Abstract
We conducted a case-control study of renal cancer (987 cases and 1298 controls) in Central and Eastern Europe and analyzed genomic DNA for 319 tagging single-nucleotide polymorphisms (SNPs) in 21 genes involved in cellular growth, differentiation and apoptosis using an Illumina Oligo Pool All (OPA). A haplotype-based method (sliding window analysis of consecutive SNPs) was used to identify chromosome regions of interest that remained significant at a false discovery rate of 10%. Subsequently, risk estimates were generated for regions with a high level of signal and individual SNPs by unconditional logistic regression adjusting for age, gender and study center. Three regions containing genes associated with renal cancer were identified: caspase 1/5/4/12(CASP 1/5/4/12), epidermal growth factor receptor (EGFR), and insulin-like growth factor binding protein-3 (IGFBP3). We observed that individuals with CASP1/5/4/12 haplotype (spanning area upstream of CASP1 through exon 2 of CASP5) GGGCTCAGT were at higher risk of renal cancer compared to individuals with the most common haplotype (OR:1.40, 95% CI:1.10–1.78, p-value = 0.007). Analysis of EGFR revealed three strong signals within intron 1, particularly a region centered around rs759158 with a global p = 0.006 (GGG: OR:1.26, 95% CI:1.04–1.53 and ATG: OR:1.55, 95% CI:1.14–2.11). A region in IGFBP3 was also associated with increased risk (global p = 0.04). In addition, the number of statistically significant (p-value<0.05) SNP associations observed within these three genes was higher than would be expected by chance on a gene level. To our knowledge, this is the first study to evaluate these genes in relation to renal cancer and there is need to replicate and extend our findings. The specific regions associated with risk may have particular relevance for gene function and/or carcinogenesis. In conclusion, our evaluation has identified common genetic variants in CASP1, CASP5, EGFR, and IGFBP3 that could be associated with renal cancer risk.
Highlights
Renal cancer is among the most commonly diagnosed cancers in men and women in the United States [1] and Eastern Europe [2]
We conducted an exploratory analysis of 319 single-nucleotide polymorphisms (SNPs) in or around 21 genes involved in cell growth/differentiation and apoptosis pathways in relation to renal cancer risk
We identified both haplotypes and SNPs in CASP1/5/4/12, epidermal growth factor receptor (EGFR), and insulin-like growth factor binding protein-3 (IGFBP3) that were statistically significantly associated with risk of renal cancer
Summary
Renal cancer is among the most commonly diagnosed cancers in men and women in the United States [1] and Eastern Europe [2]. Alterations in genes involved in such pathways are likely to contribute to cancer risk Based on this logic, we identified genes involved in cell growth and differentiation (AKR1C3, EGF, EGFR, IGFBP3, IGFBP5, PPARG, TGFA, VCAM1, and VEGF) and apoptosis (CASP1, CASP2, CASP3, CASP4, CASP5, CASP6, CASP7, CASP8, CASP9, CASP10, CASP12, and CASP14; Table 1). We identified genes involved in cell growth and differentiation (AKR1C3, EGF, EGFR, IGFBP3, IGFBP5, PPARG, TGFA, VCAM1, and VEGF) and apoptosis (CASP1, CASP2, CASP3, CASP4, CASP5, CASP6, CASP7, CASP8, CASP9, CASP10, CASP12, and CASP14; Table 1) Several of these genes have been associated with risk of cancer at other sites [10,11]; the role of these genes in the development of renal cancer remains unknown
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