Common genetic variation in TP53 and its flanking genes, WDR79 and ATP1B2, and susceptibility to breast cancer.
Germline mutations in the tumor suppressor gene TP53 are associated with high incidence of early-onset malignancies, and somatic mutations occur in 20-40% of all breast cancer cases. We investigated the association of common genetic variation in TP53 and its flanking genes, WDR79 and ATP1B2, with risk for breast cancer. Single nucleotide polymorphisms (SNPs) identified in a re-sequence analysis were genotyped in 2 large case-control studies including 731 cases and 1,124 controls from Norway, and 1,995 cases and 2,296 controls from Poland. Analyses of the pooled data showed no SNPs in TP53 to be significantly associated with risk for breast cancer. However, we found a significant and consistent association with risk for a SNP in exon 1 (R68G) of the 5' neighboring gene WDR79 (rs2287499, OR (95% CI) = 1.08 (0.95-1.23) for CG vs. CC and 1.60 (1.04-2.47) for GG vs. CC, p-trend = 0.01). Stratification by ER and PR status, showed these increases in risk to be limited to ER negative tumors (OR (95% CI) per variant allele: 1.42 (1.18-1.71) p-trend = 0.00009). In addition, 2 TP53 SNPs (rs17887200 3'of STP and rs12951053 in intron 7) showing weak and non-significant overall increases in risk, were also associated with ER negative tumors (1.48 (1.11-1.93) p-trend = 0.01 and 1.29 (1.06-1.58) p-trend = 0.009, respectively). In conclusion, this comprehensive evaluation of common genetic variation in TP53 and its flanking genes found no significant overall associations between SNPs in TP53 and breast cancer risk. However, data suggested that common variation in TP53 or WDR79 could be associated with ER negative breast cancers.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA. garciacm@exchange.nih.gov
Montserrat
M
Garcia-Closas
Vessela
V
Kristensen
Anita
A
Langerød
Ying
Y
Qi
Meredith
M
Yeager
Laurie
L
Burdett
Robert
R
Welch
Jolanta
J
Lissowska
Beata
B
Peplonska
Louise
L
Brinton
Daniela S
DS
Gerhard
Inger Torhild
IT
Gram
Charles M
CM
Perou
Anne-Lise
AL
Børresen-Dale
Stephen
S
Chanock
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000251:Adenosine Triphosphatases / Q000235:genetics*; D001943:Breast Neoplasms / Q000737:chemistry / Q000453:epidemiology* / Q000235:genetics*; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000235:genetics*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D004967:Estrogens / Q000032:analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D018832:Molecular Chaperones; D009664:Norway / Q000453:epidemiology; D016017:Odds Ratio; D011044:Poland / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D019098:Telomerase; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
C504190:ATP1B2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D027682:Cation Transport Proteins; D015816:Cell Adhesion Molecules, Neuronal; D004967:Estrogens; D018832:Molecular Chaperones; D011506:Proteins; D016159:Tumor Suppressor Protein p53; C409880:WDR7 protein, human; D019098:Telomerase; C535133:WRAP53 protein, human; D000251:Adenosine Triphosphatases