Whole-exome sequencing of duodenal adenocarcinoma identifies recurrent Wnt/β-catenin signaling pathway mutations

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Abstract

BACKGROUND:

Genomic alterations of small bowel cancers remain poorly understood due to the rarity of these diseases. In the current study, the authors report the identification of somatic mutations from patients with duodenal adenocarcinoma by whole-exome sequencing.

METHODS:

Whole-exome sequencing and follow-up analysis were conducted in 12 matched tumor-normal tissue duodenal adenocarcinoma tissue pairs to examine the genetic characteristics of this disease. Somatic mutations (single-nucleotide variants and short insertion/deletions) were obtained and filtered and then searched for recurrently mutated genes and pathways.

RESULTS:

An excess of C-to-T transitions at the CpG dinucleotide was observed in the substitution of bases. The authors identified recurrent mutations in tumor protein p53 (TP53), KRAS, catenin (cadherin-associated protein) β-1 (CTNNB1), AT-rich interactive domain 2 (ARID2), adenomatous polyposis coli (APC), erb-b2 receptor tyrosine kinase 2 (ERBB2), ARID1A, cadherin-related family member 1 (CDHR1), NRAS, Bcl-2-related ovarian killer (BOK), radial spoke head 14 homolog (chlamydomonas) (RTDR1), cell division cycle 27 (CDC27), catalytic subunit of phosphoinositide-3-kinase (PIK3CA), and SMAD family member 4 (SMAD4). Pathway scan indicated that the Wnt signaling pathway, regulation of the actin cytoskeleton pathway, ErbB signaling pathway, and the pathway of focal adhesion were the most extensively affected pathways.

CONCLUSIONS:

This genomic characterization of duodenal adenocarcinoma provides researchers with insight into its somatic landscape and highlights the vital role of the Wnt/β-catenin signaling pathway. The study data also indicate that duodenal adenocarcinomas have a genetic resemblance to gastric and colorectal cancers. These discoveries may benefit the future development of molecular diagnosis and personalized therapies. Cancer2016;122:1689-96. © 2016 American Cancer Society.

To the authors' knowledge, there have been very few well-established genomic characterizations of duodenal adenocarcinoma due its rarity. The identification of base substitutions and recurrently mutated genes and pathways suggest that duodenal adenocarcinoma is genetically akin to gastric and colorectal cancers, and the variation in the Wnt/β-catenin signaling pathway is a critical event in duodenal tumorigenesis.

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