Abstract 2316: Multilayer omics analyses in CpG island methylator phenotype clear cell renal cell carcinomas

Abstract

Abstract [Background] We have reported that CpG-island methylator phenotype (CIMP)-positive clear cell renal cell carcinomas (RCCs) are characterized by accumulation of DNA hypermethylation of CpG islands, clinicopathological aggressiveness and poorer patient outcome. We have established the criteria for CIMP diagnosis in clear cell RCCs by quantification of DNA methylation levels of RCC-specific CIMP marker genes. [Purpose] The aim of this study was to reveal the molecular pathways which significantly participate in CIMP-positive renal carcinogenesis and become a therapeutic target of CIMP-positive clear cell RCCs. [Methods] Our previous methylome analysis using Illumina Infinium HumanMethylation27 BeadArray identified CIMP-negative and -positive clear cell RCCs in the present cohort (n=101). In the present study, genome (whole-exome), transcriptome and proteome analyses using Agilent SureSelect All Exon capture followed by sequencing on an Illumina HiSeq 2000 platform, Agilent SurePrint Human Gene Expression microarray and two dimensional image converted analysis of liquid chromatography-mass spectrometry, respectively, were performed in tissue specimens of 87 CIMP-negative and 14 CIMP-positive clear cell RCCs and the corresponding non-cancerous renal cortex tissue specimens. [Results] The number of genes showing genetic aberrations in CIMP-negative clear cell RCCs was quite low, indicating that CIMP-negative RCCs lacked distinct genetic characteristics. On the other hand, many genes, such as genes encoding hisotone modification enzymes and tumor-suppressor genes, showed 10% or more incidence of genetic aberrations in CIMP-positive clear cell RCCs. Based on MetaCore pathway analysis, although mRNA or protein expression alterations in CIMP-negative clear cell RCCs were not significantly accumulated in any molecular pathways, such alterations in CIMP-positive clear cell RCCs were accumulated in the 19 pathways (P<0.05), such as molecular pathways involved in cell cycle and cell adhesion. Quantitative RT-PCR analysis verified expression alterations of genes involved in the most frequently affected pathway in CIMP-positive clear cell RCCs. [Conclusion] The most frequently affected pathway may be a novel therapeutic target of CIMP-positive clear cell RCCs. We are now examining the effectiveness of the inhibitor of the most frequently affected pathway in RCC cell lines showing CIMP. Citation Format: Eri Arai, Hiromi Sakamoto, Masaya Ono, Yoriko Takahashi, Sayaka Miyata, Hiroyuki Fujimoto, Masahiro Gotoh, Tesshi Yamada, Yae Kanai. Multilayer omics analyses in CpG island methylator phenotype clear cell renal cell carcinomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2316. doi:10.1158/1538-7445.AM2014-2316