title: Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility.
abstract: Rare inactivating mutations in BRCA1, BRCA2, ATM, TP53 and CHEK2 confer relative risks for breast cancer between about 2 and more than 10, but more common variants in these genes are generally considered of little or no clinical significance. Under the polygenic model for breast cancer carriers of multiple low-penetrance alleles are at high risk, but few such alleles have been reliably identified. We analysed 1037 potentially functional single nucleotide polymorphisms (SNPs) in candidate cancer genes in 473 women with two primary breast cancers and 2463 controls. Twenty-five of these SNPs were in BRCA1, BRCA2, ATM, TP53 and CHEK2. Among the 1037 SNPs there were a few significant findings, but hardly more than would be expected in this large experiment. There was, however, a significant trend in risk with increasing numbers of variant alleles for the 25 SNPs in BRCA1, BRCA2, ATM, TP53 and CHEK2 (P(trend) = 0.005). For the 21 of these with minor allele frequency <10% this trend was highly significant (P(trend) = 0.00004, odds ratio for 3 or more SNPs = 2.90, 95% CI 1.69-4.97). The individual effects of most of these risk alleles were undetectably small even in this well powered study, but the risk conferred by multiple variants is readily detectable and makes a substantial contribution to susceptibility. A risk score incorporating a suitably weighted sum of all potentially functional variants in these and a few other candidate genes may provide clinically useful identification of women at high genetic risk.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.
authors.forename: Nichola
authors.initials: N
authors.lastname: Johnson
authors.forename: Olivia
authors.initials: O
authors.lastname: Fletcher
authors.forename: Claire
authors.initials: C
authors.lastname: Palles
authors.forename: Matthew
authors.initials: M
authors.lastname: Rudd
authors.forename: Emily
authors.initials: E
authors.lastname: Webb
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Sellick
authors.forename: Isabel
authors.initials: I
authors.lastname: dos Santos Silva
authors.forename: Valerie
authors.initials: V
authors.lastname: McCormack
authors.forename: Lorna
authors.initials: L
authors.lastname: Gibson
authors.forename: Agnes
authors.initials: A
authors.lastname: Fraser
authors.forename: Angela
authors.initials: A
authors.lastname: Leonard
authors.forename: Clare
authors.initials: C
authors.lastname: Gilham
authors.forename: Sean V
authors.initials: SV
authors.lastname: Tavtigian
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Richard
authors.initials: R
authors.lastname: Houlston
authors.forename: Julian
authors.initials: J
authors.lastname: Peto
mesh_terms: D000328:Adult; D000368:Aged; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D064447:Checkpoint Kinase 2; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases