ArticleJournal of the National Comprehensive Cancer Network : JNCCN2023
Constitutional MLH1 Methylation Is a Major Contributor to Mismatch Repair-Deficient, MLH1-Methylated Colorectal Cancer in Patients Aged 55 Years and Younger.
Article in Journal of the National Comprehensive Cancer Network : JNCCN, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 24 citations in OpenAlex.
- Genomic mosaicism in colorectal cancer and polyposis syndromes: a systematic review and meta-analysis.International journal of colorectal disease · 2024Pooled it
- Current Status of the Diagnosis and Treatment of Mismatch Repair Deficient Colorectal Cancer.Biomedicines · 2026Review
- Article
- Lynch Syndrome as a Spectrum of Four Distinct Genetic Disorders: Toward Genotype-Guided Precision Management in the NGS Era.Cancers · 2026Review
- Blurring the Lines: Co-Occurrence of MSH6 Variant and MLH1 Constitutional Epimutation in a Young Colorectal Cancer Patient.Clinical genetics · 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
- Hereditary Endometrial Cancer: Lynch Syndrome, Mismatch Repair Deficiency, and Emerging Genetic Predispositions-A Comprehensive Review with Clinical and Laboratory Guidelines.International journal of molecular sciences · 2026Review
- Diet-Driven Epigenetic Alterations in Colorectal Cancer: From DNA Methylation and microRNA Expression to Liquid Biopsy Readouts.Biomedicines · 2026Review
- Article
- Article
- Lynch Syndrome in Focus: A Multidisciplinary Review of Cancer Risk, Clinical Management, and Special Populations.Cancers · 2025Review
- Multidimensional decoding of colorectal cancer heterogeneity: Artificial intelligence-enabled precision exploration of single-cell and spatial transcriptomics.World journal of gastrointestinal oncology · 2025Review
- Traditional and New Views on MSI-H/dMMR Endometrial Cancer.Biomolecules · 2025Review
- Epigenetic modification of cuproptosis by non-coding RNAs in cancer drug resistance.Molecular cancer · 2025Review
- MLH1 c.27G>A (p.Arg9=) is a synonymous likely/pathogenic variant underlying variably mosaic constitutional MLH1 methylation in Lynch syndrome.Familial cancer · 2025Article
- Methylation-sensitive high-resolution melting technology is a simple and sensitive method to detect germline epimutation of the MLH1 gene promoter.Clinical epigenetics · 2025Article
- Canadian consensus for the assessment and testing of Lynch syndrome.Journal of medical genetics · 2025Article
- Constitutional Epimutations: From Rare Events Toward Major Cancer Risk Factors?JCO precision oncology · 2025Review
- Triple-Negative Breast Cancer on the Rise or…? [Letter].Breast cancer (Dove Medical Press) · 2025Article
- Hereditary Colorectal Cancer: Clinical Implications of Genomic Medicine and Precision Oncology.Journal of the anus, rectum and colon · 2025Review
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundMost mismatch repair-deficient (MMRd) colorectal cancer (CRC) cases arise sporadically, associated with somatic MLH1 methylation, whereas approximately 20% have germline mismatch repair pathogenic variants causing Lynch syndrome (LS). Universal screening of incident CRC uses presence of MLH1 methylation in MMRd tumors to exclude sporadic cases from germline testing for LS. However, this overlooks rare cases with constitutional MLH1 methylation (epimutation), a poorly recognized mechanism for LS. We aimed to assess the frequency and age distribution of constitutional MLH1 methylation among incident CRC cases with MMRd, MLH1-methylated tumors.
methodsIn retrospective population-based studies, we selected all CRC cases with MMRd, MLH1-methylated tumors, regardless of age, prior cancer, family history, or BRAF V600E status, from the Columbus-area HNPCC study (Columbus) and Ohio Colorectal Cancer Prevention Initiative (OCCPI) cohorts. Blood DNA was tested for constitutional MLH1 methylation by pyrosequencing and real-time methylation-specific PCR, then confirmed with bisulfite-sequencing.
resultsResults were achieved for 95 of 98 Columbus cases and all 281 OCCPI cases. Constitutional MLH1 methylation was identified in 4 of 95 (4%) Columbus cases, ages 34, 38, 52, and 74 years, and 4 of 281 (1.4%) OCCPI cases, ages 20, 34, 50, and 55 years, with 3 showing low-level mosaic methylation. Mosaicism in blood and normal colon, plus tumor loss of heterozygosity of the unmethylated allele, demonstrated causality in 1 case with sample availability. Age stratification showed high rates of constitutional MLH1 methylation among younger patients. In the Columbus and OCCPI cohorts, respectively, these rates were 67% (2 of 3) and 25% (2 of 8) of patients aged <50 years but with half of the cases missed, and 75% (3 of 4) and 23.5% (4 of 17) of patients aged ≤55 years with most cases detected.
conclusionsAlthough rare overall, a significant proportion of younger patients with MLH1-methylated CRC had underlying constitutional MLH1 methylation. Routine testing for this high-risk mechanism is warranted in patients aged ≤55 years for a timely and accurate molecular diagnosis that will significantly alter their clinical management while minimizing additional testing.
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