MUTYH: Not just polyposis

MUTYH is a base excision repair enzyme, plays a crucial role in the correction of DNA errors from guanine oxidation and then may be considered a cell protective factor. In human 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 ones.This review evaluates the MUTYH role, focusing the attention on current studies about human neoplastic and non-neoplastic diseases different from colon polyposis and colorectal cancer. This provides novel insights into the understanding of the molecular basis underlying MUTYH-related pathogenesis. Furthermore, we described the association between MUTYHsingle nucleotide polymorphisms (SNPs) and different cancer and non-cancer diseases. We address the utility to deep our knowledge regarding MUTYH at the light of the recent advances from literature with the aim to better understand 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 results to be 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 to lung, hepatocellular and cervical cancer risk. An additional role of MUTYH seems to contribute in the prevention of numerous other disorders on 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 also in the improvement of the chemo-sensitivity of cancer cells.