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A Renal CpG Island Methylator Phenotype (R-CIMP) in Kidney Tumors Associated with Germline Mutations of FH and SDHB

ABSTRACT: Germline mutations within the Krebs cycle enzyme genes fumarate hydratase (FH) or succinate dehydrogenase (SDHB, SDHC, SDHD) have been associated with an increased risk of renal cell carcinoma (RCC). These RCCs are characterized by loss of enzyme activity and significantly increased levels of intracellular fumarate or succinate that are predicted to inhibit 2-oxoglutarate-dependent dioxygenases, such as the TET enzymes that regulate DNA methylation. These tumors represent aggressive forms of RCC that can metastasize early and require specific patient management and treatment. Therefore, identifying effective and accurate methods for diagnosing these tumors is very beneficial. This study evaluated and compared the genome-wide methylation profiles of 33 RCCs from patients with RCC susceptibility syndromes, 10 associated normal samples and 13 cell-line models using the Illumina HumanMethylation450 BeadChip assay. Fifteen tumors derived from patients with germline FH (n=9) or SDHB (n=6) mutations demonstrated a distinct pattern of hypermethylation (R-CIMP) with enrichment for hypermethylation within the CpG island regions. A small, selected panel of probes was characterized that could identify R-CIMP and distinguish between FH and SDHB tumors. Cell-line models derived from HLRCC (n=3) or SDHB (n=1) kidney tumors demonstrated similar patterns of hypermethylation to the tumors, yet re-expression of either wild-type FH or SDHB did not alter the hypermethylation pattern. Treatment of the cell line models with 5-aza-2′-deoxycytidine resulted in reduced rates of invasion.

ORGANISM(S): Homo sapiens

PROVIDER: GSE126441 | GEO | 2020/10/31

REPOSITORIES: GEO

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