Adenomatous Polyposis Syndromes: MUTYH-Associated Polyposis

Nielsen, Maartje; Aretz, Stephan

doi:10.1007/978-3-319-74259-5_9

Cited by 14 publications

(17 citation statements)

References 75 publications

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“…In our analysis, the p values were nominally significant for all models for the rs34612342 variant and for the allelic and dominant models for the rs36053993 variant. For the former variant, the magnitude of effect was greatest for the recessive model, although with wide CIs, which is intriguing as MAP, in which highly penetrant mutations are implicated, and is inherited in an autosomal recessive manner 45…”

Section: Discussionmentioning

confidence: 89%

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Systematic meta-analyses, field synopsis and global assessment of the evidence of genetic association studies in colorectal cancer

Montazeri

Nyiraneza

et al. 2019

Gut

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ObjectiveTo provide an understanding of the role of common genetic variations in colorectal cancer (CRC) risk, we report an updated field synopsis and comprehensive assessment of evidence to catalogue all genetic markers for CRC (CRCgene2).DesignWe included 869 publications after parallel literature review and extracted data for 1063 polymorphisms in 303 different genes. Meta-analyses were performed for 308 single nucleotide polymorphisms (SNPs) in 158 different genes with at least three independent studies available for analysis. Scottish, Canadian and Spanish data from genome-wide association studies (GWASs) were incorporated for the meta-analyses of 132 SNPs. To assess and classify the credibility of the associations, we applied the Venice criteria and Bayesian False-Discovery Probability (BFDP). Genetic associations classified as ‘positive’ and ‘less-credible positive’ were further validated in three large GWAS consortia conducted in populations of European origin.ResultsWe initially identified 18 independent variants at 16 loci that were classified as ‘positive’ polymorphisms for their highly credible associations with CRC risk and 59 variants at 49 loci that were classified as ‘less-credible positive’ SNPs; 72.2% of the ‘positive’ SNPs were successfully replicated in three large GWASs and the ones that were not replicated were downgraded to ‘less-credible’ positive (reducing the ‘positive’ variants to 14 at 11 loci). For the remaining 231 variants, which were previously reported, our meta-analyses found no evidence to support their associations with CRC risk.ConclusionThe CRCgene2 database provides an updated list of genetic variants related to CRC risk by using harmonised methods to assess their credibility.

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Section: Discussionmentioning

confidence: 89%

“…For the former variant, the magnitude of effect was greatest for the recessive model, although with wide CIs, which is intriguing as MAP, in which highly penetrant mutations are implicated, and is inherited in an autosomal recessive manner. 45 …”

Section: Discussionmentioning

confidence: 99%

Systematic meta-analyses, field synopsis and global assessment of the evidence of genetic association studies in colorectal cancer

Montazeri

Nyiraneza

et al. 2019

Gut

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“…While subject to revision as information on the features of MANS accrues, we propose two-yearly colonoscopy from age 18-20 or the date of diagnosis, a regimen often used for other polyposis syndromes caused by deficiency of MUTYH or NTHL1. 21,22 Regular colonoscopy may avoid the need for prophylactic or therapeutic colectomy, especially in patients with relatively low adenoma burdens. Upper gastrointestinal endoscopy is warranted in almost all other polyposis syndromes and it may be prudent to survey the stomach and duodenum at the current time, despite the lack of small bowel or gastric lesions reported in our patients.…”

Section: Discussionmentioning

confidence: 99%

Germline loss-of-function variants in the base-excision repair geneMBD4cause a Mendelian recessive syndrome of adenomatous colorectal polyposis and acute myeloid leukaemia

Palles

Chew

et al. 2021

Preprint

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Inherited defects in base-excision repair (BER) predispose to adenomatous polyposis and colorectal cancer (CRC), yet our understanding of this important DNA repair pathway remains incomplete. By combining detailed clinical, histological and molecular profiling, we reveal biallelic germline loss-of-function (LOF) variants in the BER gene MBD4 to predispose to adenomatous polyposis and -uniquely amongst CRC predisposition syndromes- to myeloid neoplasms. Neoplasms from MBD4-deficient patients almost exclusively accumulate somatic CpG>TpG mutations, resembling mutational signature SBS1. MBD4-deficient adenomas harbour mutations in known CRC driver genes, although AMER1 mutations were more common and KRAS mutations less frequent. We did not find an increased risk for colorectal tumours in individuals with a monoallelic MBD4 LOF variant. We suggest that this condition should be termed MBD4-associated neoplasia syndrome (MANS) and that MBD4 is included in testing for the genetic diagnosis of polyposis and/or early-onset AML.

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“…In approximately 0.5% of CRC cases, MUTYH-associated polyposis (MAP) is caused by biallelic germline variants in the MUTYH gene associated with base-excision repair. MAP is diagnosed in 8%-13% of FAP-like clinicopathological backgrounds without APC germline variants and is associated with the risk of CRC in 43%-63% at the age of 60 years, and the median age of onset is 48 years [89]. It is recognized that monoallelic MUTYH variants are detected in 1%-2% of the general population.…”

Section: Continuedmentioning

confidence: 99%

Cancer Genomic Profiling in Colorectal Cancer: Current Challenges in Subtyping Colorectal Cancers Based on Somatic and Germline Variants

Hinoi

2021

J Anus Rectum Colon

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Colorectal cancer (CRC) is a heterogeneous disease caused by the accumulation of multistep genetic alterations under the influence of genomic instability. Different backgrounds of genomic instability, such as chromosomal instability, microsatellite instability, hypermutated-single nucleotide variants, and genome stableinduced transformation in the colonic epithelium, can result in adenomas, adenocarcinomas, and metastatic tumors. Characterization of molecular subtypes and establishment of treatment policies based on each subtype will lead to better treatment outcomes and an improved selection of molecularly targeted agents. In Japan, cancer precision medicine has been introduced in the National Health Insurance program through the addition of the cancer genomic profiling (CGP) examination. It has also become possible to access a large amount of genomic information, including information on pathogenic somatic and germline variants, incomparable to conventional diagnostic tests. This information enables us to apply research data to clinical decision-making, benefiting patients and their healthy family members. In this article, we discuss the important molecules and signaling pathways presumed to be the driver genes of CRC progression and the signal transduction system in which they are involved. Molecular subtypes of CRC based on CGP examinations and gene expression profiles have been established in The Cancer Genome Atlas Network with the advent of next-generation sequencing technology. We will also discuss the recommended management of secondary/germline findings, pathogenic germline variants, and presumed germline pathogenic variants obtained from CGP examination and review the current challenges to better understand these data in a new era of cancer genomic medicine.

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Adenomatous Polyposis Syndromes: MUTYH-Associated Polyposis

Cited by 14 publications

References 75 publications

Systematic meta-analyses, field synopsis and global assessment of the evidence of genetic association studies in colorectal cancer

Systematic meta-analyses, field synopsis and global assessment of the evidence of genetic association studies in colorectal cancer

Germline loss-of-function variants in the base-excision repair geneMBD4cause a Mendelian recessive syndrome of adenomatous colorectal polyposis and acute myeloid leukaemia

Cancer Genomic Profiling in Colorectal Cancer: Current Challenges in Subtyping Colorectal Cancers Based on Somatic and Germline Variants

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