Melanomas of unknown primary frequently harbor TERT-promoter mutations

Abstract

Commonly, in patients with melanoma metastases of an unknown primary tumor (MUP), an extensive search for the primary tumor is carried out. Recently, highly recurrent telomerase reverse transcriptase (TERT)-promoter mutations were found in malignant melanomas, which may function as driver mutations of skin cancer. The aim of this study was to test the hypothesis that MUP and mucosal melanomas harbor different prevalences of TERT-promoter mutations. Thirty-nine patients with MUP and 53 patients with mucosal melanomas were retrieved. In total, 152 paraffin samples of 92 patients were analyzed, and in 38 patients, multiple samples were tested. Mutational analysis of the TERT-promoter, BRAF, NRAS, and KIT genes was carried out. In total, 92 patients were eligible for mutational analysis. TERT-promoter mutations were found in 33 patients (35.9%): chr5, 1,295,228 C>T (18 patients); chr5, 1,295,250 C>T (11 patients); chr5, 1,295,228-229 CC>TT (three patients); chr5, 1,295,242-243 CC>TT (one patient). The mutations were significantly more prevalent in MUP [26 (66.7%)] than in mucosal melanomas [seven patients (13.2%); P<0.001]. In MUP, BRAF mutations were found in 46.2% of patients (18 patients) and NRAS mutations in 28.2% of patients (11 patients). In mucosal melanoma, NRAS mutations were found in 18.9% of patients (10), and BRAF and KIT mutations in 7.5% of patients (four patients), respectively. The prevalence of TERT-promoter mutations was associated with the patient's sex [23 (51.1%) men, 10 (21.3%) women; P=0.004]. No significant correlation was found between TERT-mutation and patient survival. The TERT-promoter genotype of MUP points toward a cutaneous and not mucosal origin. The significant sex differences merit further attention in having putative therapeutic implications.

Molecular Characterization and Patient Outcome of Melanoma Nodal Metastases and an Unknown Primary Site

“…Based on our mutational data we have shown that a population of MUP patients have a similar distribution of BRAF/NRAS alterations to the known primary melanoma patients exposed to similar/identical environmental factors (such as UV exposure, but not exclusively), confirming data from other smaller published series 16,18,23,24,28. The incidence of mutations is consistent with those already observed for melanoma originating on skin without chronic sun damage, which is the most common type in Central and Western Europe 29.…”

“…Because the manifestation of melanoma as MUP does not alter BRAF or NRAS mutation frequency compared with melanomas with known primary site, some other genetic/immunological mechanism enhancing regression must be involved 28. Based on previously published data and our clinical data on MUP patients, supported by mutational status of known genes involved in development of melanoma as well as potential targets of new therapies, we conclude that MUP has similar molecular pattern in terms of BRAF / NRAS alterations and clinical behavior to melanoma of known primary site of the same stage (mainly developed in NCSD) and therefore should be managed and treated according to the same guidelines.…”

Telomerase reverse transcriptase (TERT) promoter mutation analysis of benign, malignant and reactive urothelial lesions reveals a subpopulation of inverted papilloma with immortalizing genetic change

“…No gender differences were found among urothelial carcinomas in this study or in previous investigations. Interestingly, TERT mutation in melanoma showed a male predominance in one study (51% in males versus 21% in females; P = 0.004), although no gender difference was noted in another study (45% in males versus 39% in females; P = 0.26) . Further investigation is warranted to explore the mechanisms and significance of gender differences of TERT mutation.…”

TERT promoter mutations in sinonasal malignant melanoma

“…Horn et al [23] also reported a germline TERT promoter mutation in a kindred with familial cutaneous malignant melanoma. A recently published study by Egberts et al [27] found a low frequency of TERT promoter mutations in mucosal melanoma, but the frequency in SNMM was not specifically reported. No former study has investigated the frequency of TERT promoter mutations in primary SNMM; therefore, the aim of the current study was to evaluate a large cohort for the presence of TERT promoter mutations and coexisting NRAS and BRAF mutations.…”