Associations between TERT Promoter Mutations and Survival in Superficial Spreading and Nodular Melanomas in a Large Prospective Patient Cohort.

Survival outcomes in melanoma and their association with mutations in the telomerase reverse transcriptase gene TERT promoter remain uncertain. In addition, few studies have examined whether these associations are affected by a nearby common germline polymorphism or vary on the basis of melanoma histopathological subtype. We analyzed 408 primary tumors from a prospective melanoma cohort for somatic TERT-124[C>T] and TERT-146[C>T] mutations, the germline polymorphism rs2853669, and BRAFV600 and NRASQ61 mutations. We tested the associations between these variants and clinicopathologic factors and survival outcomes. TERT-124[C>T] was associated with thicker tumors, ulceration, mitoses (>0/mm2), nodular histotype, and CNS involvement. In a multivariable model controlling for the American Joint Committee on Cancer stage, TERT-124[C>T] was an independent predictor of shorter recurrence-free survival (hazard ratio = 2.58, P = 0.001) and overall survival (hazard ratio = 2.47, P = 0.029). Patients with the germline variant and TERT-124[C>T]-mutant melanomas had significantly shorter recurrence-free survival than those lacking either or both sequence variants (P < 0.04). The impact of the germline variant appeared to be more pronounced in superficial spreading than in nodular melanoma. No associations were found between survival and TERT-146[C>T], BRAF, or NRAS mutations. These findings strongly suggest that TERT-124[C>T] mutation is a biomarker of aggressive primary melanomas, an effect that may be modulated by rs2853669.

Computer-assisted measurement of primary tumor area is prognostic of recurrence-free survival in stage IB melanoma patients.

Current staging guidelines are insufficient to predict which patients with thin primary melanoma are at high risk of recurrence. Computer-assisted image analysis may allow for more practical and objective histopathological analysis of primary tumors than traditional light microscopy. We studied a prospective cohort of stage IB melanoma patients treated at NYU Langone Medical Center from 2002 to 2014. Primary tumor width, manual area, digital area, and conformation were evaluated in a patient subset via computer-assisted image analysis. The associations between histologic variables and survival were evaluated using Cox proportional hazards model. Logistic regressions were used to build a classifier with clinicopathological characteristics to predict recurrence status. Of the 655 patients with stage IB melanoma studied, a subset of 149 patient tumors (63 recurred, 86 did not recur) underwent computer-assisted histopathological analysis. Increasing tumor width (hazard ratios (HR): 1.17, P=0.01) and digital area (HR: 1.08, P<0.01) were significantly associated with worse recurrence-free survival, whereas non-contiguous conformation (HR: 0.57, P=0.05) was significantly associated with better recurrence-free survival. The novel histopathological classifier composed of digital area, conformation, and baseline variables effectively distinguished recurrent cases from non-recurrent cases (AUC: 0.733, 95% confidence interval (CI): 0.647-0.818), compared to the baseline classifier alone (AUC: 0.635, 95% CI: 0.545-0.724). Primary tumor cross-sectional area, width, and conformation measured via computer-assisted analysis may help identify high-risk patients with stage IB melanoma.