Review
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Jul 24, 2020; 11(7): 428-449
Published online Jul 24, 2020. doi: 10.5306/wjco.v11.i7.428
MUTYH: Not just polyposis
Maria Cristina Curia, Teresa Catalano, Gitana Maria Aceto
Maria Cristina Curia, Gitana Maria Aceto, Department of Medical, Oral and Biotechnological Sciences, “G. d'Annunzio” University of Chieti-Pescara, Chieti, Via dei Vestini 66100, Italy
Teresa Catalano, Department of Clinical and Experimental Medicine, University of Messina, Messina, Via Consolare Valeria 98125, Italy
Author contributions: Curia MC, Catalano T and Aceto GM contributed equally to this paper with regard to the design of the study, literature review and analysis, writing, and approval of the final version.
Supported by the Italian Ministry of University and Research, with funds AT-Ricerca2019Curia, FFABRUNIME2019Catalano and AT-Ricerca2019Aceto.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest regarding the publication of this paper.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Maria Cristina Curia, PhD, DSc, Associate Professor, Department of Medical, Oral and Biotechnological Sciences, “G. d'Annunzio” University of Chieti-Pescara, Chieti, Via dei Vestini 66100, Italy. mc.curia@unich.it
Received: February 28, 2020
Peer-review started: March 2, 2020
First decision: April 2, 2020
Revised: May 8, 2020
Accepted: May 27, 2020
Article in press: May 27, 2020
Published online: July 24, 2020
Abstract

MUTYH is a base excision repair enzyme, it plays a crucial role in the correction of DNA errors from guanine oxidation and may be considered a cell protective factor. In humans it is an adenine DNA glycosylase that removes adenine misincorporated in 7,8-dihydro-8-oxoguanine (8-oxoG) pairs, inducing G:C to T:A transversions. MUTYH functionally cooperates with OGG1 that eliminates 8-oxodG derived from excessive reactive oxygen species production. MUTYH mutations have been linked to MUTYH associated polyposis syndrome (MAP), an autosomal recessive disorder characterized by multiple colorectal adenomas. MAP patients show a greatly increased lifetime risk for gastrointestinal cancers. The cancer risk in mono-allelic carriers associated with one MUTYH mutant allele is controversial and it remains to be clarified whether the altered functions of this protein may have a pathophysiological involvement in other diseases besides familial gastrointestinal diseases. This review evaluates the role of MUTYH, focusing on current studies of human neoplastic and non-neoplastic diseases different to colon polyposis and colorectal cancer. This will provide novel insights into the understanding of the molecular basis underlying MUTYH-related pathogenesis. Furthermore, we describe the association between MUTYH single nucleotide polymorphisms (SNPs) and different cancer and non-cancer diseases. We address the utility to increase our knowledge regarding MUTYH in the light of recent advances in the literature with the aim of a better understanding of the potential for identifying new therapeutic targets. Considering the multiple functions and interactions of MUTYH protein, its involvement in pathologies based on oxidative stress damage could be hypothesized. Although the development of extraintestinal cancer in MUTYH heterozygotes is not completely defined, the risk for malignancies of the duodenum, ovary, and bladder is also increased as well as the onset of benign and malignant endocrine tumors. The presence of MUTYH pathogenic variants is an independent predictor of poor prognosis in sporadic gastric cancer and in salivary gland secretory carcinoma, while its inhibition has been shown to reduce the survival of pancreatic ductal adenocarcinoma cells. Furthermore, some MUTYH SNPs have been associated with lung, hepatocellular and cervical cancer risk. An additional role of MUTYH seems to contribute to the prevention of numerous other disorders with an inflammatory/degenerative basis, including neurological and ocular diseases. Finally, it is interesting to note that MUTYH could be a new therapeutic target and future studies will shed light on its specific functions in the prevention of diseases and in the improvement of the chemo-sensitivity of cancer cells.

Keywords: MUTYH, Polyposis, Colorectal cancer, Base excision repair, Mutations, Single nucleotide polymorphism

Core tip: This review focuses on the role of MUTYH, linked to MUTYH associated polyposis syndrome, on human neoplastic and non-neoplastic diseases, different to polyposis and colorectal cancer, considering its involvement in disorders based on oxidative stress damage. MUTYH pathogenic variants are independent predictors of poor prognosis in sporadic gastric, salivary gland secretory, pancreatic ductal, lung and cervical cancers, whereas some variants are involved in degenerative disorders, including neurological and ocular diseases. This provides novel insights for identifying the molecular basis of MUTYH pathogenesis in the light of recent advances, to better understand its potential in disease prevention and identify new therapeutic targets.