BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing.

CONTEXT A mutation in the BRCA1 gene may confer substantial risk for breast and/or ovarian cancer. However, knowledge regarding all possible mutations and the relationship between risk factors and mutations is incomplete. OBJECTIVES To identify BRCA1 mutations and to determine factors that best predict presence of a deleterious BRCA1 mutation in patients with breast and/or ovarian cancer. DESIGN A complete sequence analysis of the BRCA1 coding sequence and flanking intronic regions was performed in 798 women in a collaborative effort involving institutions from the United States, Italy, Germany, Finland, and Switzerland. PARTICIPANTS Institutions selected 798 persons representing families (1 person for each family) thought to be at elevated a priori risk of BRCA1 mutation due to potential risk factors, such as multiple cases of breast cancer, early age of breast cancer diagnosis, and cases of ovarian cancer. No participant was from a family in which genetic markers showed linkage to the BRCA1 locus. MAJOR OUTCOME MEASURES Sequence variants detected in this sample are presented along with analyses designed to determine predictive characteristics of those testing positive for BRCA1 mutations. RESULTS In 102 women (12.8%), clearly deleterious mutations were detected. Fifty new genetic alterations were found including 24 deleterious mutations, 24 variants of unknown significance, and 2 rare polymorphisms. In a subset of 71 Ashkenazi Jewish women, only 2 distinct deleterious mutations were found: 185delAG in 17 cases and 5382insC in 7 cases. A bias in prior reports for mutations in exon 11 was revealed. Characteristics of a patient's specific diagnosis (unilateral or bilateral breast cancer, with or without ovarian cancer), early age at diagnosis, Ashkenazi Jewish ethnicity, and family history of cancer were positively associated with the probability of her carrying a deleterious BRCA1 mutation. CONCLUSIONS Using logistic regression analysis, we provide a method for evaluating the probability of a woman's carrying a deleterious BRCA1 mutation for a wide range of cases, which can be an important tool for clinicians as they incorporate genetic susceptibility testing into their medical practice.

[1]  Anne M. Bowcock,et al.  Identification of a RING protein that can interact in vivo with the BRCA1 gene product , 1996, Nature Genetics.

[2]  H. Anton-Culver,et al.  Detection of BRCA1 mutations by the protein truncation test. , 1995, Human molecular genetics.

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

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

[5]  Alfred A. Boyd,et al.  Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2 , 1996, Nature Genetics.

[6]  M. Skolnick,et al.  Comparison of BRCA1 polymorphisms, rare sequence variants and/or missense mutations in unaffected and breast/ovarian cancer populations. , 1996, Human molecular genetics.

[7]  D. B. Berman,et al.  Two distinct origins of a common BRCA1 mutation in breast-ovarian cancer families: a genetic study of 15 185delAG-mutation kindreds. , 1996, American journal of human genetics.

[8]  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.

[9]  E. Solomon,et al.  The 5' end of the BRCA1 gene lies within a duplicated region of human chromosome 17q21. , 1996, Oncogene.

[10]  J. Eyfjörd,et al.  A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes , 1996, Nature Genetics.

[11]  L. Tsui,et al.  A suggested nomenclature for designating mutations , 1993, Human mutation.

[12]  H. Anton-Culver,et al.  BRCA1 R841W: A strong candidate for a common mutation with moderate phenotype , 1996 .

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

[14]  Eugene V. Koonin,et al.  …Functional motifs… , 1996, Nature Genetics.

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

[16]  Yumay Chen,et al.  The Nuclear Localization Sequences of the BRCA1 Protein Interact with the Importin-α Subunit of the Nuclear Transport Signal Receptor* , 1996, The Journal of Biological Chemistry.

[17]  W. Thompson,et al.  The genetic attributable risk of breast and ovarian cancer , 1996, Cancer.

[18]  F. Couch,et al.  Mutations and Polymorphisms in the familial early‐onset breast cancer (BRCA1) gene , 1996, Human mutation.

[19]  F. Couch,et al.  BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. , 1997, The New England journal of medicine.

[20]  Kenneth Offit,et al.  The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1% , 1996, Nature Genetics.

[21]  P. Tonin,et al.  A high incidence of BRCA1 mutations in 20 breast-ovarian cancer families. , 1996, American Journal of Human Genetics.

[22]  J. D. Thompson,et al.  BRCA1 mutations in a population-based sample of young women with breast cancer. , 1996, The New England journal of medicine.

[23]  D. B. Berman,et al.  Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families , 1996, Nature Medicine.

[24]  M. Skolnick,et al.  Statement of the American Society of Clinical Oncology : Genetic testing for cancer susceptibility. Commentaries , 1996 .

[25]  G. Lenoir,et al.  A 1-kb Alu-mediated germ-line deletion removing BRCA1 exon 17. , 1997, Cancer research.