The following is a summary of “Analysis of variants induced by combined ex vivo irradiation and in vivo tumorigenesis suggests a role for the ZNF831 p.R1393Q mutation in cutaneous melanoma development.,” published in the December 2024 issue of Dermatology by Usoltsev et al.
Ultraviolet (UV) radiation is a major environmental carcinogen for cutaneous melanoma, and while genomic analyses reveal significant UV damage in melanoma tumors, direct experimental observation of UV-signature mutations has not been achieved.
Researchers conducted a retrospective study using UV-irradiating cultured immortalized human melanocytes and performed in vivo tumorigenesis assays to replicate recurrent UV mutations from TCGA_SKCM specimens.
They UV-irradiated cultured immortalized human melanocytes and established xenograft tumor models for in vivo tumorigenesis assays. Exome sequencing was performed on the xenografted tumors to identify UV-signature mutations. These variants were compared with UV-hotspot mutations from TCGA skin cutaneous melanoma.
The results showed that exome sequencing of xenografted tumors revealed an increase in UV-signature mutations, with 48 induced variants overlapping TCGA skin cutaneous melanoma UV-hotspot mutations. The ZNF831 p.R1393Q mutation was linked to reduced survival (HR: 5.44; 95% CI: 1.92-15.47, P =0.0015) and was more frequent in melanomas than in all TCGA tumors (P =4.42×10-7). Additionally, loss of ZNF831 mRNA expression correlated with lower survival (HR=2.14, 95% CI: 1.62-2.83, P =7.91×10-8), with transcripts possibly originating from multiple cell types, including T cells.
Investigators concluded the overexpression of wildtype ZNF831 in multiple melanoma lines reduced spheroid growth, increased apoptosis, and enhanced cell motility, while the ZNF831 p.R1393Q variant partially or fully abolished these effects, thereby recovering a “functional UV-hotspot mutation” in ZNF831 observed in human melanoma specimens.
Source: sciencedirect.com/science/article/abs/pii/S0022202X2403015X
