Potential Susceptibility Loci Identified for Renal Cell Carcinoma by Targeting Obesity-Related Genes

Background: Obesity is an established risk factor for renal cell carcinoma (RCC). Although genome-wide association studies (GWAS) of RCC have identified several susceptibility loci, additional variants might be missed due to the highly conservative selection.

Methods: We conducted a multiphase study utilizing three independent genome-wide scans at MD Anderson Cancer Center (MDA RCC GWAS and MDA RCC OncoArray) and National Cancer Institute (NCI RCC GWAS), which consisted of a total of 3,530 cases and 5,714 controls, to investigate genetic variations in obesity-related genes and RCC risk.

Results: In the discovery phase, 32,946 SNPs located at ±10 kb of 2,001 obesity-related genes were extracted from MDA RCC GWAS and analyzed using multivariable logistic regression. Proxies (R² > 0.8) were searched or imputation was performed if SNPs were not directly genotyped in the validation sets. Twenty-one SNPs with P < 0.05 in both MDA RCC GWAS and NCI RCC GWAS were subsequently evaluated in MDA RCC OncoArray. In the overall meta-analysis, significant (P < 0.05) associations with RCC risk were observed for SNP mapping to IL1RAPL2 [rs10521506-G: OR_meta = 0.87 (0.81–0.93), P_meta = 2.33 x 10^–5], PLIN2 [rs2229536-A: OR_meta = 0.87 (0.81–0.93), P_meta = 2.33 x 10^–5], SMAD3 [rs4601989-A: OR_meta = 0.86 (0.80–0.93), P_meta = 2.71 x 10^–4], MED13L [rs10850596-A: OR_meta = 1.14 (1.07–1.23), P_meta = 1.50 x 10^–4], and TSC1 [rs3761840-G: OR_meta = 0.90 (0.85–0.97), P_meta = 2.47 x 10^–3]. We did not observe any significant cis-expression quantitative trait loci effect for these SNPs in the TCGA KIRC data.

Conclusions: Taken together, we found that genetic variation of obesity-related genes could influence RCC susceptibility.

Impact: The five identified loci may provide new insights into disease etiology that reveal importance of obesity-related genes in RCC development. Cancer Epidemiol Biomarkers Prev; 26(9); 1436–42. ©2017 AACR.

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