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

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.

[1]  L. Essioux,et al.  Loss of heterozygosity and linkage analysis in breast carcinoma: indication for a putative third susceptibility gene on the short arm of chromosome 8. , 1995, Oncogene.

[2]  J. Rommens,et al.  The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds , 1996, Nature Genetics.

[3]  D. Easton,et al.  Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. , 1993, American journal of human genetics.

[4]  D. Clayton,et al.  Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype–phenotype correlation , 1995, Nature Genetics.

[5]  D J Prockop,et al.  Conformation-sensitive gel electrophoresis for rapid detection of single-base differences in double-stranded PCR products and DNA fragments: evidence for solvent-induced bends in DNA heteroduplexes. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[6]  D E Goldgar,et al.  Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12-13. , 1997, American journal of human genetics.

[7]  M. King,et al.  THRA1 and D17S183 flank an interval of < 4 cM for the breast-ovarian cancer gene (BRCA1) on chromosome 17q21. , 1993, American journal of human genetics.

[8]  J. Weber,et al.  Dinucleotide repeat polymorphism at the D15S87 locus. , 1990, Nucleic acids research.

[9]  C. Larsson,et al.  Mutation analysis of the BRCA2 gene in 49 site–specific breast cancer families , 1996, Nature Genetics.

[10]  M. King,et al.  Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q , 1994, Nature Genetics.

[11]  Steven E. Bayer,et al.  A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. , 1994, Science.

[12]  P. Laurent-Puig,et al.  BRCA1 sequence variations in 160 individuals referred to a breast/ovarian family cancer clinic. Institut Curie Breast Cancer Group. , 1997, American journal of human genetics.

[13]  P. Tonin,et al.  Mutations in BRCA1 and BRCA2 in breast cancer families: are there more breast cancer-susceptibility genes? , 1997, American journal of human genetics.

[14]  GROWTH RETARDATION AND TUMOUR INHIBITION BY BRCA1 , 1996 .

[15]  R C Elston,et al.  'Twixt cup and lip: how intractable is the ascertainment problem? , 1995, American journal of human genetics.

[16]  D. Easton,et al.  Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. , 1995, American journal of human genetics.

[17]  J. Weber,et al.  Closing in on a breast cancer gene on chromosome 17q. , 1992, American journal of human genetics.

[18]  Jing Li,et al.  Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome , 1997, Nature Genetics.

[19]  D. Bentley,et al.  Identification of the breast cancer susceptibility gene BRCA2 , 1995, Nature.

[20]  D. Easton,et al.  Genetic heterogeneity of breast-ovarian cancer revisited. Breast Cancer Linkage Consortium. , 1995, American journal of human genetics.

[21]  J. Ott,et al.  Strategies for multilocus linkage analysis in humans. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Cécile Fizames,et al.  The 1993–94 Généthon human genetic linkage map , 1994, Nature Genetics.

[23]  Å. Borg,et al.  Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer. , 1997, American journal of human genetics.

[24]  A A Schäffer,et al.  Faster sequential genetic linkage computations. , 1993, American journal of human genetics.

[25]  A. Whittemore,et al.  An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families. Breast Cancer Linkage Consortium. , 1995, American journal of human genetics.

[26]  Darryl Shibata,et al.  Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis , 1997, Nature Genetics.

[27]  D. Easton,et al.  Risks of cancer in BRCA1-mutation carriers , 1994, The Lancet.

[28]  P. Schlag,et al.  Strong indication for a breast cancer susceptibility gene on chromosome 8p12-p22: linkage analysis in German breast cancer families , 1997, Oncogene.

[29]  H. Mefford,et al.  BRCA2 in American families with four or more cases of breast or ovarian cancer: recurrent and novel mutations, variable expression, penetrance, and the possibility of families whose cancer is not attributable to BRCA1 or BRCA2. , 1997, American journal of human genetics.

[30]  J. Klijn,et al.  Rapid detection of BRCA1 mutations by the protein truncation test , 1995, Nature Genetics.

[31]  M. King,et al.  Linkage of early-onset familial breast cancer to chromosome 17q21. , 1990, Science.

[32]  S. Seal,et al.  Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. , 1994, Science.

[33]  S. Seal,et al.  Brave new now , 2013, Nature Genetics.

[34]  D. F. Easton,et al.  Genetic linkage analysis in familial breast and ovarian cancer: Results from 214 families , 1993 .

[35]  M. King,et al.  Growth retardation and tumour inhibition by BRCA1 , 1996, Nature Genetics.

[36]  B. Ponder,et al.  Rapid detection of regionally clustered germ-line BRCA1 mutations by multiplex heteroduplex analysis. UKCCCR Familial Ovarian Cancer Study Group. , 1996, American journal of human genetics.

[37]  P. Hartge,et al.  The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. , 1997, The New England journal of medicine.

[38]  N Risch,et al.  Genetic analysis of breast cancer in the cancer and steroid hormone study. , 1991, American journal of human genetics.

[39]  G. Pals,et al.  A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families. , 1997, American journal of human genetics.