World Journal of W J C O Clinical Oncology Submit a Manuscript: https://www.f6publishing.com World J Clin Oncol 2020 July 24; 11(7): 428-449 DOI: 10.5306/wjco.v11.i7.428 ISSN 2218-4333 (online) REVIEW MUTYH: Not just polyposis Maria Cristina Curia, Teresa Catalano, Gitana Maria Aceto ORCID number: Maria Cristina Curia Maria Cristina Curia, Gitana Maria Aceto, Department of Medical, Oral and Biotechnological 0000-0003-4979-887X; Teresa Sciences, “G. d'Annunzio” University of Chieti-Pescara, Chieti, Via dei Vestini 66100, Italy Catalano 0000-0001-6713-3818; Gitana Maria Aceto 0000-0002-6845- Teresa Catalano, Department of Clinical and Experimental Medicine, University of Messina, 1321. Messina, Via Consolare Valeria 98125, Italy Author contributions: Curia MC, Corresponding author: Maria Cristina Curia, PhD, DSc, Associate Professor, Department of Catalano T and Aceto GM Medical, Oral and Biotechnological Sciences, “G. d'Annunzio” University of Chieti-Pescara, contributed equally to this paper Chieti, Via dei Vestini 66100, Italy. [email protected] with regard to the design of the study, literature review and analysis, writing, and approval of the final version. Abstract MUTYH is a base excision repair enzyme, it plays a crucial role in the correction Supported by the Italian Ministry of DNA errors from guanine oxidation and may be considered a cell protective of University and Research, with factor. In humans it is an adenine DNA glycosylase that removes adenine funds AT-Ricerca2019Curia, misincorporated in 7,8-dihydro-8-oxoguanine (8-oxoG) pairs, inducing G:C to T:A FFABRUNIME2019Catalano and transversions. MUTYH functionally cooperates with OGG1 that eliminates 8- AT-Ricerca2019Aceto. oxodG derived from excessive reactive oxygen species production. MUTYH mutations have been linked to MUTYH associated polyposis syndrome (MAP), an Conflict-of-interest statement: The autosomal recessive disorder characterized by multiple colorectal adenomas. authors declare that they have no MAP patients show a greatly increased lifetime risk for gastrointestinal cancers. conflicts of interest regarding the The cancer risk in mono-allelic carriers associated with one MUTYH mutant allele publication of this paper. is controversial and it remains to be clarified whether the altered functions of this Open-Access: This article is an protein may have a pathophysiological involvement in other diseases besides open-access article that was familial gastrointestinal diseases. This review evaluates the role of MUTYH, selected by an in-house editor and focusing on current studies of human neoplastic and non-neoplastic diseases fully peer-reviewed by external different to colon polyposis and colorectal cancer. This will provide novel insights reviewers. It is distributed in into the understanding of the molecular basis underlying MUTYH-related accordance with the Creative pathogenesis. Furthermore, we describe the association between MUTYH single Commons Attribution nucleotide polymorphisms (SNPs) and different cancer and non-cancer diseases. NonCommercial (CC BY-NC 4.0) We address the utility to increase our knowledge regarding MUTYH in the light license, which permits others to of recent advances in the literature with the aim of a better understanding of the distribute, remix, adapt, build potential for identifying new therapeutic targets. Considering the multiple upon this work non-commercially, functions and interactions of MUTYH protein, its involvement in pathologies and license their derivative works based on oxidative stress damage could be hypothesized. Although the development of extraintestinal cancer in MUTYH heterozygotes is not completely on different terms, provided the defined, the risk for malignancies of the duodenum, ovary, and bladder is also original work is properly cited and increased as well as the onset of benign and malignant endocrine tumors. The the use is non-commercial. See: htt presence of MUTYH pathogenic variants is an independent predictor of poor p://creativecommons.org/licenses prognosis in sporadic gastric cancer and in salivary gland secretory carcinoma, /by-nc/4.0/ WJCO https://www.wjgnet.com 428 July 24, 2020 Volume 11 Issue 7 Curia MC et al. MUTYH in polyposis, cancer and other disorders Manuscript source: Invited while its inhibition has been shown to reduce the survival of pancreatic ductal manuscript adenocarcinoma cells. Furthermore, some MUTYH SNPs have been associated with lung, hepatocellular and cervical cancer risk. An additional role of MUTYH Received: February 28, 2020 seems to contribute to the prevention of numerous other disorders with an Peer-review started: March 2, 2020 inflammatory/degenerative basis, including neurological and ocular diseases. First decision: April 2, 2020 Finally, it is interesting to note that MUTYH could be a new therapeutic target Revised: May 8, 2020 and future studies will shed light on its specific functions in the prevention of Accepted: May 27, 2020 diseases and in the improvement of the chemo-sensitivity of cancer cells. Article in press: May 27, 2020 Published online: July 24, 2020 Key words: MUTYH; Polyposis; Colorectal cancer; Base excision repair; Mutations; Single nucleotide polymorphism P-Reviewer: Ju SQ, Tarnawski AS S-Editor: Zhang H ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved. L-Editor: Webster JR E-Editor: Wang LL 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. Citation: Curia MC, Catalano T, Aceto GM. MUTYH: Not just polyposis. World J Clin Oncol 2020; 11(7): 428-449 URL: https://www.wjgnet.com/2218-4333/full/v11/i7/428.htm DOI: https://dx.doi.org/10.5306/wjco.v11.i7.428 INTRODUCTION Biallelic germline MUTYH (MutY homolog Escherichia coli, homolog of MYH, hMYH) gene variants were historically identified in a fraction of Adenomatous Polyposis Coli ( APC) mutation-negative cases with a phenotype overlapping with attenuated familial adenomatous polyposis (AFAP) or classical familial adenomatous polyposis (FAP) (MIM# 604933)[1,2]. In humans, MUTYH protein is considered a cell protective factor able to counteract oxidative damage. It is a DNA glycosylase involved in the restoration of post-replicative mispairs in double-stranded DNA, where MUTYH recognizes and specifically removes adenine or 2-hydroxyadenines misincorporated in 7,8-dihydro-8-oxoguanine (8-oxoG) pairs with adenine or cytosine inducing G:C to T:A transversions as a consequence of DNA replication errors or DNA recombination[3-5]. In 1996 E. coli mutY gene (mutY) was cloned and characterized for the first time[6]. It encodes a protein involved in the bacterial repair system together with mutM, homologous of human 8-Oxoguanine glycosylase 1 (OGG1), and mutT that hydrolyzes 8-oxo-dGTP[7-9]. In E. coli MutY, MutM and MutT compose the GO (formally known as Guanine Oxidation) system responsible for removing and correcting mutations due to adducts[7]. Human MUTYH and OGG1 act like their E. coli homologs MutT and MutM to avoid the mutagenic consequences induced by 8-oxoG. Moreover, MUTYH shows 41% of homology to the E. coli corresponding protein[6]. In 1998, the sequence of SpMYH gene, the mutY homolog of the yeast Schizosaccharomyces pombe, was identified[10]. The SpMYH protein, that removes misincorporated G from 8-oxoG, shows 28% and 31% identity to E. coli MutY and human MUTYH, respectively[10,11]. In 2002, the role of the MUTYH gene in inherited predisposition to colorectal cancer (CRC) was identified in a British family, suggesting that an inefficient MUTYH protein and a defective base excision repair (BER) increase the incidence of somatic G > T transversions in APC gene[1]. Subsequent studies described germline biallelic mutations involved in MUTYH associated polyposis (MAP), a recessive heritable colorectal polyposis with an increased risk of CRC[12,13]. Further research explored MUTYH modifications associated with a hypermutable phenotype involving different organs and the development of various diseases, including cancers, through the WJCO https://www.wjgnet.com 429 July 24, 2020 Volume 11 Issue 7 Curia MC et al. MUTYH in polyposis, cancer and other disorders accumulation of unrepaired 8-oxoG under conditions of oxidative stress. In this review we evaluate biochemical and functional aspects as well as the role of MUTYH in BER. Moreover, we focus on current and updated studies on human diseases induced by alteration of MUTYH through research that associate it with neoplastic and non-neoplastic pathologies different to colon polyposis and CRC. This will produce 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