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

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.

Small Bowel Adenocarcinoma

“…For instance, abnormal p53 is frequently observed (41-42%) and is associated with poor prognosis. 29,[33][34][35] Alteration of p53 is considered a late step in the adenoma-to-carcinoma sequence, as no additional mutations are likely needed to complete carcinogenesis, given its profound tumor suppressor activity. Another tumor suppressor, p16, or CDKN2A, which inhibits the cell cycle, is also increased in SBA.…”

A Case of Metastatic Biliary Tract Cancer Diagnosed Through Identification of an IDH1 Mutation

“…For example, IDH1 and IDH2 mutations are present in approximately 16%–36% of intrahepatic BTCs, but are more rare in other solid malignancies . We identified only five cases from two series in the literature of IDH1 mutations in small intestinal adenocarcinoma, all of which occurred in the ileum . In this case, identification of an IDH1 mutation in both ctDNA and tissue made the diagnosis of duodenal adenocarcinoma unlikely and suggested a pancreaticobiliary cancer was the true diagnosis.…”

Small Bowel Adenocarcinoma: Etiology, Presentation, and Molecular Alterations

“…The low rate of APC alterations in SBA compared with CRC has been noted in prior smaller studies and represents one of the most fundamental genomic differences between large bowel adenocarcinoma and SBA. [54][55][56][57] In another comparative analysis of copy number changes between SBA, CRC, and gastric cancer, unsupervised clustering showed that SBA clustered more commonly with CRC than gastric cancer. 58 Another critical molecular insight relates to the comparison of molecular alterations across the different small bowel subsites: duodenum, jejunum, and ileum.…”