Mutational signatures and increased retrotransposon insertions in xeroderma pigmentosum variant skin tumors.

This article focuses on the mutational profiles and genomic characteristics of skin tumors from xeroderma pigmentosum variant (XP-V) patients, a genetic disorder caused by deficiency in the translesion synthesis (TLS) DNA polymerase eta (Pol η). Whole-exome sequencing of 11 skin tumors from six XP-V patients in a Brazilian genetic cluster revealed classical UV-induced mutation signatures (notably C>T transitions at dipyrimidine sites) in seven tumors, while four tumors exhibited distinct mutation patterns including C>A transversions linked to tobacco chewing or smoking. Additionally, XP-V tumors showed a higher burden of somatic retrotransposon insertions compared to non-XP skin cancers, suggesting a novel role for Pol η in suppressing retrotransposition. The high tumor mutational burden observed supports the potential efficacy of immune checkpoint blockade immunotherapy for XP-V patients.