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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Monoallelic deleterious MUTYH germline variants as a driver for tumorigenesis

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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]
Total Authors: 8
[1] Univ Sao Paulo, Inst Quim, Dept Bioquim, Sao Paulo - Brazil
[2] Hosp Sirio Libanes, Ctr Oncol Mol, Sao Paulo - Brazil
Total Affiliations: 2
Document type: Journal article
Source: JOURNAL OF PATHOLOGY; v. 256, n. 2 NOV 2021.
Web of Science Citations: 0

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)

FAPESP's process: 18/15579-8 - Retroelements: a driving force generating genetic novelties in the human and mouse genome
Grantee:Pedro Alexandre Favoretto Galante
Support type: Research Grants - Young Investigators Grants - Phase 2
FAPESP's process: 20/06091-1 - Analyses of genetic variants determining the infection and evolution course of COVID-19 in young adults
Grantee:Pedro Alexandre Favoretto Galante
Support type: Regular Research Grants
FAPESP's process: 19/04927-8 - Characterization of the D184Y variant in the BRIP1 gene in a family with breast and pancreatic cancer history.
Grantee:Paula Fontes Asprino
Support type: Regular Research Grants