ArticleCancer medicine2018
Contribution of MLH1 constitutional methylation for Lynch syndrome diagnosis in patients with tumor MLH1 downregulation.
Article in Cancer medicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers, 2 of them syntheses that pooled it.
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Who cites it
27 citing papers in PubMed, 2 syntheses or guidelines pooled it, 57 citations in OpenAlex.
- Genomic mosaicism in colorectal cancer and polyposis syndromes: a systematic review and meta-analysis.International journal of colorectal disease · 2024Pooled it
- 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
- Current Status of the Diagnosis and Treatment of Mismatch Repair Deficient Colorectal Cancer.Biomedicines · 2026Review
- Article
- Lynch Syndrome in Focus: A Multidisciplinary Review of Cancer Risk, Clinical Management, and Special Populations.Cancers · 2025Review
- Constitutional Epimutations: From Rare Events Toward Major Cancer Risk Factors?JCO precision oncology · 2025Review
- Altered chromatin landscape and 3D interactions associated with primary constitutional MLH1 epimutations.Clinical epigenetics · 2024Article
- Review
- Testing region selection and prognostic analysis ofGastroenterology report · 2024Article
- Comparison of immediate germline sequencing and multi-step screening for Lynch syndrome detection in high-risk endometrial and colorectal cancer patients.Journal of gynecologic oncology · 2024Article
- Early-Onset Ovarian Cancer <30 Years: What Do We Know about Its Genetic Predisposition?International journal of molecular sciences · 2023Review
- Article
- DNA Methylation in the Fields of Prenatal Diagnosis and Early Detection of Cancers.International journal of molecular sciences · 2023Review
- Identifying primary and secondary MLH1 epimutation carriers displaying low-level constitutional MLH1 methylation using droplet digital PCR and genome-wide DNA methylation profiling of colorectal cancers.Clinical epigenetics · 2023Article
- Pharmacogenetic Review: Germline Genetic Variants Possessing Increased Cancer Risk With Clinically Actionable Therapeutic Relationships.Frontiers in genetics · 2022Review
- Recent advances in Lynch syndrome.Experimental hematology & oncology · 2021Review
- Silencing of long non-coding RNA FOXD2-AS1 inhibits the progression of gallbladder cancer by mediating methylation of MLH1.Gene therapy · 2021Article
- Lynch Syndrome: Its Impact on Urothelial Carcinoma.International journal of molecular sciences · 2021Review
- Should All Individuals Be Screened for Genetic Predisposition to Cancer?Genetics research · 2021Review
- Current prognostic and predictive biomarkers for gastrointestinal tumors in clinical practice.Pathologica · 2020Review
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Constitutional epimutation of the two major mismatch repair genes, MLH1 and MSH2, has been identified as an alternative mechanism that predisposes to the development of Lynch syndrome. In the present work, we aimed to investigate the prevalence of MLH1 constitutional methylation in colorectal cancer (CRC) patients with abnormal expression of the MLH1 protein in their tumors. In a series of 38 patients who met clinical criteria for Lynch syndrome genetic testing, with loss of MLH1 expression in the tumor and with no germline mutations in the MLH1 gene (35/38) or with tumors presenting the BRAF p.Val600Glu mutation (3/38), we screened for constitutional methylation of the MLH1 gene promoter using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in various biological samples. We found four (4/38; 10.5%) patients with constitutional methylation in the MLH1 gene promoter. RNA studies demonstrated decreased MLH1 expression in the cases with constitutional methylation when compared with controls. We could infer the mosaic nature of MLH1 constitutional hypermethylation in tissues originated from different embryonic germ layers, and in one family we could show that it occurred de novo. We conclude that constitutional MLH1 methylation occurs in a significant proportion of patients who have loss of MLH1 protein expression in their tumors and no MLH1 pathogenic germline mutation. Furthermore, we provide evidence that MLH1 constitutional hypermethylation is the molecular mechanism behind about 3% of Lynch syndrome families diagnosed in our institution, especially in patients with early onset or multiple primary tumors without significant family history.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.