AUTHOR=Kim Yoon-Seob , Lee Minho , Chung Yeun-Jun 

TITLE=Two subtypes of cutaneous melanoma with distinct mutational signatures and clinico-genomic characteristics

JOURNAL=Frontiers in Genetics

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.987205

DOI=10.3389/fgene.2022.987205

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold> To decipher mutational signatures and their associations with biological implications in cutaneous melanomas (CMs), including those with a low ultraviolet (UV) signature.</p><p><bold>Materials and Methods:</bold> We applied non-negative matrix factorization (NMF) and unsupervised clustering to the 96-class mutational context of The <italic>Cancer</italic> Genome Atlas (TCGA) cohort (<italic>N</italic> = 466) as well as other publicly available datasets (<italic>N</italic> = 527). To explore the feasibility of mutational signature-based classification using panel sequencing data, independent panel sequencing data were analyzed.</p><p><bold>Results:</bold> NMF decomposition of the TCGA cohort and other publicly available datasets consistently found two mutational signatures: UV (SBS7a/7b dominant) and non-UV (SBS1/5 dominant) signatures. Based on mutational signatures, TCGA CMs were classified into two clusters: UV-high and UV-low. CMs belonging to the UV-low cluster showed significantly worse overall survival and landmark survival at 1-year than those in the UV-high cluster; low or high UV signature remained the most significant prognostic factor in multivariate analysis. The UV-low cluster showed distinct genomic and functional characteristic patterns: low mutation counts, increased proportion of triple wild-type and <italic>KIT</italic> mutations, high burden of copy number alteration, expression of genes related to keratinocyte differentiation, and low activation of tumor immunity. We verified that UV-high and UV-low clusters can be distinguished by panel sequencing.</p><p><bold>Conclusion:</bold> Our study revealed two mutational signatures of CMs that divide CMs into two clusters with distinct clinico-genomic characteristics. Our results will be helpful for the clinical application of mutational signature-based classification of CMs.</p>