Monoallelic deleterious MUTYH germline variants as a driver for tumorigenesis

Autor(es)

Sequeira Barreiro, Rodrigo Araujo ^{[1, 2]} ; Sabbaga, Jorge ^[2] ; Rossi, Benedito M. ^[2] ; Achatz, Maria Isabel W. ^[2] ; Bettoni, Fabiana ^[2] ; Camargo, Anamaria A. ^[2] ; Asprino, Paula F. ^[2] ; Galante, Pedro A. F. ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Quim, Dept Bioquim, Sao Paulo - Brazil

^[2] Hosp Sirio Libanes, Ctr Oncol Mol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF PATHOLOGY; v. 256, n. 2 NOV 2021.
• Citações Web of Science: 0

Resumo

MUTYH encodes a glycosylase involved in the base excision repair of DNA. Biallelic pathogenic germline variants in MUTYH cause an autosomal recessive condition known as MUTYH-associated adenomatous polyposis and consequently increase the risk of colorectal cancer. However, reports of increased cancer risk in individuals carrying only one defective MUTYH allele are controversial and based on studies involving few individuals. Here, we describe a comprehensive investigation of monoallelic pathogenic MUTYH germline variants in 10,389 cancer patients across 33 different tumour types and 117,000 healthy individuals. Our results indicate that monoallelic pathogenic MUTYH germline variants can lead to tumorigenesis through a mechanism of somatic loss of heterozygosity of the functional MUTYH allele in the tumour. We confirmed that the frequency of monoallelic pathogenic MUTYH germline variants is higher in individuals with cancer than in the general population, although this frequency is not homogeneous among tumour types. We also demonstrated that the MUTYH mutational signature is present only in tumours with loss of the functional allele and found that the characteristic MUTYH base substitution (C>A) increases stop-codon generation. We identified key genes that are affected during tumorigenesis. In conclusion, we propose that carriers of the monoallelic pathogenic MUTYH germline variant are at a higher risk of developing tumours, especially those with frequent loss of heterozygosity events, such as adrenal adenocarcinoma, although the overall risk is still low. (c) 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley \& Sons, Ltd. (AU)

• Processo FAPESP: 18/15579-8 - Retroelementos: uma força motriz criando novidades genéticas no genoma humano e de camundongos
• Beneficiário: Pedro Alexandre Favoretto Galante
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores - Fase 2
• Processo FAPESP: 20/06091-1 - Análise de variantes genéticas determinantes para a infecção e evolução do quadro clínico em jovens adultos com COVID-19
• Beneficiário: Pedro Alexandre Favoretto Galante
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 19/04927-8 - Caracterização da variante D184Y no gene BRIP1 em família com histórico de câncer de mama e pâncreas.
• Beneficiário: Paula Fontes Asprino
• Modalidade de apoio: Auxílio à Pesquisa - Regular