Evidence for accelerated colorectal adenoma–carcinoma progression in<i>MUTYH</i>-associated polyposis?

Nieuwenhuis, Marry H.; Vogt, Stefanie; Jones, Natalie; Nielsen, Maartje; Hes, Frederik J.; Sampson, Julian R.; Aretz, Stefan; Vasen, Hans F. A.

doi:10.1136/gut.2010.229104

Cited by 59 publications

(56 citation statements)

References 24 publications

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“…We revealed that MAP adenomas have approximately two to four times the number of coding region somatic mutations when compared to FAP adenomas, and that these mutations are overwhelmingly G:C → T:A mutations, in keeping with the expected signature associated with MUTYH loss. This observation confirms, for the first time, the expectation that deficiency of MUTYH leads to a mutator phenotype in colorectal tumours, and is consistent with the observation of substantial colorectal cancer risk in MAP, even in the absence of dense polyposis 35. We find significant complexity in the patterns of mutated genes, such that, with the exception of APC , KRAS and WTX mutations, few adenomas have the same set of mutated driver genes, a novel observation that may have implications for the definition of high‐risk adenomas in the era of molecular pathology.…”

Section: Discussionsupporting

confidence: 90%

Adenoma development in familial adenomatous polyposis and MUTYH‐associated polyposis: somatic landscape and driver genes

Rashid

Fischer

Wilson

et al. 2015

The Journal of Pathology

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Familial adenomatous polyposis (FAP) and MUTYH‐associated polyposis (MAP) are inherited disorders associated with multiple colorectal adenomas that lead to a very high risk of colorectal cancer. The somatic mutations that drive adenoma development in these conditions have not been investigated comprehensively. In this study we performed analysis of paired colorectal adenoma and normal tissue DNA from individuals with FAP or MAP, sequencing 14 adenoma whole exomes (eight MAP, six FAP), 55 adenoma targeted exomes (33 MAP, 22 FAP) and germline DNA from each patient, and a further 63 adenomas by capillary sequencing (41 FAP, 22 MAP). With these data we examined the profile of mutated genes, the mutational signatures and the somatic mutation rates, observing significant diversity in the constellations of mutated driver genes in different adenomas, and loss‐of‐function mutations in WTX (9%; p < 9.99e‐06), a gene implicated in regulation of the WNT pathway and p53 acetylation. These data extend our understanding of the early events in colorectal tumourigenesis in the polyposis syndromes. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Discussionsupporting

confidence: 90%

Adenoma development in familial adenomatous polyposis and MUTYH‐associated polyposis: somatic landscape and driver genes

Rashid

Fischer

Wilson

et al. 2015

The Journal of Pathology

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“…To improve clinical identification of affected patients endoscopists as well as gastroenterologists, oncologists and abdominal surgeons must -in addition to other hereditary CRC syndromes (e.g., Lynch-Syndrome or APC mutation positive FAP)-be aware of MUTYH-associated disease. Because of the high lifetime relative risk of developing CRC in biallelic mutation carriers (63% develop CRC until the age of 60 [31]; odds ratio 28 [28]) and the high risk of developing CRC under surveillance [31] specific follow-up is needed for MAP patients (follow-up colonoscopies at shorter intervals, more aggressive surgery, screening for extracolonic manifestations) and their potentially affected but asymptomatic siblings (genetic testing, CRC prevention strategies). Whereas biallelic mutation carriers obviously benefit from timely identification it is unclear whether testing-associated anxiety may overcome advantages in monoallelic mutation carriers with only slightly elevated CRC risk [7,[12][13][14][15]28] compared to patients carrying wild-type alleles.…”

Section: Discussionmentioning

confidence: 99%

MUTYHhotspot mutations in unselected colonoscopy patients

et al. 2011

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Aim: Biallelic MUTYH germline mutations predispose to recessively inherited adenomatous polyposis, designated MUTYH-associated polyposis (MAP), and colorectal cancer (CRC).The hotspot mutations p.Y179C and p.G396D account for the majority of pathogenic variants in Caucasians. Our aim was to evaluate the prevalence of MUTYH mutations in clinical routine patients with different colorectal diseases. Method:The hotspot mutations p.Y179C and p.G396D were genotyped in 352 consecutive patients undergoing colonoscopy at our tertiary referral centre. Exons 2-14 were sequenced in hotspot mutation carriers to exclude additional variants.

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“…Overall, MUTYH-associatedpolyposis cancers appear to follow a distinct pathway compared to other colorectal cancers: some features overlap with chromosomal instability colorectal cancer phenotype, including frequent APC and KRAS mutations, 9,13 some others with microsatellite instability phenotype, including loss of HLA class I protein expression. 14 Recently, Nieuwenhuis and collaborators 15 have suggested the occurrence of an accelerated disease progression in MUTYH-associated-polyposis, underlying the high risk for patients to develop colorectal cancer even under surveillance.…”

mentioning

confidence: 99%

Oxidative DNA damage drives carcinogenesis in MUTYH-associated-polyposis by specific mutations of mitochondrial and MAPK genes

et al. 2013

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MUTYH is a DNA-base-excision-repair gene implicated in the activation of nuclear and mitochondrial cell-death pathways. MUTYH germline mutations cause an inherited polyposis, MUTYH-associated-polyposis, characterized by multiple adenomas and increased susceptibility to colorectal cancer. Since this carcinogenesis remains partially unknown, we searched for nuclear and mitochondrial gene alterations that may drive the tumorigenic process. Ninety-six adenomas and 7 carcinomas from 12 MUTYH-associated-polyposis and 13 classical/ attenuated adenomatous polyposis patients were investigated by sequencing and pyrosequencing for the presence of mutations in KRAS, BRAF, MT-CO1/MT-CO2 and MT-TD genes. KRAS mutations were identified in 24% MUTYH-associated-polyposis vs 15% classical/attenuated familial polyposis adenomas; mutated MUTYHassociated-polyposis adenomas exhibited only c.34G4T transversions in codon 12, an alteration typically associated with oxidative DNA damage, or mutations in codon 13; neither of these mutations was found in classical/attenuated familial polyposis adenomas (Po0.001). Mutated MUTYH-associated-polyposis carcinomas showed KRAS c.34G4T transversions, prevalently occurring with BRAFV600E; none of the classical/ attenuated familial polyposis carcinomas displayed these alterations. Comparing mitochondrial DNA from lymphocytes and adenomas of the same individuals, we detected variants in 82% MUTYH-associated-polyposis vs 38% classical/attenuated familial polyposis patients (P ¼ 0.040). MT-CO1/MT-CO2 missense mutations, which cause aminoacid changes, were only found in MUTYH-associated-polyposis lesions and were significantly associated with KRAS mutations (P ¼ 0.0085). We provide evidence that MUTYH-associated-polyposis carcinogenesis is characterized by the occurrence of specific mutations in both KRAS and phylogenetically conserved genes of mitochondrial DNA which are involved in controlling oxidative phosphorylation; this implies the existence of a colorectal tumorigenesis in which changes in mitochondrial functions cooperate with RAS-induced malignant transformation.

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Evidence for accelerated colorectal adenoma–carcinoma progression inMUTYH-associated polyposis?

Cited by 59 publications

References 24 publications

Adenoma development in familial adenomatous polyposis and MUTYH‐associated polyposis: somatic landscape and driver genes

Adenoma development in familial adenomatous polyposis and MUTYH‐associated polyposis: somatic landscape and driver genes

MUTYHhotspot mutations in unselected colonoscopy patients

Oxidative DNA damage drives carcinogenesis in MUTYH-associated-polyposis by specific mutations of mitochondrial and MAPK genes

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