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

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art_CORRADI_Mutational_signatures_and_increased_retrotransposon_insertions_in_xeroderma_2023.PDF (37.11 MB)
Citações na Scopus
2
Tipo de produção
article
Data de publicação
2023
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
OXFORD UNIV PRESS
Autores
CORRADI, Camila
VILAR, Juliana B.
BUZATTO, Vanessa C.
SOUZA, Tiago A. de
CASTRO, Ligia P.
MUNFORD, Veridiana
VECCHI, Rodrigo De
GALANTE, Pedro A. F.
ORPINELLI, Fernanda
MILLER, Thiago L. A.
Citação
CARCINOGENESIS, v.44, n.6, p.511-524, 2023
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
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.
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URI
https://observatorio.fm.usp.br/handle/OPI/56182
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MPT
Artigos e Materiais de Revistas Científicas - HC/InCor
Artigos e Materiais de Revistas Científicas - LIM/05
Artigos e Materiais de Revistas Científicas - LIM/53
Artigos e Materiais de Revistas Científicas - ODS/03