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

Muhammad A Alvi, Darragh G McArt, Paul Kelly, Marc-Aurel Fuchs, Matthew Alderdice, Clare M McCabe, Victoria Bingham, Claire McGready, Shailesh Tripathi, Frank Emmert-Streib, Maurice B Loughrey, Stephen McQuaid, Perry Maxwell, Peter W Hamilton, Richard Turkington, Jacqueline A James, Richard H Wilson, Manuel Salto-Tellez

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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.

Original languageEnglish
Pages (from-to)20863-74
Number of pages12
JournalOncotarget
Volume6
Issue number25
DOIs
Publication statusPublished - 30 Jul 2015

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Molecular Pathology
DNA Methylation
Gene Expression
Adenocarcinoma
Mutation
Methylation
Neoplasms
Down-Regulation
Biomarkers
RNA
Survival
Incidence

Cite this

Alvi, Muhammad A ; McArt, Darragh G ; Kelly, Paul ; Fuchs, Marc-Aurel ; Alderdice, Matthew ; McCabe, Clare M ; Bingham, Victoria ; McGready, Claire ; Tripathi, Shailesh ; Emmert-Streib, Frank ; Loughrey, Maurice B ; McQuaid, Stephen ; Maxwell, Perry ; Hamilton, Peter W ; Turkington, Richard ; James, Jacqueline A ; Wilson, Richard H ; Salto-Tellez, Manuel. / Comprehensive molecular pathology analysis of small bowel adenocarcinoma reveals novel targets with potential for clinical utility. In: Oncotarget. 2015 ; Vol. 6, No. 25. pp. 20863-74.
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Alvi, MA, McArt, DG, Kelly, P, Fuchs, M-A, Alderdice, M, McCabe, CM, Bingham, V, McGready, C, Tripathi, S, Emmert-Streib, F, Loughrey, MB, McQuaid, S, Maxwell, P, Hamilton, PW, Turkington, R, James, JA, Wilson, RH & Salto-Tellez, M 2015, 'Comprehensive molecular pathology analysis of small bowel adenocarcinoma reveals novel targets with potential for clinical utility', Oncotarget, vol. 6, no. 25, pp. 20863-74. https://doi.org/10.18632/oncotarget.4576

Comprehensive molecular pathology analysis of small bowel adenocarcinoma reveals novel targets with potential for clinical utility. / Alvi, Muhammad A; McArt, Darragh G; Kelly, Paul; Fuchs, Marc-Aurel; Alderdice, Matthew; McCabe, Clare M; Bingham, Victoria; McGready, Claire; Tripathi, Shailesh; Emmert-Streib, Frank; Loughrey, Maurice B; McQuaid, Stephen; Maxwell, Perry; Hamilton, Peter W; Turkington, Richard; James, Jacqueline A; Wilson, Richard H; Salto-Tellez, Manuel.

In: Oncotarget, Vol. 6, No. 25, 30.07.2015, p. 20863-74.

Research output: Contribution to journalArticle

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T1 - Comprehensive molecular pathology analysis of small bowel adenocarcinoma reveals novel targets with potential for clinical utility

AU - Alvi, Muhammad A

AU - McArt, Darragh G

AU - Kelly, Paul

AU - Fuchs, Marc-Aurel

AU - Alderdice, Matthew

AU - McCabe, Clare M

AU - Bingham, Victoria

AU - McGready, Claire

AU - Tripathi, Shailesh

AU - Emmert-Streib, Frank

AU - Loughrey, Maurice B

AU - McQuaid, Stephen

AU - Maxwell, Perry

AU - Hamilton, Peter W

AU - Turkington, Richard

AU - James, Jacqueline A

AU - Wilson, Richard H

AU - Salto-Tellez, Manuel

PY - 2015/7/30

Y1 - 2015/7/30

N2 - 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.

AB - 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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