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

Abstract Xeroderma pigmentosum variant (XP-V) is an autosomal recessive disease with an increased risk of developing cutaneous neoplasms in sunlight-exposed regions. These cells are deficient in the translesion synthesis (TLS) DNA polymerase eta, responsible for bypassing different types of DNA lesions. From the exome sequencing of 11 skin tumors of a genetic XP-V patients’ cluster, classical mutational signatures related to sunlight exposure, such as C>T transitions targeted to pyrimidine dimers, were identified. However, basal cell carcinomas also showed distinct C>A mutation spectra reflecting a mutational signature possibly related to sunlight-induced oxidative stress. Moreover, four samples carry different mutational signatures, with C>A mutations associated with tobacco chewing or smoking usage. Thus, XP-V patients should be warned of the risk of these habits. Surprisingly, higher levels of retrotransposon somatic insertions were also detected when the tumors were compared with non-XP skin tumors, revealing other possible causes for XP-V tumors and novel functions for the TLS polymerase eta in suppressing retrotransposition. Finally, the expected high mutation burden found in most of these tumors renders these XP patients good candidates for checkpoint blockade immunotherapy. This manuscript describes the genetic alterations found in the skin tumors of XP-V patients deficient in translesion synthesis. The alterations include mutation signatures and retrotransposition insertions, which provide mechanistic information about DNA polymerase eta functions. Graphical Abstract This work provides the genetic variation detected in the exome of 11 skin tumors from XP-V patients (deficient in the translesion synthesis DNA polymerase eta). Seven of these tumors had an expected increase in C>T mutations in dipyrimidine sites, corresponding to a classical sunlight-induced mutation signature. However, the other four showed different mutation signatures, including those related to tobacco smoke. Most of the skin tumors also presented a novel C>A signature. Surprisingly, we also detected increased retrotransposition insertions in XPV tumors compared with non-XP skin tumors. Finally, an expected increase in the single base substitutions (high mutation burden) was found in these skin tumors compared with non-XP skin tumors. Created with BioRender.com.