Mutational signatures and increased retrotransposon insertions in Xeroderma Pigmentosum variant skin tumors

Xeroderma Pigmentosum variant (XP-V) is an autosomal recessive disease with an increased risk to develop cutaneous neoplasms in sunlight exposed regions. These cells are deficient in the translesion synthesis DNA polymerase eta. Eleven skin tumors from a genetic cluster of XP-V patients had their exome sequenced. Mutational signatures identified for most tumors were related to ultraviolet exposure, such as C>T transitions targeted to pyrimidine dimers. However, four samples carry different mutational signatures, with C>A mutations associated with tobacco usage. Basal cell carcinomas showed a distinct C>A mutation spectra reflecting a novel mutational signature. Higher levels for retroposon insertions were detected in the XP-V tumors, compared to non-XP skin tumors. The results reveal other possible causes for XP-V tumors and the involvement of polymerase eta in suppressing retrotransposition. The expected high mutation burden, found in most of these tumors, renders these XP patients good candidates for immunotherapy with checkpoint blockers. ### Competing Interest Statement R.D.V. is an employee of L'Oreal Research & Innovation. However, the authors declare that the research was conducted in the absence of any commercial, financial, and non-financial relationships that could be construed as a potential conflict of interest. ### Funding Statement This work was supported by FAPESP (Sao Paulo Research Foundation, SP, Brazil) [grants #2019/19435-3, #2013/08028-1 and #2017/24418-5] under the International Collaboration Research from FAPESP and The Netherlands Organization for Scientific Research (NWO, The Netherlands); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brasilia, DF, Brazil, grant #308868/2018-8); Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES, Brasilia, DF, Brazil, financial code 001). This work was also supported by a grant from L Oreal Research & Innovation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Ethics Committee for Human Research of the Institute of Biomedical Sciences, University of Sao Paulo (SP, Brazil; protocols #1007 CEP, OF. CEPSH 045-13, and CAAE: 48347515.3.0000.5467). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.