Genetic variation in TP53 and risk of breast cancer in a population-based case control study.
Whereas germ line missense mutations in the tumor suppressor gene TP53 are associated with a marked predisposition to breast cancer, single-nucleotide polymorphisms (SNPs) may play a more modest role in breast cancer susceptibility. We examined genetic variation in TP53 in relation to breast cancer risk among women aged 20-74 years in a population-based case-control study in Wisconsin, Massachusetts and New Hampshire. Analyses were conducted separately for in situ (176 cases/581 controls) and invasive (1,490 cases/1,291 controls) breast cancer. Oral mucosal DNA samples were genotyped for the codon 72 polymorphism in exon 4 (rs1,042,522), seven intronic SNPs and three SNPs residing in the 3' untranslated region (UTR). Logistic regression was used to obtain age- and state-adjusted odds ratios for individual SNPs. Haplotypes were reconstructed using PHASE software, and the overall association with breast cancer risk was assessed using a global score test. None of the 11 individual SNPs or eight common haplotypes were significantly related to breast carcinoma in situ risk. Among all women, two linked SNPs (D' = 0.99, r(2) = 0.95) on intron 7 (rs12,951,053, rs12,947,788) were associated with modest increases in invasive breast cancer risk; however, associations were only significant for heterozygous carriers. The data suggested that additional variants in the 3' UTR (rs9,894,946), and in two correlated SNPs (D' = 0.94, r(2) = 0.81) in introns 6 (rs1,625,895) and 4 (rs2,909,430), were associated with reduced invasive breast cancer risk among women aged 50 and younger only (P(interaction) < 0.03). These results indicate that common variation in the TP53 gene could modify the risk of invasive breast cancer.
Sprague
Brian L
BL
Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI 53726, USA.
Trentham-Dietz
Amy
A
Garcia-Closas
Montserrat
M
Newcomb
Polly A
PA
Titus-Ernstoff
Linda
L
Hampton
John M
JM
Chanock
Stephen J
SJ
Haines
Jonathan L
JL
Egan
Kathleen M
KM
D000293:Adolescent; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005828:Genetics, Population; D006801:Humans; D008593:Menopause / Q000235:genetics; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53