title: 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.
authors: Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: Muhammad A
authors: MA
authors: Alvi
authors: Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: Darragh G
authors: DG
authors: McArt
authors: Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.
authors: Paul
authors: P
authors: Kelly
authors: Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: Marc-Aurel
authors: MA
authors: Fuchs
authors: Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: Matthew
authors: M
authors: Alderdice
authors: Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: Clare M
authors: CM
authors: McCabe
authors: Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: Victoria
authors: V
authors: Bingham
authors: Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: Claire
authors: C
authors: McGready
authors: Computational Biology and Machine Learning Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: Shailesh
authors: S
authors: Tripathi
authors: Computational Biology and Machine Learning Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: Frank
authors: F
authors: Emmert-Streib
authors: Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.
authors: Maurice B
authors: MB
authors: Loughrey
authors: Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.|Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.
authors: Stephen
authors: S
authors: McQuaid
authors: Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.|Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.
authors: Perry
authors: P
authors: Maxwell
authors: Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: Peter W
authors: PW
authors: Hamilton
authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: Richard
authors: R
authors: Turkington
authors: Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.|Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.
authors: Jacqueline A
authors: JA
authors: James
authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: Richard H
authors: RH
authors: Wilson
authors: Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.|Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.
authors: Manuel
authors: M
authors: Salto-Tellez
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology* / Q000628:therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D020740:Chimerin Proteins / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007414:Intestinal Neoplasms / Q000473:pathology* / Q000628:therapy*; D007421:Intestine, Small / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000090243:Nucleophosmin; D020411:Oligonucleotide Array Sequence Analysis; D057089:Pathology, Molecular; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D020740:Chimerin Proteins; C000716967:NPM1 protein, human; C000593185:chimaerin-beta3 protein, human; D000090243:Nucleophosmin
keywords: CHN2; Kazald1; Pathology Section; p53; small intestine cancer