Effects of common germline genetic variation in cell cycle control genes on breast cancer survival: results from a population-based cohortReport as inadecuate




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Breast Cancer Research

, 10:R47

First Online: 28 May 2008Received: 19 February 2008Revised: 15 May 2008Accepted: 28 May 2008

Abstract

IntroductionSomatic alterations have been shown to correlate with breast cancer prognosis and survival, but less is known about the effects of common inherited genetic variation. Of particular interest are genes involved in cell cycle pathways, which regulate cell division.

MethodsWe examined associations between common germline genetic variation in 13 genes involved in cell cycle control CCND1, CCND2, CCND3, CCNE1, CDK2 p33, CDK4, CDK6, CDKN1A p21, Cip1, CDKN1B p27, Kip1, CDKN2A p16, CDKN2B p15, CDKN2C p18, and CDKN2D p19 and survival among women diagnosed with invasive breast cancer participating in the SEARCH Studies of Epidemiology and Risk factors in Cancer Heredity breast cancer study. DNA from up to 4,470 women was genotyped for 85 polymorphisms that tag the known common polymorphisms minor allele frequency > 0.05 in the genes. The genotypes of each polymorphism were tested for association with survival using Cox regression analysis.

ResultsThe rare allele of the tagging single nucleotide polymorphism SNP rs2479717 is associated with an increased risk of death hazard ratio = 1.26 per rare allele carried, 95% confidence interval: 1.12 to 1.42; P = 0.0001, which was not attenuated after adjusting for tumour stage, grade, and treatment. This SNP is part of a large linkage disequilibrium block, which contains CCND3, BYSL, TRFP, USP49, C6ofr49, FRS3, and PGC. We evaluated the association of survival and somatic expression of these genes in breast tumours using expression microarray data from seven published datasets. Elevated expression of the C6orf49 transcript was associated with breast cancer survival, adding biological interest to the finding.

ConclusionIt is possible that CCND3 rs2479717, or another variant it tags, is associated with prognosis after a diagnosis of breast cancer. Further study is required to validate this finding.

AbbreviationsCIconfidence interval

ECRICEastern Cancer Registration and Information Centre

ERestrogen receptor

HRhazard ratio

LDlinkage disequilibrium

SEARCHStudies of Epidemiology and Risk factors in Cancer Heredity

SNPsingle nucleotide polymorphism

tagSNPtagging single nucleotide polymorphism

TNM = tumournode, metastasis.

Electronic supplementary materialThe online version of this article doi:10.1186-bcr2100 contains supplementary material, which is available to authorized users.

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Author: Elizabeth M Azzato - Kristy E Driver - Fabienne Lesueur - Mitul Shah - David Greenberg - Douglas F Easton - Andrew E Te

Source: https://link.springer.com/







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