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Comprehensive molecular pathology analysis of small bowel adenocarcinoma reveals novel targets with potential for clinical utility

Research output: Contribution to journalArticleScientificpeer-review

Details

Original languageEnglish
Pages (from-to)20863-20874
Number of pages12
JournalOncotarget
Volume6
Issue number25
Publication statusPublished - 28 Aug 2015
Externally publishedYes
Publication typeA1 Journal article-refereed

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.

Keywords

  • small intestine cancer, p53, Kazald1, CHN2, Pathology Section, DNA METHYLATION DATA, BREAST-CANCER, POOR-PROGNOSIS, UNITED-STATES, R-PACKAGE, GENE, SURVIVAL