Malignant melanoma is a neoplasm of pigment-producing cells called melanocytes that occurs most often in the skin, but may also occur in the eyes, ears, gastrointestinal tract, leptomeninges, and oral and genital mucous membranes (summary by Habif, 2010). ... Malignant melanoma is a neoplasm of pigment-producing cells called melanocytes that occurs most often in the skin, but may also occur in the eyes, ears, gastrointestinal tract, leptomeninges, and oral and genital mucous membranes (summary by Habif, 2010). For a discussion of genetic heterogeneity of cutaneous malignant melanoma, see CMM1 (155600).
Bertolotto et al. (2011) identified a germline missense substitution in MITF (156845.0009), E318K, that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, renal cell carcinoma (RCC) (144700), or both cancers when compared with ... Bertolotto et al. (2011) identified a germline missense substitution in MITF (156845.0009), E318K, that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, renal cell carcinoma (RCC) (144700), or both cancers when compared with controls. Overall, the E318K carriers had a higher than 5-fold increased risk of developing melanoma, RCC, or both cancers. Codon 318 is located in a small ubiquitin-like modifier (SUMO) consensus site, and E318K severely impaired SUMOylation of MITF. The E318K mutation enhanced MITF protein binding to the HIF1A (603348) promoter and increased its transcriptional activity compared to wildtype MITF. Further, Bertolotto et al. (2011) observed a global increase in E318K-mutated MITF-occupied loci. In an RCC cell line, gene expression profiling identified a MITF E318K signature related to cell growth, proliferation, and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration, and invasion, consistent with a gain-of-function role in tumorigenesis. Bertolotto et al. (2011) concluded that their data provided insights into the link between SUMOylation, transcription, and cancer. The allelic frequency of the E318K mutation was found to be 0.003 among controls, 0.016 among patients with melanoma and/or RCC, 0.040 among patients with melanoma and RCC, 0.014 among patients with melanoma only, and 0.015 among patients with RCC only. The odds ratio of having this mutation and melanoma and RCC was 14.46 with a 95% confidence interval of 3.74 to 48.04; for melanoma alone the odds ratio was 4.78 with a 95% confidence interval of 2.05 to 11.75. Yokoyama et al. (2011) independently identified the E318K (156845.0009) mutation in the MITF gene as increasing the risk of melanoma in both families and sporadic cases. The variant cosegregated with melanoma in some but not all cases of melanoma in the initial family identified, but linkage analysis of 31 families subsequently identified to carry the variant generated a lod score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case-control sample. Likewise, it was similarly associated in an independent case-control sample from the United Kingdom. The variant allele was also associated with increased nevus count and nonblue eye color. Yokoyama et al. (2011) showed that E318K prevents MITF sumoylation and results in differential expression of MITF target genes.