An MGRN1-Based Biomarker Combination Accurately Predicts Melanoma Patient Survival

With ever-increasing incidence and high metastatic potential, cutaneous melanoma is the deadliest skin cancer. Risk prediction based on the Tumor-Node-Metastasis (TNM) staging system has medium accuracy with intermediate IIB-IIIB stages, as roughly 25% of patients with low-medium-grade TNM, and hence a favorable prognostic, undergo an aggressive disease with short survival and around 15% of deaths arise from metastases of thin, low-risk lesions. Therefore, reliable prognostic biomarkers are required. We used genomic and clinical information of melanoma patients from the TCGA-SKCM cohort and two GEO studies for discovery and validation of potential biomarkers, respectively. Neither mutation nor overexpression of major melanoma driver genes provided significant prognostic information. Conversely, expression of <i>MGRN1</i> and the melanocyte-specific genes <i>MLANA</i>, <i>PMEL</i>, and <i>TYRP1</i> provided a simple 4-gene signature identifying with high-sensitivity (>80%), low-medium TNM patients with adverse outcomes. Transcriptomic analysis of tumors with this signature, or from low-medium-grade TNM patients with poor outcomes, revealed comparable dysregulation of an inflammatory response, cell cycle progression, and DNA damage/repair programs. A functional analysis of <i>MGRN1</i>-knockout cells confirmed these molecular features. Therefore, the simple <i>MGRN1-MLANA-PMEL-TYRP1</i> combination of biomarkers complemented TNM staging prognostic accuracy and pointed to the dysregulation of immunological responses and genomic stability as determinants of a melanoma outcome.