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

Abstract

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 +/− 10kb 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 SNPs mapping to IL1RAPL2 [rs10521506-G: ORmeta=0.87 (0.81–0.93), Pmeta=2.33×10−5], PLIN2 [rs2229536-A: ORmeta=0.87 (0.81–0.93), Pmeta=2.33×10−5], SMAD3 rs4601989-A: ORmeta=0.86 (0.80–0.93), Pmeta=2.71×10−4], MED13L [rs10850596-A: ORmeta=1.14 (1.07–1.23), Pmeta=1.50×10−4] and TSC1 [rs3761840-G: ORmeta=0.90 (0.85–0.97), Pmeta=2.47×10−3]. We did not observe any significant cis-expression quantitative trait loci (cis-eQTL) effect for these SNPs in the TCGA KIRC data. Conclusions Taken together, we found genetic variation of obesity-related genes could influence RCC susceptibility. Impact The five identified loci may provide new insights into disease etiology that reveals importance of obesity-related genes in RCC development.

Renal Cell Cancer and Obesity

“…The analysis of genes with expressions that correlated with both ccRCC and obesity revealed five candidates: immunoglobulin heavy constant alpha 1 ( IGHA1 ) and immunoglobulin κ constant ( IGKC ), which act as oncogenes, as well as monoamine oxidase A ( MAOA ), mucin-20 ( MUC20 ) and transient receptor potential melastatin 3 ( TRPM3 ), being tumour suppressor genes. In turn, a multiphase study of three independent genome-wide scans (of 3530 cases and 5714 controls) assessing genetic variations in obesity-related genes and RCC risk identified five RCC susceptibility loci: IL1RAPL2 (rs10521506-G), PLIN2 (rs2229536-A), SMAD3 (rs4601989-A), MED13L (rs10850596-A) and TSC1 (rs3761840-G) [ 210 ]. IL1RAPL2 belongs to the interleukin-1 receptor (IL-1R) family, PLIN2 encodes perilipin 2 (also called adipophilin or adipose differentiation-related protein), SMAD3 plays an important role in regulating glucose energy homeostasis, and TSC1 is a critical tumour suppressor in mTOR pathway.…”