  • Breast Cancer
  • Ovarian Cancer
  • Linkage Analysis
  • Mutation Analysis
  • Cancer, Breast
  • Cancer, Ovarian

Cite this

Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. / 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; Gayther, S A; Birch, JM; Lindblom, A; Stoppa-Lyonnet, D; Bignon, Y; Borg, A; Hamann, U; Haites, Neva Elizabeth; Scott, RJ; Maugard, CM; Vasen, H; Seitz, S; Cannon-Albright, LA; Schofield, Andrew Craig; Zelada-Hedman, M.

In: American Journal of Human Genetics, Vol. 62, No. 3, 01.03.1998, 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, H, Ponder, BA, Gayther, SA, Birch, JM, Lindblom, A, Stoppa-Lyonnet, D, Bignon, Y, Borg, A, Hamann, U, Haites, NE, Scott, RJ, Maugard, CM, Vasen, H, Seitz, S, Cannon-Albright, LA, Schofield, AC & Zelada-Hedman, M 1998, 'Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium', 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, H ; Ponder, B A ; Gayther, S A ; Birch, JM ; Lindblom, A ; Stoppa-Lyonnet, D ; Bignon, Y ; Borg, A ; Hamann, U ; Haites, Neva Elizabeth ; Scott, RJ ; Maugard, CM ; Vasen, H ; Seitz, S ; Cannon-Albright, LA ; Schofield, Andrew Craig ; Zelada-Hedman, M. / Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. 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. The Breast Cancer Linkage Consortium

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, H

AU - Ponder, B A

AU - Gayther, S A

AU - Birch, JM

AU - Lindblom, A

AU - Stoppa-Lyonnet, D

AU - Bignon, Y

AU - Borg, A

AU - Hamann, U

AU - Haites, Neva Elizabeth

AU - Scott, RJ

AU - Maugard, CM

AU - Vasen, H

AU - Seitz, S

AU - Cannon-Albright, LA

AU - Schofield, Andrew Craig

AU - Zelada-Hedman, M

PY - 1998/3/1

Y1 - 1998/3/1

N2 - 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

AB - 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

KW - Adult

KW - Aged

KW - BRCA2 Protein

KW - Breast Neoplasms

KW - Female

KW - Genes, BRCA1

KW - Genetic Heterogeneity

KW - Genetic Predisposition to Disease

KW - Heterozygote Detection

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation

KW - Neoplasm Proteins

KW - Transcription Factors

KW - BRCA1

KW - BRCA2

KW - Breast Cancer

KW - Ovarian Cancer

KW - Linkage Analysis

KW - Mutation Analysis

KW - Cancer, Breast

KW - Cancer, Ovarian

U2 - 10.1086/301749

DO - 10.1086/301749

M3 - Article

VL - 62

SP - 676

EP - 689

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 3

ER -