A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families

Germline mutations in BRCA1 and BRCA2 genes predispose to hereditary breast and ovarian cancer. Our aim was to find associations between the clinical characteristics and positive mutation status in 148 breast cancer families in order to predict the probability of finding a BRCA mutation in a family. Several factors were associated with mutations in univariate analysis, whereas in multivariate analysis (logistic regression with backward selection) only the age of the youngest breast cancer patient and the number of ovarian cancer cases in a family were independent predictors of BRCA mutations. A logistic model was devised to estimate the probability for a family of harbouring a mutation in either BRCA1 or BRCA2. Altogether, 63 out of 148 families (43%) and 28 out of 29 (97%) mutation carrier families obtained probabilities over 10%. The mean probability was 55% for mutation-positive families and 11% for mutation-negative families. The models by Couch et al (1997) and Shattuck-Eidens et al (1997) previously designed for BRCA1 were also tested for their applicability to distinguish carrier families with mutations in either gene. The probability model should be a useful tool in genetic counselling and focusing the mutation analyses, and thus increasing also the cost-effectiveness of the genetic screening. © 2001 Cancer Research Campaign

[1]  F. Couch,et al.  Genetic heterogeneity in hereditary breast cancer: role of BRCA1 and BRCA2. , 1996, American journal of human genetics.

[2]  K Offit,et al.  BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. , 1997, JAMA.

[3]  W. Foulkes,et al.  The importance of a family history of breast cancer in predicting the presence of a BRCA mutation. , 1999, American Journal of Human Genetics.

[4]  J. Chang-Claude,et al.  Risk Estimation as a Decision-Making Tool for Genetic Analysis of the Breast Cancer Susceptibility Genes , 2002, Disease markers.

[5]  M. King,et al.  Population genetics of BRCA1 and BRCA2. , 1997, American journal of human genetics.

[6]  I. Bleiweiss,et al.  Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients. , 1998, American journal of human genetics.

[7]  D. Berry,et al.  Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. , 1997, Journal of the National Cancer Institute.

[8]  E. Gillanders,et al.  Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

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

[10]  J. Hopper,et al.  Modeling the probability that Ashkenazi Jewish women carry a founder mutation in BRCA1 or BRCA2. , 1999, American journal of human genetics.

[11]  R. Winqvist,et al.  Evidence of founder mutations in Finnish BRCA1 and BRCA2 families. , 1998, American journal of human genetics.

[12]  M. King,et al.  Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families. , 1995, 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]  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.

[15]  C. Lewis,et al.  Risk factors for detecting germline BRCA1 and BRCA2 founder mutations in Ashkenazi Jewish women with breast or ovarian cancer , 1999, Journal of medical genetics.

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

[17]  B. Neyns,et al.  High frequency of BRCA1/2 germline mutations in 42 Belgian families with a small number of symptomatic subjects , 1999, Journal of medical genetics.

[18]  H. Nevanlinna,et al.  Familial breast cancer in southern Finland: how prevalent are breast cancer families and can we trust the family history reported by patients? , 2000, European journal of cancer.

[19]  J Chang-Claude,et al.  Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. , 1998, American journal of human genetics.

[20]  S. Seal,et al.  Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. , 1999, Journal of the National Cancer Institute.

[21]  Nazneen,et al.  Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. , 1999, Journal of the National Cancer Institute.

[22]  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.

[23]  C. Szabó.  Medical genetics : advances in brief Population genetics of BRCA 1 and BRCA 2 , 2022 .

[24]  Jaana M. Hartikainen,et al.  Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland , 2000, European Journal of Human Genetics.

[25]  J. Thompson,et al.  BRCA1 mutations and breast cancer in the general population: analyses in women before age 35 years and in women before age 45 years with first-degree family history. , 1998, JAMA.

[26]  M. Stratton.  Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases , 1997, The Lancet.

[27]  K Holli,et al.  Population-based study of BRCA1 and BRCA2 mutations in 1035 unselected Finnish breast cancer patients. , 2000, Journal of the National Cancer Institute.

[28]  B. Ponder,et al.  A low proportion of BRCA2 mutations in Finnish breast cancer families. , 1997, American journal of human genetics.

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

[30]  G. Giles,et al.  Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Australian Breast Cancer Family Study. , 1999, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[31]  J. Struewing,et al.  Population-based study of risk of breast cancer in carriers of BRCA2 mutation , 1998, The Lancet.

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

[33]  D. Berry,et al.  Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. , 1998, American journal of human genetics.

[34]  W. Foulkes,et al.  Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. , 1999, Journal of the National Cancer Institute.

[35]  O. Kallioniemi,et al.  Low proportion of BRCA1 and BRCA2 mutations in Finnish breast cancer families: evidence for additional susceptibility genes. , 1997, Human molecular genetics.

[36]  E. Mariman,et al.  Characteristics of small breast and/or ovarian cancer families with germline mutations in BRCA1 and BRCA2 , 1999, British Journal of Cancer.