Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
Two subtypes of cutaneous melanoma with distinct mutational signatures and clinico-genomic characteristics
Ist Teil von
Frontiers in genetics, 2022-09, Vol.13, p.987205-987205
Ort / Verlag
Frontiers Media S.A
Erscheinungsjahr
2022
Link zum Volltext
Quelle
EZB Electronic Journals Library
Beschreibungen/Notizen
Background:
To decipher mutational signatures and their associations with biological implications in cutaneous melanomas (CMs), including those with a low ultraviolet (UV) signature.
Materials and Methods:
We applied non-negative matrix factorization (NMF) and unsupervised clustering to the 96-class mutational context of The
Cancer
Genome Atlas (TCGA) cohort (
N
= 466) as well as other publicly available datasets (
N
= 527). To explore the feasibility of mutational signature-based classification using panel sequencing data, independent panel sequencing data were analyzed.
Results:
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
KIT
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.
Conclusion:
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.