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

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. 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.

Automated summary

This manuscript discusses the genetic alterations, including mutation signatures and retrotransposition insertions, found in the skin tumors of XP-V patients deficient in translesion synthesis (TLS). These alterations provide mechanistic insights into the functions of DNA polymerase eta. The study also highlights the importance of warning XP-V patients about the risks associated with sunlight exposure and tobacco usage, as well as the potential for using checkpoint blockade immunotherapy in these patients.