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Oncotarget. 2015 Feb 28;6(6):4097-109.

Multilevel-analysis identify a cis-expression quantitative trait locus associated with risk of renal cell carcinoma.

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Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Cancer Genomics Research Laboratory, SAIC-Frederick Inc., National Cancer Institute-Frederick, Frederick, Maryland, USA.
Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.


We conducted multilevel analyses to identify potential susceptibility loci for renal cell carcinoma (RCC), which may be overlooked in traditional genome-wide association studies (GWAS). A gene set enrichment analysis was performed utilizing a GWAS dataset comprised of 894 RCC cases and 1,516 controls using GenGen, SNP ratio test, and ALIGATOR. The antigen processing and presentation pathway was consistently significant (P = 0.001, = 0.004, and < 0.001, respectively). Versatile gene-based association study approach was applied to the top-ranked pathway and identified the driven genes. By comparing the expression of the genes in RCC tumor and adjacent normal tissues, we observed significant overexpression of HLA genes in tumor tissues, which was also supported by public databases. We sought to validate genetic variants in antigen processing and presentation pathway in an independent GWAS dataset comprised of 1,311 RCC cases and 3,424 control subjects from the National Cancer Institute; one SNP, rs1063355, was significant in both populations (P(meta-analysis) = 9.15 × 10⁻⁴, P(heterogeneity) = 0.427). Strong correlation indicated that rs1063355 was a cis-expression quantitative trait loci which associated with HLA-DQB1 expression (Spearman's rank r = -0.59, p = 5.61 × 10⁻⁶). The correlation was further validated using a public dataset. Our results highlighted the role of immune-related pathway and genes in the etiology of RCC.

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