Common variants in the ATM, BRCA1, BRCA2, CHEK2 and TP53 cancer susceptibility genes are unlikely to increase breast cancer risk.
BACKGROUND
Certain rare, familial mutations in the ATM, BRCA1, BRCA2, CHEK2 or TP53 genes increase susceptibility to breast cancer but it has not, until now, been clear whether common polymorphic variants in the same genes also increase risk.


METHODS
We have attempted a comprehensive, single nucleotide polymorphism (SNP)- and haplotype-tagging association study on each of these five genes in up to 4,474 breast cancer cases from the British, East Anglian SEARCH study and 4,560 controls from the EPIC-Norfolk study, using a two-stage study design. Nine tag SNPs were genotyped in ATM, together with five in BRCA1, sixteen in BRCA2, ten in CHEK2 and five in TP53, with the aim of tagging all other known, common variants. SNPs generating the common amino acid substitutions were specifically forced into the tagging set for each gene.


RESULTS
No significant breast cancer associations were detected with any individual or combination of tag SNPs.


CONCLUSIONS
It is unlikely that there are any other common variants in these genes conferring measurably increased risks of breast cancer in our study population.
Baynes
Caroline
C
Cancer Research-UK Dept of Oncology, Cancer Research-UK Genetic Epidemiology Unit and EPIC, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK. cbaynes@srl.cam.ac.uk
Healey
Catherine S
CS
Pooley
Karen A
KA
Scollen
Serena
S
Luben
Robert N
RN
Thompson
Deborah J
DJ
Pharoah
Paul D P
PD
Easton
Douglas F
DF
Ponder
Bruce A J
BA
Dunning
Alison M
AM
D000328:Adult; D000368:Aged; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D064447:Checkpoint Kinase 2; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012306:Risk; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; 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