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

Oncotarget. 2015 Aug 28;6(25):20863-74. doi: 10.18632/oncotarget.4576.

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: CHN2; Kazald1; Pathology Section; p53; small intestine cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / pathology*
  • Adenocarcinoma / therapy*
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor
  • Chimerin Proteins / genetics
  • CpG Islands
  • DNA Methylation
  • DNA Mutational Analysis
  • Epigenesis, Genetic
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genes, p53
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Intestinal Neoplasms / pathology*
  • Intestinal Neoplasms / therapy*
  • Intestine, Small / pathology*
  • Male
  • Middle Aged
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Pathology, Molecular
  • Retrospective Studies
  • Treatment Outcome

Substances

  • Biomarkers, Tumor
  • Chimerin Proteins
  • chimaerin-beta3 protein, human