Association of germline variants in telomere maintenance genes (POT1, TERF2IP, ACD, and TERT) with spitzoid morphology in familial melanoma: A multi-center case series
Alisa M. Goldstein, Richard Qin, Emily Y. Chu, David E. Elder, Daniela Massi, David J. Adams, Paul W. Harms, Carla Daniela Robles‐Espinoza, Julia Newton‐Bishop, D. Timothy Bishop, Mark Harland, Elizabeth A. Holland, Anne Ε. Cust, Helen Schmid, Graham J. Mann, Susana Puig, Míriam Potrony, Llúcia Alós, Eduardo Nagore, David Millán-Esteban, Nicholas K. Hayward, Natasa Broit, Jane M. Palmer, Vaishnavi Nathan, Elizabeth Berry, Esteban Astiazarán-Symonds, Xiaohong R. Yang, Margaret A. Tucker, Maria Teresa Landi, Ruth M. Pfeiffer, Michael R. Sargen
Abstract
BackgroundSpitzoid morphology in familial melanoma has been associated with germline variants in POT1, a telomere maintenance gene (TMG), suggesting a link between telomere biology and spitzoid differentiation.ObjectiveTo assess if familial melanoma cases associated with germline variants in TMG (POT1, ACD, TERF2IP, and TERT) commonly exhibit spitzoid morphology.MethodsIn this case series, melanomas were classified as having spitzoid morphology if at least 3 of 4 dermatopathologists reported this finding in ≥25% of tumor cells. Logistic regression was used to calculate odds ratios (OR) of spitzoid morphology compared to familial melanomas from unmatched noncarriers that were previously reviewed by a National Cancer Institute dermatopathologist.ResultsSpitzoid morphology was observed in 77% (23 of 30), 75% (3 of 4), 50% (2 of 4), and 50% (1 of 2) of melanomas from individuals with germline variants in POT1, TERF2IP, ACD, and TERT, respectively. Compared to noncarriers (n = 139 melanomas), POT1 carriers (OR = 225.1, 95% confidence interval: 51.7-980.5; P < .001) and individuals with TERF2IP, ACD, and TERT variants (OR = 82.4, 95% confidence interval: 21.3-494.6; P < .001) had increased odds of spitzoid morphology.LimitationsFindings may not be generalizable to nonfamilial melanoma cases.ConclusionSpitzoid morphology in familial melanoma could suggest germline alteration of TMG. Spitzoid morphology in familial melanoma has been associated with germline variants in POT1, a telomere maintenance gene (TMG), suggesting a link between telomere biology and spitzoid differentiation. To assess if familial melanoma cases associated with germline variants in TMG (POT1, ACD, TERF2IP, and TERT) commonly exhibit spitzoid morphology. In this case series, melanomas were classified as having spitzoid morphology if at least 3 of 4 dermatopathologists reported this finding in ≥25% of tumor cells. Logistic regression was used to calculate odds ratios (OR) of spitzoid morphology compared to familial melanomas from unmatched noncarriers that were previously reviewed by a National Cancer Institute dermatopathologist. Spitzoid morphology was observed in 77% (23 of 30), 75% (3 of 4), 50% (2 of 4), and 50% (1 of 2) of melanomas from individuals with germline variants in POT1, TERF2IP, ACD, and TERT, respectively. Compared to noncarriers (n = 139 melanomas), POT1 carriers (OR = 225.1, 95% confidence interval: 51.7-980.5; P < .001) and individuals with TERF2IP, ACD, and TERT variants (OR = 82.4, 95% confidence interval: 21.3-494.6; P < .001) had increased odds of spitzoid morphology. Findings may not be generalizable to nonfamilial melanoma cases. Spitzoid morphology in familial melanoma could suggest germline alteration of TMG.