MUTYH: Not just polyposis

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.

MUTYH Actively Contributes to Microglial Activation and Impaired Neurogenesis in the Pathogenesis of Alzheimer’s Disease

“…Recently, the insulin secretagogues “sulfonylureas,” such as acetohexamide and glimepiride but not gliclazide or glibenclamide, were reported to induce MUTYH degradation dependent on proteasomes [ 76 ]; therefore, our hypothesis suggests that the inhibition or depletion of MUTYH in the brain by such drugs can ameliorate the AD pathogenesis which may be confirmed in the near future using these compounds, even with clinical subjects. Moreover, mutations in the MUTYH gene are known to predispose patients to the development of both colorectal polyposis and cancer [ 42 , 77 ]; however, our hypothesis suggests that they may be less susceptible to AD with efficient care for carcinogenesis.…”

“…The AD brain exhibits insulin resistance, and T2DM is a major risk factor for AD [ 1 – 3 , 31 ]; therefore, insulin secretagogues which can induce MUTYH degradation are promising therapeutic agents for the prevention of the AD pathogenesis. Because patients with mutations in the MUTYH gene do not predispose to brain tumors [ 42 , 77 ] and since we observed intestinal tumors but neither brain tumors nor neurodegeneration in MUTYH-deficient mice [ 25 , 33 ], the brain-specific delivery of drugs should be considered in order to minimize such adverse effects, including hypoglycemia.…”

Emerging Role of Oxidative Stress on EGFR and OGG1-BER Cross-Regulation: Implications in Thyroid Physiopathology

“…Although OGG1-BER protects the genome integrity by repairing the lesion or eliminating cells with malignant potential and its overexpression improves H 2 O 2 -induced cell death [ 22 ], in the case of TPC-1 cells, the lack of MUTYH gene expression could favor the maintenance of tumor phenotype loop [ 59 ]. Furthermore, this confirms that OGG1, as a sensor in the BER response, can be controlled both at the gene and protein level by the Pi3K/AKT pathway, while this was not detected following stimulation by EGF and H 2 O 2 .…”

Case Report: The Role of Molecular Analysis of the MUTYH Gene in Asymptomatic Individuals

“…Recently, it has been estimated that MUTYH mutations could cause some diseases that are not associated with polyposis, such as Parkinson’s disease, Alzheimer’s disease, Friedreich’s ataxia, Huntington’s disease, retinitis pigmentosa, and neurofibromatosis ( Curia et al, 2020 ).…”

“…MUTYH mutations can contribute to the development of sporadic gastric cancer. 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 ( Curia et al, 2020 ).…”