The MITF(E318K) variant confers moderate risk for cutaneous melanoma.,While there are small studies suggesting that this risk is associated with other malignancies (e.g. renal cell carcinoma), little is known about the role of this variant in specifying risk for other cancers.,In this study, we perform a systematic review and meta-analysis of the published data as a backdrop to a whole-exome sequence(WES)-based characterization of MITF(E318K) risk for various cancers in sporadic samples from the TCGA and several genetically-enriched patient cohorts.,We found minimal evidence of MITF(E318K)’s contribution to non-melanoma cancer risk among individuals with low inherited risks of melanoma (OR 1.168; 95% CI 0.78-1.74; p = 0.454), suggesting that earlier reports of an association between this variant and other malignancies may be related to shared environmental or polygenic risk factors rather than MITF(E318K).,Interestingly, an association was observed with uterine carcinosarcoma, (OR 9.24; 95% CI 2.08-37.17; p = 0.024), which was not previously described.,While more research needs to be completed, this study will help update cancer screening recommendations for patients with the MITF(E318K) variant.
Most genetic susceptibility to cutaneous melanoma remains to be discovered.,Meta-analysis genome-wide association study (GWAS) of 36,760 melanoma cases (67% newly-genotyped) and 375,188 controls identified 54 significant loci with 68 independent SNPs.,Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation.,Combining this meta-analysis with nevus count and hair color GWAS, and transcriptome association approaches, uncovered 31 potential secondary loci, for a total of 85 cutaneous melanoma susceptibility loci.,These findings provide substantial insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation, and telomere maintenance together with identifying potential new pathways for cutaneous melanoma pathogenesis.