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Updated: Apr 4, 2026
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Comprehensive molecular pathology analysis of small bowel adenocarcinoma reveals novel targets with potential for
Muhammad A Alvi1, Darragh G McArt1, Paul Kelly2
1Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
Abstract:
Small bowel accounts for only 0.5% of cancer cases in the US but incidence rates have been rising at 2.4% per year over the past decade. One-third of these are adenocarcinomas but little is known about their molecular pathology and no molecular markers are available for clinical use. Using a retrospective 28 patient matched normal-tumor cohort, next-generation sequencing, gene expression arrays and CpG methylation arrays were used for molecular profiling. Next-generation sequencing identified novel mutations in IDH1, CDH1, KIT, FGFR2, FLT3, NPM1, PTEN, MET, AKT1, RET, NOTCH1 and ERBB4. Array data revealed 17% of CpGs and 5% of RNA transcripts assayed to be differentially methylated and expressed respectively (p < 0.01). Merging gene expression and DNA methylation data revealed CHN2 as consistently hypermethylated and downregulated in this disease (Spearman -0.71, p < 0.001). Mutations in TP53 which were found in more than half of the cohort (15/28) and Kazald1 hypomethylation were both were indicative of poor survival (p = 0.03, HR = 3.2 and p = 0.01, HR = 4.9 respectively). By integrating high-throughput mutational, gene expression and DNA methylation data, this study reveals for the first time the distinct molecular profile of small bowel adenocarcinoma and highlights potential clinically exploitable markers.
Insights
Small bowel adenocarcinoma, a rare cancer, is increasingly common. This study profiles its molecular landscape, identifying novel mutations and methylation patterns, including TP53 mutations and Kazald1 hypomethylation, linked to poor survival.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Small bowel adenocarcinoma (SBA) is rare but rising in incidence.
- Its molecular pathology is poorly understood, lacking clinical biomarkers.
- Current knowledge gaps hinder effective diagnosis and treatment strategies.
Purpose of the Study:
- To comprehensively characterize the molecular profile of small bowel adenocarcinoma.
- To identify novel mutations, gene expression, and DNA methylation alterations.
- To discover potential biomarkers for clinical application in SBA.
Main Methods:
- Retrospective analysis of a 28-patient normal-tumor cohort.
- Utilized next-generation sequencing for mutational profiling.
- Employed gene expression and CpG methylation arrays for comprehensive molecular analysis.
Main Results:
- Identified novel mutations in genes including IDH1, CDH1, KIT, and TP53.
- Discovered widespread differential DNA methylation (17% CpGs) and RNA expression (5% transcripts).
- CHN2 was consistently hypermethylated and downregulated; TP53 mutations and Kazald1 hypomethylation correlated with poor survival.
Conclusions:
- This study provides the first integrated molecular profile of small bowel adenocarcinoma.
- Identified distinct molecular alterations, including novel mutations and epigenetic changes.
- Highlights potential clinically actionable targets and prognostic markers for SBA.
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