ArticleInternational journal of cancer2011
De novo constitutional MLH1 epimutations confer early-onset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one.
Article in International journal of cancer, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers, 3 of them syntheses that pooled it.
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Who cites it
45 citing papers in PubMed, 3 syntheses or guidelines pooled it.
- Japanese Society of Medical Oncology/Japan Society of Clinical Oncology/Japanese Society of Pediatric Hematology/Oncology-led clinical recommendations on the diagnosis and use of immunotherapy in patients with DNA mismatch repair deficient (dMMR) tumors, third edition.International journal of clinical oncology · 2023Guideline
- Mosaicism in Patients With Colorectal Cancer or Polyposis Syndromes: A Systematic Review.Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association · 2020Pooled it
- Japan Society of Clinical Oncology provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors, cooperated by Japanese Society of Medical Oncology, First Edition.International journal of clinical oncology · 2020Guideline
- Constitutional methylation of the MLH1 promoter: a case series including tumors not typically caused by Lynch Syndrome.European journal of human genetics : EJHG · 2026Article
- Germline MLH1 c.-42 C > T is a likely pathogenic variant predisposing to a reduced-penetrance/modified Lynch syndrome phenotype featuring MLH1-methylated cancers.Familial cancer · 2026Article
- MLH1 c.27G>A (p.Arg9=) is a synonymous likely/pathogenic variant underlying variably mosaic constitutional MLH1 methylation in Lynch syndrome.Familial cancer · 2025Article
- Towards the development of next-generation lung cancer immunotherapy.Translational lung cancer research · 2025Review
- Prediction of long-term recurrence-free and overall survival in early-onset colorectal cancer: the ENCORE multi-centre study.NPJ precision oncology · 2025Article
- Constitutional Epimutations: From Rare Events Toward Major Cancer Risk Factors?JCO precision oncology · 2025Review
- Unveiling pembrolizumab effectiveness in diverse subtypes of MSI-high endometrial cancers.Journal of gynecologic oncology · 2024Article
- Unraveling noncoding DNA variants and epimutations: a paradigm shift in hereditary cancer research.Future oncology (London, England) · 2024Review
- Constitutional MLH1 Methylation Is a Major Contributor to Mismatch Repair-Deficient, MLH1-Methylated Colorectal Cancer in Patients Aged 55 Years and Younger.Journal of the National Comprehensive Cancer Network : JNCCN · 2023Article
- MLH1-methylated endometrial cancer under 60 years of age as the "sentinel" cancer in female carriers of high-risk constitutional MLH1 epimutation.Gynecologic oncology · 2023Article
- Review article: Lynch Syndrome-a mechanistic and clinical management update.Alimentary pharmacology & therapeutics · 2022Review
- Hypermethylation ofEXCLI journal · 2022Article
- Young-onset colorectal cancer: A review.World journal of gastrointestinal oncology · 2021Review
- Recent advances in Lynch syndrome.Experimental hematology & oncology · 2021Review
- Microsatellite Instability: Diagnosis, Heterogeneity, Discordance, and Clinical Impact in Colorectal Cancer.Cancers · 2019Review
- Constitutional Mosaic Epimutations - a hidden cause of cancer?Cell stress · 2019Review
- Primary constitutional MLH1 epimutations: a focal epigenetic event.British journal of cancer · 2018Article
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15 authors.
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Abstract
Lynch syndrome is an autosomal dominant cancer predisposition syndrome classically caused by germline mutations of the mismatch repair genes, MLH1, MSH2, MSH6 and PMS2. Constitutional epimutations of the MLH1 gene, characterized by soma-wide methylation of a single allele of the promoter and allelic transcriptional silencing, have been identified in a subset of Lynch syndrome cases lacking a sequence mutation in MLH1. We report two individuals with no family history of colorectal cancer who developed that disease at age 18 and 20 years. In both cases, cancer had arisen because of the de novo occurrence of a constitutional MLH1 epimutation and somatic loss-of-heterozygosity of the functional allele in the tumors. We show for the first time that the epimutation in one case arose on the paternally inherited allele. Analysis of 13 tumors from seven individuals with constitutional MLH1 epimutations showed eight tumors had lost the second MLH1 allele, two tumors had a novel pathogenic missense mutation and three had retained heterozygosity. Only 1 of 12 tumors demonstrated the BRAF V600E mutation and 3 of 11 tumors harbored a mutation in KRAS. The finding that epimutations can originate on the paternal allele provides important new insights into the mechanism of origin of epimutations. It is clear that the second hit in MLH1 epimutation-associated tumors typically has a genetic not epigenetic basis. Individuals with mismatch repair-deficient cancers without the BRAF V600E mutation are candidates for germline screening for sequence or methylation changes in MLH1.
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