Carcinogenesis Advance Access originally published online on April 21, 2007
Carcinogenesis 2007 28(8):1680-1686; doi:10.1093/carcin/bgm097
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Genetic variation in TP53 and risk of breast cancer in a population-based case–control study
1 Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI 53726, USA
2 University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, WI 53726, USA
3 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20952, USA
4 Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
5 Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, NH 03756, USA
6 Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
7 Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
* To whom correspondence should be addressed. Tel: +1 608 263 1946; Fax: +1 608 265 5330; Email: trentham{at}wisc.edu
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 (1490 cases/1291 controls) breast cancer. Oral mucosal DNA samples were genotyped for the codon 72 polymorphism in exon 4 (rs1042522), 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, r2 = 0.95) on intron 7 (rs12951053, rs12947788) 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 (rs9894946), and in two correlated SNPs (D' = 0.94, r2 = 0.81) in introns 6 (rs1625895) and 4 (rs2909430), were associated with reduced invasive breast cancer risk among women aged 50 and younger only (Pinteraction < 0.03). These results indicate that common variation in the TP53 gene could modify the risk of invasive breast cancer.
Abbreviations: 95% CI, 95% confidence interval; HWE, Hardy–Weinberg equilibrium; OR, odds ratio; SNP, single-nucleotide polymorphism; UTR, untranslated region
Received February 1, 2007; revised April 9, 2007; accepted April 11, 2007.