CDK4 and TERT amplification in head and neck mucosal melanoma

Abstract

Background Recent high‐throughput sequencing studies have revealed frequent CDK4 and TERT amplification in mucosal melanoma, suggesting that they are potential therapeutic targets. In this study, we investigated the statuses of CDK4 and TERT in head and neck mucosal melanoma (HNMM) with the aim of providing preclinical data to support future clinical trials. Methods In total, 29 HNMM samples were collected, including 16 oral mucosal melanoma (OMM) samples and 13 nasal cavity/sinuses melanoma (SNMM) samples. Fluorescence in situ hybridization was used to analyze CDK4 and TERT amplification, and immunohistochemistry was used to analyze CDK4 and TERT protein expression patterns. CDK4 expression was knocked down in the ME cells (an OMM cell line), and changes in cell cycle were analyzed. Cell viability assays were performed to determine the sensitivity of ME to abemaciclib (a CDK4 inhibitor) combined with dacarbazine (an anti‐melanoma chemotherapy drug). Results We detected five samples exhibited CDK4 amplifications and nine samples exhibited TERT amplifications in our HNMM series, and found that CDK4 amplification tended to occur in combination with TERT amplification. Amplifications of CDK4 and TERT were more common in OMM than in SNMM. Amplifications of CDK4 and TERT were associated with greater CDK4 and TERT protein expression levels. CDK4 knockdown led to delayed G1/S phase transition in ME cells. Furthermore, ME cells were sensitive to abemaciclib (IC50 = 5.23 nM). Abemaciclib and dacarbazine synergistically inhibited ME cells’ viability. Conclusion We confirmed high frequencies of CDK4 and TERT amplification in OMM. Combined therapy with a CDK4/6 inhibitor and anti‐melanoma chemotherapeutic agents will be a reasonable strategy for future clinical trials concerning unresectable or metastatic OMM.

Mucosal melanomas of different anatomic sites share a common global DNA methylation profile with cutaneous melanoma but show location‐dependent patterns of genetic and epigenetic alterations

“…Two recent whole-genome sequencing studies were able to associate amplifications in these regions with structural rearrangements [10,48]. Also in line with these reports, we observed that focal amplification of TERT at the 5p15 gene locus primarily occurred in tumors of the oral cavity [49]. Furthermore, we observed that 11q13-14 amplification was enriched in melanomas of the nasal cavity, which has not previously been reported.…”

Potential role of cyclin-dependent kinase 4/6 inhibitors in the treatment of mucosal melanoma

“…The recent study conducted by Lyu et al revealed that amplification of CDK4 was often observed concurrently with TERT amplification in head and neck mucosal melanoma. Additionally, the study found that amplifications of CDK4 and TERT were correlated with higher levels of CDK4 and TERT protein expression [88]. These findings collectively suggest that gene amplification in the CDK4 pathway is a frequent genetic occurrence in the development of melanoma, and alterations in the copy number of genes within the CDK4 pathway could serve as a promising therapeutic target for mucosal melanoma.…”

Immortalized bovine satellite cells for cultured meat applications

“…The second consumer consideration relates to the fact that, in vivo , senescence escape and overexpression of TERT and CDK4 can be associated with various cancers 35,36 . There is to-date no evidence for DNA transfer from gene edited foods to humans 37 .…”