Association of Germline Variants in Telomere Maintenance Genes (POT1, TERF2IP, ACD, TERT) with Spitzoid Morphology in Familial Melanoma: A Multi-Center Case Series.

Goldstein AM, Qin R, Chu EY, Elder DE, Massi D, Adams DJ, Harms PW, Robles-Espinoza CD, Newton-Bishop JA, Bishop DT, Harland M, Holland EA, Cust AE, Schmid H, Mann GJ, Puig S, Potrony M, Alos L, Nagore E, Millán-Esteban D, Hayward NK, Broit N, Palmer JM, Nathan V, Berry EG, Astiazaran-Symonds E, Yang XR, Tucker MA, Landi MT, Pfeiffer RM, Sargen MR. JAAD International, (Jan 28 2023), doi:10.1016/j.jdin.2023.01.013.


Background: 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.
Objective: To assess if familial melanoma cases associated with germline variants in TMG (POT1, ACD, TERF2IP, and TERT) commonly exhibit spitzoid morphology.
Methods: 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.
Results: 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.
Limitations: Findings may not be generalizable to nonfamilial melanoma cases.
Conclusion: Spitzoid morphology in familial melanoma could suggest germline alteration of TMG.