title: Multilevel-analysis identify a cis-expression quantitative trait locus associated with risk of renal cell carcinoma.
abstract: 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.
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Shu
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Purdue
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Wood
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Chen
authors.affiliation: Cancer Genomics Research Laboratory, SAIC-Frederick Inc., National Cancer Institute-Frederick, Frederick, Maryland, USA.
authors.forename: Zhaoming
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Pu
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Maosheng
authors.initials: M
authors.lastname: Huang
authors.affiliation: Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Stevens
authors.affiliation: Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.
authors.forename: W Ryan
authors.initials: WR
authors.lastname: Diver
authors.affiliation: Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Gapstur
authors.affiliation: Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Jarmo
authors.initials: J
authors.lastname: Virtamo
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Wong-Ho
authors.initials: WH
authors.lastname: Chow
authors.affiliation: Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Nizar M
authors.initials: NM
authors.lastname: Tannir
authors.affiliation: Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Colin P
authors.initials: CP
authors.lastname: Dinney
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci