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 DNA polymerase eta, responsible for bypassing different types of DNA lesions. From the exome sequencing of eleven 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 to 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.

Oral mucosa involvement in pediatric patients with xeroderma pigmentosum: a comprehensive review

“…Although the NER mechanism is the primary DNA repair pathway in UV exposure‐related damage, studies show that NER is also essential in repairing environmental chemical‐induced DNA damage such as smoking, chemotherapeutics, and aflatoxins 7 . Molecular studies in various tumors in XP patients showed that signature mutations associated with environmental factors, like smoking and aflatoxin exposure, were prominently expressed 8 …”