title: Associations of ATR and CHEK1 single nucleotide polymorphisms with breast cancer.
abstract: DNA damage and replication checkpoints mediated by the ATR-CHEK1 pathway are key to the maintenance of genome stability, and both ATR and CHEK1 have been proposed as potential breast cancer susceptibility genes. Many novel variants recently identified by the large resequencing projects have not yet been thoroughly tested in genome-wide association studies for breast cancer susceptibility. We therefore used a tagging SNP (tagSNP) approach based on recent SNP data available from the 1000 genomes projects, to investigate the roles of ATR and CHEK1 in breast cancer risk and survival. ATR and CHEK1 tagSNPs were genotyped in the Sheffield Breast Cancer Study (SBCS; 1011 cases and 1024 controls) using Illumina GoldenGate assays. Untyped SNPs were imputed using IMPUTE2, and associations between genotype and breast cancer risk and survival were evaluated using logistic and Cox proportional hazard regression models respectively on a per allele basis. Significant associations were further examined in a meta-analysis of published data or confirmed in the Utah Breast Cancer Study (UBCS). The most significant associations for breast cancer risk in SBCS came from rs6805118 in ATR (p=7.6 x 10(-5)) and rs2155388 in CHEK1 (p=3.1 x 10(-6)), but neither remained significant after meta-analysis with other studies. However, meta-analysis of published data revealed a weak association between the ATR SNP rs1802904 (minor allele frequency is 12%) and breast cancer risk, with a summary odds ratio (confidence interval) of 0.90 (0.83-0.98) [p=0.0185] for the minor allele. Further replication of this SNP in larger studies is warranted since it is located in the target region of 2 microRNAs. No evidence of any survival effects of ATR or CHEK1 SNPs were identified. We conclude that common alleles of ATR and CHEK1 are not implicated in breast cancer risk or survival, but we cannot exclude effects of rare alleles and of common alleles with very small effect sizes.
authors.affiliation: Department of Oncology, Institute for Cancer Studies, CRUK/YCR Cancer Research Centre, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Wei-Yu
authors.initials: WY
authors.lastname: Lin
authors.forename: Ian W
authors.initials: IW
authors.lastname: Brock
authors.forename: Dan
authors.initials: D
authors.lastname: Connley
authors.forename: Helen
authors.initials: H
authors.lastname: Cramp
authors.forename: Rachel
authors.initials: R
authors.lastname: Tucker
authors.forename: Jon
authors.initials: J
authors.lastname: Slate
authors.forename: Malcolm W R
authors.initials: MW
authors.lastname: Reed
authors.forename: Sabapathy P
authors.initials: SP
authors.lastname: Balasubramanian
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cannon-Albright
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Camp
authors.forename: Angela
authors.initials: A
authors.lastname: Cox
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D000071877:Checkpoint Kinase 1; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011494:Protein Kinases / Q000235:genetics*; D012306:Risk
chemical_list: D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1