Defective MITF Sumoylation Underlies Melanoma and RCC Co-occurrence

Co-occurrence of melanoma and renal cell carcinoma (RCC) in the same patients suggests a shared genetic cause, as a common environmental risk factor has not been identified. Bertolotto and colleagues hypothesized the microphthalmia-associated transcription factor (MITF), previously identified as a melanoma oncogene, may also be linked to RCC because it shares a key target (hypoxia inducible factor, or HIF1A) with kidney cancer susceptibility genes. The authors therefore sequenced MITF in a panel of patients with both melanoma and RCC undergoing genetic testing and identified a germline heterozygous missense mutation (E318K) in 5 patients. Analysis of a larger population of patients with both cancers and in cancer-free controls showed that E318K carriers had a 14-fold higher risk of melanoma and RCC co-occurrence. When these patients were pooled with patients with melanoma or RCC alone, the authors observed that the E318K mutation conferred a greater than 5-fold risk of developing either cancer. Replacement of glutamic acid residue 318 with a lysine disrupted a SUMOylation consensus sequence and led to a strong decrease in SUMO-modified MITF. Interestingly, diminished MITF SUMOylation correlates with increased genome-wide MITF occupancy and transcriptional activity of a subset of MITF targets such as HIF1A, suggesting that E318K is a gain-of-function mutation. This altered MITF activity is tumorigenic, as stable expression of E318K in either a melanoma or RCC cell line led to increased migration, invasion, and colony formation. The authors propose that E318K impairs cellular stress responses and initiates tumor formation in physiologically hypoxic tissues. Together, these results shed light on the role of SUMOylation in cancer and implicate the MITF E318K mutation as a genetic risk factor for both melanoma and RCC, although further studies will be required in a larger series of unselected cases of sporadic RCC and melanoma.

Bertolotto C, Lesueur F, Giuliano S, Strub T, de Lichy M, Bille K, et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature. 2011 Oct 19. [Epub ahead of print].

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