Journal
ONCOTARGET
Volume 6, Issue 25, Pages 20863-20874Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.4576
Keywords
small intestine cancer; p53; Kazald1; CHN2; Pathology Section
Categories
Funding
- Cancer Research UK [C11512/A18067]
- Experimental Cancer Medicine Centre Network from Cancer Research UK [C36697/A15590]
- NI Health and Social Care Research and Development Division
- Sean Crummey Memorial Fund
- Tom Simms Memorial Fund
- HSC Research and Development Division of the Public Health Agency in Northern Ireland
- Cancer Research UK through the Belfast CRUK Centre
- Northern Ireland Experimental Cancer Medicine Centre
- Friends of the Cancer Centre
- Sean Crummey Foundation
- Public Health Agency [SPI/5151/15, SPI/3315/06] Funding Source: researchfish
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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.
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