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

Abstract

Introduction: Somatic 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.

Methods: We 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.

Results: The 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.

Conclusion: It 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.

Figure 1

Kaplan-Meier survival function by CCND3 rs2479717 genotype. Kaplan-Meier survival probabilities for women diagnosed with invasive breast cancer in the SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity) breast cancer study by rs2479717 genotype are shown.

Figure 2

Linkage disequilibrium block surrounding CCND3 rs2479717. This 219-kilo-base pair section on chromosome 6 contains the genes CCND3, BYSL, TRFP, USP49, C6ofr49, FRS3, and PGC, mapped relative to common single nucleotide polymorphisms on HapMap CEU. Squares indicate pairwise r² on a grayscale (black = 1, white = 0). The position of rs2479717 is denoted by a red asterisk.

Figure 3

Association of BYSL (a) and C6orf49 (b) breast tumour expression with breast cancer outcome. Forest plots are shown for random-effects meta-analyses of breast tumour expression of BYSL and C6orf49 evaluated by microarray and association with breast cancer recurrence or death. Study-specific hazard ratios with confidence intervals and an overall estimate of effect are shown. Grey boxes indicate the weight of study in random-effects meta-analysis.