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American Association for Cancer Research, Cancer Research, 14_Supplement(76), p. 2660-2660, 2016

DOI: 10.1158/1538-7445.am2016-2660

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Abstract 2660: A renal CpG island methylator phenotype (R-CIMP) in kidney tumors associated with germline mutations ofFHandSDHB

This paper was not found in any repository, but could be made available legally by the author.
This paper was not found in any repository, but could be made available legally by the author.

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Abstract

Abstract Germline mutations of the genes encoding the Krebs cycle enzymes fumarate hydratase (FH) and succinate dehydrogenase (SDHB, SDHC, SDHD) have both been associated with an increased risk of renal cell carcinoma (RCC). These renal tumors demonstrate complete loss of enzyme activity and significantly increased levels of intracellular fumarate or succinate that are predicted to infer with the actions of multiple cellular processes primarily through the inhibition of 2-oxoglutarate-dependent dioxygenases, such as the prolyl hydroxylases that regulate the HIF pathway and the TET enzymes that regulate DNA methylation. This study evaluated and compared the genome-wide methylation profiles of 33 tumor samples (including 9 FH -/- and 7 SDHB -/- tumors), 10 associated normal samples and 13 cell-lines (including cell-line models derived from FH -/- and SDHB -/- tumors) using the Illumina HumanMethylation450 BeadChip arrays. Tumors derived from patients with germline FH or SDHB mutations demonstrated a distinct pattern of hypermethylation across the genome with enrichment for hypermethylation within the CpG island regions. SDHB mutation associated tumors demonstrated that was more variable and less extensive pattern of hypermethylation than the tumors associated with germline FH mutations. Cell-line models derived from HLRCC or SDHB tumors demonstrated patterns of hypermethylation similar to the patterns observed in the tumors, yet re-expression of either wild-type FH or SDHB within these cell-line models did not alter the methylation profiles. All the HLRCC and SDHB-RCC cell lines, including the cell-line re-expressing of either wild-type FH or SDHB, demonstrated growth inhibition and reduced invasion rates in response to treatment with 5-aza-2′-deoxycytidine. Thus, renal cell carcinomas associated with FH or SDHB germline mutation demonstrate a specific R-CIMP hypermethylation profile that differentiates these tumors from tumors derived from other RCC susceptibility syndromes. These tumors represent the most aggressive types of familial-associated RCC and this could provide a useful biomarker for identifying these tumors and de-methylating agents, such as 5-aza-2′-deoxycytidine, may be effective as part of a therapeutic regime for the treatment of these tumors. Citation Format: Christopher Ricketts, J. Keith Killian, Cathy D. Vocke, Carole Sourbier, Youfeng Yang, Maria J. Merino, Paul S. Meltzer, W. Marston Linehan. A renal CpG island methylator phenotype (R-CIMP) in kidney tumors associated with germline mutations of FH and SDHB. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2660.