Current status of the genetic susceptibility in attenuated adenomatous polyposis

Lorca, Víctor; Garré, Pilar

doi:10.4251/wjgo.v11.i12.1101

Cited by 6 publications

(30 citation statements)

References 114 publications

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“…With the recent development of sequencing technology, new genetic alterations that cause AAP are being identi ed [7][8][9][10]. Other than APC and MUTYH genetic alterations, variations in POLE, POLD1, NTHL1, MSH3, and MLH3 genes have been reported in AAP cases [1].…”

Section: Discussionmentioning

confidence: 99%

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Attenuated adenomatous polyposis with MSH6 variation: two case reports

Kim

Lee

Ahn

et al. 2023

Preprint

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Background: Adenomatous polyposis (AP) is a genetic disorder characterized by the occurrence of numerous adenomatous polyps in the colon and rectum and can be classified into classical AP (CAP) and attenuated AP (AAP). AAP is diagnosed when the number of observed adenomas is between 10 and 99. The detection of AAP is significantly increasing mainly due to the improvement of the imaging technique and application of the screening program for colorectal cancer detection. Currently, the germline variations of the APC and MUTYH genes are reported as the main cause of CAP. However, the underlying genetic basis of AAP is not well understood. In this study, we report two cases of AAP with MSH6 variations. Case reports: The two patients had multiple colon polyps and were diagnosed with AAP. The two received genetic consultation; and, for follow-up purposes, both patients agreed to be tested for an underlying genetic condition through next generation sequencing (NGS). Germline MSH6 variations were detected in both patients. Conclusion: Minor portion of AAP can cause by genetic mutation in MSH6, and further research is needed.

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Section: Discussionmentioning

confidence: 99%

“…Adenomatous polyposis (AP) is a genetic disorder characterized by occurrence of numerous adenomatous polyps in the colon and rectum [1]. Adenomatous polyposis is classi ed as classical AP (CAP) and attenuated AP (AAP) according to the number of adenomas [1].…”

Section: Introductionmentioning

confidence: 99%

Attenuated adenomatous polyposis with MSH6 variation: two case reports

Kim

Lee

Ahn

et al. 2023

Preprint

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“…MUTYH loss of function alterations leads to defective BER and an increased incidence of G:C to T:A transversions throughout the genome. The most commonly described germline loss of function MUTYH variants are Y179C (rs34612342) and G396D (rs36053993), which account for 75% of the reported mutations and are most prevalent in Caucasians [24][25][26].…”

Section: Discussionmentioning

confidence: 99%

Complete Response to Immunotherapy in a Patient with MUTYH-Associated Polyposis and Gastric Cancer: A Case Report

Mathias-Machado¹,

Peixoto²,

Ashton‐Prolla

et al. 2023

Case Rep Oncol

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MUTYH-associated polyposis syndrome is an uncommon, autosomal recessive colorectal polyposis syndrome caused by biallelic inactivation of <i>MUTYH</i>. Most patients present with multiple colorectal polyps. However, other primary tumor sites have been described as less frequent. In this report, we describe the case of a young patient with a germline biallelic pathogenic MUTYH mutation with three different primary tumors. We focused on a metastatic gastric adenocarcinoma that presented with complete bowel obstruction secondary to extensive peritoneal carcinomatosis and achieved complete response upon treatment with immunotherapy. The patient’s tumor presented with a high tumor mutational burden and a 100% combined positive score, which certainly contributed to the complete response to immunotherapy. To date, no studies have described the association of <i>MUTYH</i>-related tumors with high PD-L1 expression, but we hypothesized that it may be linked to the increased antigenicity of these cancers.

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“…Mutations located throughout the entire MUTYH have been described in MAP, but only two missense mutations, p.Tyr179Cys and p.Gly396Asp, are the most prevalent in Caucasians and account for approximately 75% of the reported mutations in MAP patients[ 74 ]. Other population-specific MUTYH mutations have been found[ 34 , 52 , 69 , 75 ].…”

Section: Mutyh In Polyposis and Colorectal Cancermentioning

confidence: 99%

MUTYH: Not just polyposis

Curia

Catalano

Aceto

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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Current status of the genetic susceptibility in attenuated adenomatous polyposis

Cited by 6 publications

References 114 publications

Attenuated adenomatous polyposis with MSH6 variation: two case reports

Attenuated adenomatous polyposis with MSH6 variation: two case reports

Complete Response to Immunotherapy in a Patient with MUTYH-Associated Polyposis and Gastric Cancer: A Case Report

MUTYH: Not just polyposis

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