ArticleBMC cancer2010
Early onset MSI-H colon cancer with MLH1 promoter methylation, is there a genetic predisposition?
Article in BMC cancer, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 4 of them syntheses that pooled it.
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Who cites it
30 citing papers in PubMed, 4 syntheses or guidelines pooled it, 53 citations in OpenAlex.
- Mismatch repair deficiency is rare in bone and soft tissue tumors.Histopathology · 2021Pooled 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
- Global differences in the prevalence of the CpG island methylator phenotype of colorectal cancer.BMC cancer · 2019Pooled it
- Association between MutL homolog 1 polymorphisms and the risk of colorectal cancer: a meta-analysis.Journal of cancer research and clinical oncology · 2015Pooled it
- Closing the Diagnostic Gap in Early-Onset Colorectal Cancer: Red-Flag Symptoms, Screening, and Inherited Risk.Cancers · 2026Review
- DNA Methylation in Ovarian and Endometrial Cancers: Predictive and Mechanistic Roles in PARP Inhibitor and ICI Response.Cancer science · 2025Review
- The utility of liquid biopsy-based methylation biomarkers for colorectal cancer detection.Frontiers in oncology · 2024Article
- 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
- Article
- Protons and High-Linear Energy Transfer Radiation Induce Genetically Similar Lymphomas With High Penetrance in a Mouse Model of the Aging Human Hematopoietic System.International journal of radiation oncology, biology, physics · 2020Article
- Early-onset colorectal cancer: initial clues and current views.Nature reviews. Gastroenterology & hepatology · 2020Review
- Clinical, Pathological, and Molecular Characteristics of CpG Island Methylator Phenotype in Colorectal Cancer: A Systematic Review and Meta-analysis.Translational oncology · 2018Article
- Contribution of MLH1 constitutional methylation for Lynch syndrome diagnosis in patients with tumor MLH1 downregulation.Cancer medicine · 2018Article
- Pooling-analysis on hMLH1 polymorphisms and cancer risk: evidence based on 31,484 cancer cases and 45,494 cancer-free controls.Oncotarget · 2017Article
- Finding the needle in a haystack: identification of cases of Lynch syndrome with MLH1 epimutation.Familial cancer · 2016Review
- Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients.PloS one · 2016Article
- Expression and promoter methylation status of hMLH1, MGMT, APC, and CDH1 genes in patients with colon adenocarcinoma.Experimental biology and medicine (Maywood, N.J.) · 2015Article
- Constitutional epimutation as a mechanism for cancer causality and heritability?Nature reviews. Cancer · 2015Review
- Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2015Article
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundTo investigate the etiology of MLH1 promoter methylation in mismatch repair (MMR) mutation-negative early onset MSI-H colon cancer. As this type of colon cancer is associated with high ages, young patients bearing this type of malignancy are rare and could provide additional insight into the etiology of sporadic MSI-H colon cancer.
methodsWe studied a set of 46 MSI-H colon tumors cases with MLH1 promoter methylation which was enriched for patients with an age of onset below 50 years (n=13). Tumors were tested for CIMP marker methylation and mutations linked to methylation: BRAF, KRAS, GADD45A and the MLH1 -93G>A polymorphism. When available, normal colon and leukocyte DNA was tested for GADD45A mutations and germline MLH1 methylation. SNP array analysis was performed on a subset of tumors.
resultsWe identified two cases (33 and 60 years) with MLH1 germline promoter methylation. BRAF mutations were less frequent in colon cancer patients below 50 years relative to patients above 50 years (p-value: 0.044). CIMP-high was infrequent and related to BRAF mutations in patients below 50 years. In comparison with published controls the G>A polymorphism was associated with our cohort. Although similar distribution of the pathogenic A allele was observed in the patients with an age of onset above and below 50 years, the significance for the association was lost for the group under 50 years. GADD45A sequencing yielded an unclassified variant. Tumors from both age groups showed infrequent copy number changes and loss-of-heterozygosity.
conclusionSomatic or germline GADD45A mutations did not explain sporadic MSI-H colon cancer. Although germline MLH1 methylation was found in two individuals, locus-specific somatic MLH1 hypermethylation explained the majority of sporadic early onset MSI-H colon cancer cases. Our data do not suggest an intrinsic tendency for CpG island hypermethylation in these early onset MSI-H tumors other than through somatic mutation of BRAF.
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