ArticleThe Journal of pathology2013
MLH1-silenced and non-silenced subgroups of hypermutated colorectal carcinomas have distinct mutational landscapes.
Article in The Journal of pathology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers, 1 of them a synthesis that pooled it.
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Who cites it
47 citing papers in PubMed, 1 synthesis or guideline pooled it, 71 citations in OpenAlex.
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- A set cover algorithm identifies minimal circulating tumour DNA sequencing targets for colorectal cancer detection.Scientific reports · 2025Article
- Somatic mutations in aging and disease.GeroScience · 2024Review
- Impact of Molecular Status on Cytoreductive Surgery for Peritoneal Metastases from Colorectal Cancer.Clinics in colon and rectal surgery · 2023Review
- High-LET-Radiation-Induced Persistent DNA Damage Response Signaling and Gastrointestinal Cancer Development.Current oncology (Toronto, Ont.) · 2023Review
- Characterization of RNF43 frameshift mutations that drive Wnt ligand- and R-spondin-dependent colon cancer.The Journal of pathology · 2022Article
- Tumor-derived mutations in postoperative plasma of colorectal cancer with microsatellite instability.Translational oncology · 2021Article
- A comparative prognostic performance of definitions of Crohn-like lymphoid reaction in colorectal carcinoma.Journal of pathology and translational medicine · 2021Article
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- The most common RNF43 mutant G659Vfs*41 is fully functional in inhibiting Wnt signaling and unlikely to play a role in tumorigenesis.Scientific reports · 2019Article
- GermlineCold Spring Harbor molecular case studies · 2019Article
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- Comprehensive profiling of JMJD3 in gastric cancer and its influence on patient survival.Scientific reports · 2019Article
- Evaluating intrinsic and non-intrinsic cancer risk factors.Nature communications · 2018Review
- Aberrant methylation of mutL homolog 1 is associated with increased risk of non-small cell lung cancer.Journal of clinical laboratory analysis · 2018Article
- Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer.Cancer cell · 2018Article
- The co-regulatory networks of tumor suppressor genes, oncogenes, and miRNAs in colorectal cancer.Genes, chromosomes & cancer · 2017Article
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
Approximately 15% of colorectal carcinomas (CRCs) exhibit a hypermutated genotype accompanied by high levels of microsatellite instability (MSI-H) and defects in DNA mismatch repair. These tumours, unlike the majority of colorectal carcinomas, are often diploid, exhibit frequent epigenetic silencing of the MLH1 DNA mismatch repair gene, and have a better clinical prognosis. As an adjunct study to The Cancer Genome Atlas consortium that recently analysed 224 colorectal cancers by whole exome sequencing, we compared the 35 CRCs (15.6%) with a hypermutated genotype to those with a non-hypermutated genotype. We found that 22 (63%) of the hypermutated CRCs exhibited transcriptional silencing of the MLH1 gene, a high frequency of BRAF V600E gene mutations, and infrequent APC and KRAS mutations, a mutational pattern significantly different from their non-hypermutated counterparts. However, the remaining 13 (37%) hypermutated CRCs lacked MLH1 silencing, contained tumours with the highest mutation rates ('ultramutated' CRCs), and exhibited higher incidences of APC and KRAS mutations, but infrequent BRAF mutations. These patterns were confirmed in an independent validation set of 250 exome-sequenced CRCs. Analysis of mRNA and microRNA expression signatures revealed that hypermutated CRCs with MLH1 silencing had greatly reduced levels of WNT signalling and increased BRAF signalling relative to non-hypermutated CRCs. Our findings suggest that hypermutated CRCs include one subgroup with fundamentally different pathways to malignancy than the majority of CRCs. Examination of MLH1 expression status and frequencies of APC, KRAS, and BRAF mutation in CRC may provide a useful diagnostic tool that could supplement the standard microsatellite instability assays and influence therapeutic decisions.
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