BACKGROUND: MUC16 is a mucin marker that is frequently mutated in melanoma, but whether MUC16 mutations could be useful as a surrogate biomarker for tumor mutation burden (TMB) remains unclear. METHODS: This study rigorously evaluates the MUC16 mutation as a clinical biomarker in cutaneous melanoma by utilizing genomic and clinical data from patient samples from The Cancer Genome Atlas (TCGA) and two independent validation cohorts. We further extended the analysis to studies with patients treated with immunotherapies. RESULTS: Analysis results showed that samples with MUC16 mutations had a higher TMB than the samples of wild-type, with strong statistical significance (P < 0.001) in all melanoma cohorts tested. Associations between MUC16 mutations and TMB remained statistically significant after adjusting for potential confounding factors in the TCGA cohort [OR, 9.28 (95% confidence interval (CI), 5.18-17.39); P < 0.001], Moffitt cohort [OR, 31.95 (95% CI, 8.71-163.90); P < 0.001], and Yale cohort [OR, 8.09 (95% CI, 3.12-23.79); P < 0.01]. MUC16 mutations were also found to be associated with overall survival in the TCGA [HR, 0.62; (95% CI, 0.45-0.85); P < 0.01] and Moffitt cohorts [HR, 0.49 (95% CI, 0.28-0.87); P = 0.014]. Strikingly, MUC16 is the only top frequently mutated gene for which prognostic significance was observed. MUC16 mutations were also found valuable in predicting anti-CTLA-4 and anti-PD-1 therapy responses. CONCLUSIONS: MUC16 mutation appears to be a useful predictive marker of global TMB and patient survival in melanoma. IMPACT: This is, to the best of our knowledge, the first systematic evaluation of MUC16 mutation as a clinical biomarker and a predictive biomarker for immunotherapy in melanoma.

In this perspective, we identify emerging frontiers in clinical and basic research of melanocyte biology and its associated biomedical disciplines. We describe challenges and opportunities in clinical and basic research of normal and diseased melanocytes that impact current approaches to research in melanoma and the dermatological sciences. We focus on four themes: (1) clinical melanoma research, (2) basic melanoma research, (3) clinical dermatology, and (4) basic pigment cell research, with the goal of outlining current highlights, challenges, and frontiers associated with pigmentation and melanocyte biology. Significantly, this document encapsulates important advances in melanocyte and melanoma research including emerging frontiers in melanoma immunotherapy, medical and surgical oncology, dermatology, vitiligo, albinism, genomics and systems biology, epidemiology, pigment biophysics and chemistry, and evolution.

The Melanoma Research Foundation (MRF) has charted a comprehensive assessment of the current state of melanoma research and care. Intensive discussions among members of the MRF Scientific Advisory Council and Breakthrough Consortium, a group that included clinicians and scientists, focused on four thematic areas - diagnosis/early detection, prevention, tumor cell dormancy (including metastasis), and therapy (response and resistance). These discussions extended over the course of 2015 and culminated at the Society of Melanoma Research 2015 International Congress in November. Each of the four groups has outlined their thoughts as per the current status, challenges, and opportunities in the four respective areas. The current state and immediate and long-term needs of the melanoma field, from basic research to clinical management, are presented in the following report.