Evidence map›Paper›PMID 37162286›Full record

ArticleCancer medicine2023

Multi-omic analysis in normal colon organoids highlights MSH4 as a novel marker of defective mismatch repair in Lynch syndrome and microsatellite instability.

Matthew Devall, Mourad W Ali, Stephen Eaton, Daniel J Weisenberger, Matthew J Reilley, Steven M Powell, Li Li, Graham Casey

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cancer medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed, 1 pooled it
2.6field-weighted citation impact, top 11% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

9 citing papers in PubMed, 1 synthesis or guideline pooled it, 10 citations in OpenAlex.

  1. Pooled it
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  3. Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 4 institutions in 1 country.

Matthew DevallCenter for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.ORCID 0000-0001-5943-4397
Mourad W AliCenter for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
Stephen EatonCenter for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
Daniel J WeisenbergerDepartment of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, California, USA.
Matthew J ReilleyUniversity of Virginia Comprehensive Cancer Center, University of Virginia, Charlottesville, Virginia, USA.
Steven M PowellDigestive Health Center, University of Virginia, Charlottesville, Virginia, USA.
Li LiDepartment of Family Medicine, University of Virginia, Charlottesville, Virginia, USA.
Graham CaseyCenter for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
University of Virginia · USUniversity of Virginia Cancer CenterUniversity of Southern California · USUniversity of Virginia Health System · US

Funding

Inherited colorectal cancer risk variants: from association to biologyR01CA143237 · NCI · UNIVERSITY OF VIRGINIA · PI CASEY, GRAHAM · 2010 to 2020
$8.4M
Biology of Colorectal Cancer Risk EnhancersR01CA204279 · NCI · UNIVERSITY OF VIRGINIA · PI CASEY, GRAHAM, SCACHERI, PETER CHRISTOPHER · 2016 to 2020
$3.0M
NCI NIH HHS R01 CA143237NCI NIH HHS R01 CA204279
6 · The paper itself

Abstract

introductionLynch syndrome (LS) is a hereditary condition that increases the risk of colorectal (CRC) and extracolonic cancers that exhibit microsatellite instability (MSI-H). MSI-H is driven by defective mismatch repair (dMMR), and approximately 15% of nonhereditary CRCs also exhibit MSI-H. Here, we aimed to better define mechanisms underlying tumor initiation in LS and MSI-H cancers through multi-omic analyses of LS normal colon organoids and MSI-H tumors.

methodsRight (n = 35) and left (n = 23) colon organoids generated from normal colon biopsies at routine colonoscopy of LS and healthy individuals were subjected to Illumina EPIC array. Differentially methylated region (DMR) analysis was performed by DMRcate. RNA-sequencing (n = 16) and bisulfite-sequencing (n = 15) were performed on a subset of right colon organoids. CRISPR-cas9-mediated editing of MMR genes in colon organoids of healthy individuals was followed by quantitative PCR of MSH4. The relationship between MSH4 expression and tumor mutational burden was further explored in three independent tumor data sets.

resultsWe identified a hypermethylated region of MSH4 in both the right and left colon organoids of LS versus healthy controls, which we validated using bisulfite-sequencing. DMR analysis in three gastrointestinal and one endometrial data set revealed that this region was also hypermethylated in MSI-H versus microsatellite stable (MSS) tumors. MSH4 expression was increased in colon organoids of LS versus healthy subjects and in publicly available MSI-H versus MSS tumors across four RNA-seq and four microarray data sets. CRISPR-cas9 editing of MLH1 and MSH2, but not MSH6, in normal colon organoids significantly increased MSH4 expression. MSH4 expression was significantly associated with tumor mutational burden in three publicly available data sets.

conclusionsOur findings implicate DNA methylation and gene expression differences of MSH4 as a marker of dMMR and as a potential novel biomarker of LS. Our study of LS colon organoids supports the hypothesis that dMMR exists in the colons of LS subjects prior to CRC.

Indexed as

Colorectal Neoplasms, Hereditary NonpolyposisBiomarkers, TumorCell Cycle ProteinsDNA Mismatch RepairHumansMicrosatellite InstabilityMultiomicsSulfitesBiomarkers, TumorCell Cycle Proteinshydrogen sulfiteMSH4 protein, humanSulfitescolon organoidscolorectal cancerLynch syndromemicrosatellite instability

Identifiers

PMID37162286
PMCPMC10315803
OpenAlexW4376121436

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

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 Socratic graph.