Telomere Maintenance Associated Mutations in the Genetic Landscape of Gynecological Mucosal Melanoma

Abstract

Purpose Gynecological melanomas (GMs) are rare tumors with a poor prognosis. Here, we performed exome sequencing to generate the mutational landscape of GMs. Methods Next-generation sequencing was carried out on mucosal melanoma samples ( n = 35) obtained from gynecological sites. The alternative telomere lengthening (ALT) phenotype was verified by fluorescence in situ hybridization and the C-circle assay. Immunohistochemistry was performed to detect ATRX protein. Copy number variations in TERT were detected by droplet digital polymerase chain reaction. Results In the 58 formalin-fixed paraffin-embedded samples, we identified 33 (56.9%) ALT-positive cases, with 23 showing loss of ATRX protein. TERT promoter mutation was not detected in GMs ( n = 40), but copy number variations in the TERT region were observed in 20% (7/35) of the samples. TERT amplification was mutually exclusive with ALT ( P < 0.05). Kaplan–Meier revealed that ALT relative to TERT amplification was associated with longer overall survival in GM patients without metastasis. Conclusion These findings indicate that telomere maintenance mechanisms play a critical role in the tumorigenesis of GMs and may aid in the prediction of clinical prognosis and the development of targeted therapy for the treatment of GM.

Anorectal and Genital Mucosal Melanoma: Diagnostic Challenges, Current Knowledge and Therapeutic Opportunities of Rare Melanomas

“…TERT is a gene encoding for the catalytic subunit of telomerase, which maintains telomeric integrity, ensuring cell immortality in human cancer [ 31 ]. Differently from CM, in which mutations occur mainly in the promoter region [ 32 ], the TERT alterations described in MM do not affect the promoter but consist in copy number variations, ultimately determining overexpression and stopping senescence [ 15 , 33 , 34 ]. ALK fusions, which are well-known tumors driven in lung adenocarcinomas, have been identified in ~11% of CMs, and, interestingly, MMs could also harbour such alterations [ 19 , 35 ].…”

Systematic review and meta‐analysis of genomic alterations in acral melanoma

“…ATRX acts with the histone chaperone DAXX to insert histone variant H3.3 (Nandakumar et al, 2017; Pritchard, 2019), and loss of ATRX leads to increased homologous recombination facilitating telomere destabilization and alternative lengthening of telomeres (ALT; Abedalthagafi et al, 2013; Dyer et al, 2017; Marinoni et al, 2014; Yuan et al, 2020). LoF mutations (1.7%) and copy loss (HD: 0.8%, 0 %; LoH: 20%, 0 %) were observed in AM at a similar frequency to CM, but are slightly more common in MM (3.7%), where they are associated with tumors of the lower anatomy (Broit et al, 2021) (Table 2).…”

ATRX Loss in the Development and Prognosis of Conjunctival Melanoma

“…ALT activation is described in sarcoma, astrocytoma, neuroblastoma, and carcinoma [ 18 ] cases as well as CM [ 16 ] and is related to functional loss of ATRX and/or histone H3.3 chaperone DAXX. In mucosal-melanoma-inactivating ATRX mutations can be revealed using immunohistochemistry [ 19 ]. In the current study ATRX loss was only found in (pre)malignant lesions and not in benign lesions.…”