Editors' ChoiceGenetics

Decoding Renal Cell Carcinoma

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Science Translational Medicine  13 Jan 2010:
Vol. 2, Issue 14, pp. 14ec6
DOI: 10.1126/scitranslmed.3000807

Renal cell carcinoma (RCC) represents the most common malignancy of the adult kidney, ranking among the top 10 cancer killers in the United States. The identification of these tumors often occurs incidentally at advanced stages because of clinically silent disease and unidentifiable risk factors. In addition, surgery and highly toxic medical therapy frequently result in tumor recurrence, which underscores our need to better delineate the pathogenesis and improve the effectiveness of current therapeutic options for RCC. Now, Dagliesh et al. identify over 85 variants in 10 genes previously unreported to be associated with clear cell renal carcinoma, the most common subtype of RCC.

In the first stage, the authors performed extensive resequencing of the coding exons in over 3500 genes in 101 patients and five cell lines of RCC and found predominance for small insertion/deletion mutations in RCC, hinting at the possibility of an unidentified defect in DNA repair. In a follow-up stage, RCC-associated genes with two or more nonsynonymous mutations were then validated in an additional 311 samples of RCC. Strikingly, the investigators note that four of the genes clustered for a role in cancer development (SETD2, JARID1C, UTX, and MLL2) are critically involved in histone methylation, which is a key epigenetic mediator of transcriptional regulation. Further, SETD2 and JARID1C mutations, each present in 3% of cases, showed a distinct expression profile, highlighting the unique downstream impact of each gene. The screen also identified the genes NF2, WRN, NBN, and ZUBR1, which are involved in DNA double-strand break repair and key tumor suppressor processes. These findings exemplify the power of deep gene resequencing for the identification of genetic subtypes that confer significant risk for disease—a process that was previously unfeasible given the exorbitant cost and the labor-intensive process involved with extensive DNA sequencing. Going forward, scientists should be able to leverage these findings in collaboration with rapidly evolving genome scanning technology so as to develop more effective therapies with reduced toxicity in RCC.

G. L. Dalgliesh et al., Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 6 January 2010 (10.1038/nature08672). [Abstract]

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