CRTC Gene Expression Is Associated with Pigmentation and Overall Survival in Melanoma, Anna Sarah Erem, Simon Roy, Zachary Wolner, Allison Osmond, Matt J. Cecchini

Summary: Background: Excessive melanin synthesis in melanoma has been associated with increased expression of the microphthalmic associated transcription factor (MITF). Novel CREB-regulated transcription factor coactivators (CRTCs) involved in the regulation of MITF may play an important role in hyperpigmentation of melanocytic lesions. Experimental models have demonstrated that CRTC has an important function in melanosome maturation and pigmentation. The exact role of CRTC in melanoma is unclear, but it has been proposed as a potential therapeutic target. The Cancer Genome Atlas (TCGA) dataset was utilized to identify human melanomas and correlate CRTC expression with tumoral pigmentation and overall survival. Design: Expression of CRTC1, CRTC2, and CRTC3 was evaluated in the TCGA melanoma dataset. Cases with available gene expression were reviewed (n= 443), and overall survival was compared to cases with ≥3 fold overexpression of any CRTC gene compared to those without elevated expression. Survival differences were assessed utilizing a log-rank test to determine the hazard ratio (HR) between the two groups. Additional analysis was completed to compare tumors with upregulation (≥3 fold) to downregulated tumors (≤1 fold) to assess the degree of pigmentation. The percent of pigmentation was estimated in each case by three independent reviewers. The average for each case was compared between groups using a t-test. Results: Overexpression of at least one CRTC gene was associated with a worse overall survival HR, 1.74 (95% CI 1.07 - 2.82, p = 0.005) (Figure 1). The median survival was 50.1 months for cases with overexpression of CRTC gene(s) compared with 93.0 months for cases without overexpression. We also identified a correlation between CRTC gene expression and degree of pigmentation as visually assessed by pathologists. There was a significant difference in the estimate of the percentage of melanocytic pigment with a mean in the CRTC upregulated group of 20.97 compared with the downregulated group of 2.49, p < 0.0001 (Figure 2).