Hereditary Colorectal Tumors: A Literature Review on MUTYH-Associated Polyposis

Kantor, Micaella; Sobrado, Javier; Patel, Sima; Eiseler, Sara; Ochner, Christopher N.

doi:10.1155/2017/8693182

Cited by 22 publications

(9 citation statements)

References 18 publications

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“…In particular, with regard to MUTYH p.Tyr179Cys, because of the rarity of the variant (allele frequency 0.002), the evidence presented raises the possibility of a mono-allelic effect for this variant[ 76 ]. Nevertheless, a two-fold increase in CRC risk was observed in mono-allelic carriers, thus providing evidence of a mono-allelic effect of the MUTYH gene, and was demonstrated in other studies[ 68 , 79 - 82 ].…”

Section: Mutyh In Polyposis and Colorectal Cancersupporting

confidence: 77%

MUTYH: Not just polyposis

Curia

Catalano

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2020

WJCO

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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.

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Section: Mutyh In Polyposis and Colorectal Cancersupporting

confidence: 77%

MUTYH: Not just polyposis

Curia

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2020

WJCO

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“…LOH was identified in the proband’s thyroid tumor sample. However, bi-allelic and mono-allelic carriers of MUTYH mutations are not known to be at risk of melanoma, renal or thyroid carcinoma ( Kantor et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Early Onset Multiple Primary Tumors in Atypical Presentation of Cowden Syndrome Identified by Whole-Exome-Sequencing

et al. 2018

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A family with an aggregation of rare early onset multiple primary tumors has been managed in our oncogenetics department: the proband developed four early onset carcinomas between ages 31 and 33 years, including acral melanoma, bilateral clear cell renal carcinoma (RC), and follicular variant of papillary thyroid carcinoma. The proband’s parent developed orbital lymphoma and small intestine mucosa-associated lymphoid tissue (MALT) lymphoma between 40 and 50 years old. Whole-exome-sequencing (WES) of the nuclear family (proband, parents, and sibling) identified in the proband a de novo deleterious heterozygous mutation c.1003C > T (p.Arg335∗) in the phosphatase and tensin homolog (PTEN) gene. Furthermore, WES allowed analysis of the nuclear family’s genetic background, and identified deleterious variants in two candidate modifier genes: CEACAM1 and MIB2. CEACAM1, a tumor suppressor gene, presents loss of expression in clear cell RC and is involved in proliferation of B cells. It could explain in part the phenotype of proband’s parent and the occurrence of clear cell RC in the proband. Deleterious mutations in the MIB2 gene are associated with melanoma invasion, and could explain the occurrence of melanoma in the proband. Cowden syndrome is a hereditary autosomal dominant disorder associated with increased risk of muco-cutaneous features, hamartomatous tumors, and cancer. This atypical presentation, including absence of muco-cutaneous lesions, four primary early onset tumors and bilateral clear cell RC, has not been described before. This encourages including the PTEN gene in panel testing in the context of early onset RC, whatever the histological subtype. Further studies are required to determine the implication of CEACAM1 and MIB2 in the severity of Cowden syndrome in our proband and occurrence of early onset MALT lymphoma in a parent.

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“…A recent eminent study shows that OGG1 inhibition is able to alleviate inflammatory conditions in vivo [157]. MUTYH is a base excision repair glycosylase that removes adenine opposite 8oxoguanine [158]. MUTYH has evolved from an OG:A mispair glycosylase to a multifunctional scaffold for rapid DNA damage response to a wide variety of DNA damaging signaling including PARP activation, ATR signaling, and SIRT6 activity.…”

Section: Oxidative Stressmentioning

confidence: 99%

Molecular Aspects of Colorectal Adenomas: The Interplay among Microenvironment, Oxidative Stress, and Predisposition

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Curia

2020

BioMed Research International

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The development of colorectal cancer (CRC) is a multistep process initiated by a benign polyp that has the potential to evolve into in situ carcinoma through the interactions between environmental and genetic factors. CRC incidence rates are constantly increased for young adult patients presenting an advanced tumor stage. The majority of CRCs arise from colonic adenomas originating from aberrant cell proliferation of colon epithelium. Endoscopic polypectomy represents a tool for early detection and removal of polyps, although the occurrence of cancers after negative colonoscopy shows a significant incidence. It has long been recognized that the aberrant regulation of Wingless/It (Wnt)/β-Catenin signaling in the pathogenesis of colorectal cancer is supported by its critical role in the differentiation of stem cells in intestinal crypts and in the maintenance of intestinal homeostasis. For this review, we will focus on the development of adenomatous polyps through the interplay between renewal signaling in the colon epithelium and reactive oxygen species (ROS) production. The current knowledge of molecular pathology allows us to deepen the relationships between oxidative stress and other risk factors as lifestyle, microbiota, and predisposition. We underline that the chronic inflammation and ROS production in the colon epithelium can impair the Wnt/β-catenin and/or base excision repair (BER) pathways and predispose to polyp development. In fact, the coexistence of oxidative DNA damage and errors in DNA polymerase can foster C>T transitions in various types of cancer and adenomas, leading to a hypermutated phenotype of tumor cells. Moreover, the function of Adenomatous Polyposis Coli (APC) protein in regulating DNA repair is very important as therapeutic implication making DNA damaging chemotherapeutic agents more effective in CRC cells that tend to accumulate mutations. Additional studies will determine whether approaches based on Wnt inhibition would provide long-term therapeutic value in CRC, but it is clear that APC disruption plays a central role in driving and maintaining tumorigenesis.

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Hereditary Colorectal Tumors: A Literature Review on MUTYH-Associated Polyposis

Cited by 22 publications

References 18 publications

MUTYH: Not just polyposis

MUTYH: Not just polyposis

Early Onset Multiple Primary Tumors in Atypical Presentation of Cowden Syndrome Identified by Whole-Exome-Sequencing

Molecular Aspects of Colorectal Adenomas: The Interplay among Microenvironment, Oxidative Stress, and Predisposition

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