Duodenal Adenomas and Cancer in MUTYH-associated Polyposis: An International Cohort Study

Thomas, Laura E.; Hurley, Joanna J.; Alonso, Ángel; Aznárez, M R; Bäckman, Anders; Björk, Jan; Capellà, Gabriel; Clark, Sue; Colas, Chrystelle; Dekker, Evelien; Dolwani, Sunil; Ghorbanoghli, Zeinab; Gonn, Mark; Romero, Sandra; Hes, Frederik J.; Jundi, Hala; Kelland, Sarah; Latchford, Andrew; Brito, Helena Leon; Lynch, Patrick M.; Meuser, Elena; Mork, Maureen E.; Mort, Matthew; García, Montse; Nielsen, Maartje; Parc, Yann; Ricci, Maria Teresa; Saurin, JC; Tuin, Karin van der; Vasen, Hans F. A.; Vilar, Eduardo; Vinet, Olivier; Vitellaro, Marco; Walton, Sarah-Jane; West, Hannah; Sampson, Julian R.

doi:10.1053/j.gastro.2020.10.038

Cited by 26 publications

(46 citation statements)

References 11 publications

(4 reference statements)

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“…Individuals with the MUTYH Y104*+/+ and MUTYH Y179C+/+ genotypes exhibited greater increases in somatic mutation rates than individuals with the MUTYH Y179C+/-G396D+/genotype. Previous detailed clinical phenotyping of large series indicates that individuals with biallelic truncating mutations or MUTYH Y179C+/+ show higher rates of accumulation of adenomas and earlier age of onset of carcinoma 22,23 than MUTYH Y179C+/-G396D+/-. The correlation between elevation of mutation rate and severity of clinical phenotype is further highlighted by individual PD44890 (16 years of age, MUTYH Y179C+/-G396D+/-) who exhibited a substantially higher mutation rate than others of this genotype, and showed a much accelerated rate of colorectal adenoma development (Extended Data Table 1-2).…”

Section: Discussionmentioning

confidence: 99%

“…These included five missense mutation homozygotes (four MUTYH Y179C+/+ , one MUTYH G286E+/+ ), three compound heterozygotes for the same pair of missense mutations (MUTYH Y179C+/-;G396D+/-), and two siblings homozygous for a nonsense mutation (MUTYH Y104*+/+ ). These MUTYH germline mutations have all been previously recognised as predisposing to MAP 22,23 . All 10 individuals had colorectal polyposis, with between 16 and >100 colonic adenomas, six were known to have duodenal polyps, five had colorectal cancer and one developed jejunal and pancreatic neuroendocrine cancer (Extended Data An intestinal crypt is constituted predominantly of a population of epithelial cells arising from a single recent common ancestor [34][35][36] .…”

Section: Clinical Informationmentioning

confidence: 94%

“…Mutations in MUTYH engineered in experimental systems can impair its glycosylase activity, reducing its ability to excise mispaired bases and leading to an increased rate of predominantly C>A mutations [14][15][16][17][18] . MUTYH mutations inherited in the germline in humans cause an autosomal recessive syndrome (MUTYH-associated polyposis, MAP) characterised by intestinal adenomatous polyposis and an elevated risk of early onset colorectal and duodenal cancer [19][20][21][22] . The age of onset and the burden of intestinal polyps are highly variable between individuals, ranging from 10s to 100s leading to a substantially increased incidence of colorectal cancer.…”

Section: Introductionmentioning

confidence: 99%

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Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells

Robinson

Thomas

Abascal

et al. 2021

Preprint

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Cellular DNA damage caused by reactive oxygen species is repaired by the base excision repair (BER) pathway which includes the DNA glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, the mechanistic progression from germline MUTYH mutations to MUTYH-Associated Polyposis (MAP) is incompletely understood. Here, we sequenced normal tissue DNAs from 10 individuals with MAP. Somatic base substitution mutation rates in intestinal epithelial cells were elevated 2 to 5-fold in all individuals, except for one showing a 33-fold increase, and were also increased in other tissues. The increased mutation burdens were of multiple mutational signatures characterised by C>A changes. Different mutation rates and signatures between individuals were likely due to different MUTYH mutations or additional inherited mutations in other BER pathway genes. The elevated base substitution rate in normal cells likely accounts for the predisposition to neoplasia in MAP. Despite ubiquitously elevated mutation rates, individuals with MAP do not display overt evidence of premature ageing. Thus, accumulation of somatic mutations may not be sufficient to cause the global organismal functional decline of ageing.

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Section: Discussionmentioning

confidence: 99%

Section: Clinical Informationmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells

Robinson

Thomas

Abascal

et al. 2021

Preprint

Self Cite

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“…Аденома ДПК -редкая опухоль ЖКТ (0,4%) [2], однако с увеличением частоты применения ЭГДС ее стали обнаруживать чаще [26]. Предрасполагающие факторы: семейный аденоматозный полипоз (САП) и MUTYHассоциированный полипоз [26], причем при САП аденому диагностируют в 3-4 раза чаще, чем при MUTYH-ассоциированном полипозе [27]. Описаны и спорадические наблюдения [2].…”

Section: обсуждение результатовunclassified

Computer-assisted and magnetic resonance imaging assessment of tumors and tumor invasion of the duodenum

Kаrmаzаnovsky

Abuladze²

2022

Ann. hir. gepatol.

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Aim: To present the computed tomography and magnetic resonance imaging assessments of benign and malignant duodenal tumors, pancreatic head adenocarcinoma invading the duodenum, and duodenal dystrophy.Methods: We searched for scientific papers and clinical guidelines in the information and analytical databases PubMed and Google Scholar from the 2013–2021 period using the following search terms: duodenal neoplasms, adenocarcinoma, duodenum, duodenal neuroendocrine tumors, duodenal adenoma, gastrointestinal stromal tumor, cholangiocarcinoma, radiology, magnetic resonance imaging, computed tomography, pancreatic head cancer. Then, we examined the reference lists of all the identified studies to collate the papers that would meet the eligibility criteria.Results: We analyzed 1494 articles, 22 of which were included in our review. From the papers published within 1992–2021, 35 articles from the reference lists were additionally included. Based on the search results, several domains of articles were clustered; the articles from those domains were reviewed and evaluated that involved the abovementioned diagnostic features.Conclusion: The early diagnosis and selection of appropriate management methods remain extremely relevant for the treatment of duodenal tumors, and hence, require careful attention from diagnosticians and clinicians.

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“…The mutation spectrum varies according to ethnic groups, suggesting population specific ancestral variants [ 98 ]. The Collaborative Group on MAP reported that the risk of duodenal polyposis in these patients is related to genotype, showing that p.Y179C homozygote patients have an increased risk [ 99 , 100 ].…”

Section: Small Bowel Adenomas In Hereditary Syndromesmentioning

confidence: 99%

Small Bowel Epithelial Precursor Lesions: A Focus on Molecular Alterations

Vanoli

Grillo

Furlan

et al. 2021

IJMS

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The wider use of gastrointestinal endoscopic procedures has led to an increased detection of small intestinal preneoplastic and neoplastic epithelial lesions, most of which are identified in the duodenum and ampullary region. Like their malignant counterparts, small intestinal glandular precursor lesions, which include adenomas and hamartomas, may arise sporadically or be associated with hereditary tumor syndromes, such as familial adenomatous polyposis, MUTYH-associated polyposis, Lynch syndrome, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and Cowden syndrome. In addition, dysplastic, preinvasive lesions have been observed adjacent to small bowel adenocarcinomas complicating immune-related disorders, such as celiac or Crohn’s disease. Adenomatous lesions may exhibit an intestinal-type, gastric-type, or, very rarely, serrated differentiation, related to different molecular pathogenetic mechanisms. Finally, in the background of multiple endocrine neoplasia 1 syndrome, precursor neuroendocrine growths have been described. In this review we offer a comprehensive description on the histo-molecular features of the main histotypes of small bowel epithelial precursors lesions, including: (i) sporadic adenomas (intestinal-type and gastric-type; non-ampullary and ampullary); (ii) syndromic adenomas; (iii) small bowel dysplasia in celiac and Crohn’s disease; (iv) serrated lesions; (v) hamartomatous lesions; and (vi) neuroendocrine precursor lesions.

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Duodenal Adenomas and Cancer in MUTYH-associated Polyposis: An International Cohort Study

Cited by 26 publications

References 11 publications

Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells

Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells

Computer-assisted and magnetic resonance imaging assessment of tumors and tumor invasion of the duodenum

Small Bowel Epithelial Precursor Lesions: A Focus on Molecular Alterations

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