Clinical and pathological characteristics of familial melanoma with germline TERT promoter variants

Around 10% of melanoma occurs in patients with a suspected familial predisposition. TERT promoter mutations are the most common somatic hotspot mutations in human cancers. However, only two families with germline mutations have been identified to date. We present detailed histological, clinical, and molecular pathologic analyses of affected patients and details of newly identified individuals in one of these previously reported families. TERT (NM_198253.3) Chr.5:1,295,161T>C (c.-57 T>C) promoter variants were detected in all melanoma-affected (n = 18) and one non-diseased family member. The median age at diagnosis was 30 years (n = 18, range 16-46 years, 2 unknown). While most primary melanomas arose on the upper extremities (n = 7, 21%) and were superficial spreading melanoma (SSM, n = 8, 24%), many primary melanomas also originated from non-UV-exposed mucosal (n = 2, 6%) and acral (n = 4, 12%) locations. One SSM sample harbored a Chr.5:1,295,228C>T TERT promoter mutation in addition to the germline Chr.5:1,295,161T>C variant, arguing additional pathway activation can support tumor pathogenesis. Patients treated with BRAF inhibitor and/or immune checkpoint inhibition (ICI) showed responses, although of limited duration. One mucosal melanoma harbored both a KIT copy number gain and an activating c.1727 p.Leu576Pro mutation. Following the modest response to ICI, subsequent KIT inhibitor (imatinib) therapy demonstrated an ongoing complete pathological response (currently 7 months).

Automated summary

Around 10% of melanoma cases have a suspected familial predisposition. TERT promoter mutations are common in human cancers, but only a few cases with germline mutations have been identified so far. This study provides detailed analysis of affected patients in a previously reported family, including their histological, clinical, and molecular pathologic characteristics. The study also identifies TERT promoter variants in all melanoma-affected members of the family. Primary melanomas in these patients commonly occur on the upper extremities and are of the superficial spreading melanoma subtype, but can also occur in non-UV-exposed mucosal and acral locations. Additional genetic mutations were found in some samples, suggesting the involvement of other pathways in tumor development. Treatment with BRAF inhibitor and/or immune checkpoint inhibition showed responses, but with limited duration. One mucosal melanoma case showed a positive response to KIT inhibitor therapy after an initial response to immune checkpoint inhibition.