Carcinogenesis Advance Access published online on April 21, 2007
Carcinogenesis, 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: 608 265 5330; Email: trentham{at}wisc.edu
While germline 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 eleven individual SNPs nor 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 seven (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.
Received February 1, 2007; revised April 9, 2007; accepted April 11, 2007.
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