Duodenal Adenocarcinoma (DA)

Overview

Duodenal adenocarcinoma (OncoTree code: DA) arises in the duodenum and sits within the Small Bowel Cancer branch of OncoTree (parent: SBC). It is one of the three periampullary cancers — alongside AMPCA and EHCH — that are typically managed by pancreatoduodenectomy (Whipple procedure). Despite anatomical proximity to ampullary and distal bile-duct cancers, duodenal adenocarcinoma has a molecular profile more similar to colorectal cancer, particularly in its high WNT-pathway mutation frequency and MSI enrichment.

Cohorts in the corpus

  • ampca_bcm_2016 — 18 duodenal adenocarcinomas from the APGI/BCM/MD Anderson/TU Dresden periampullary cancer consortium, all from curative-intent pancreatoduodenectomy; whole-exome sequencing + SNP-array CNAs; RNA-seq available on 2/18 tumors; reference genome GRCh37 PMID:26804919.

Recurrent alterations

  • WNT pathway mutated in 72% of duodenal adenocarcinomas — the highest rate among the three periampullary tumor types (vs. 49% AMPCA, 30% EHCH; ChiSq p < 0.05); driven predominantly by APC and SOX9 PMID:26804919.
  • TGFBR2 — more frequently mutated in DA than in the other periampullary sites; 5 of 12 TGFBR2 mutations across all sites targeted an A8 homopolymer (an MSI hotspot), enriched in the duodenal group PMID:26804919.
  • ELF3 inactivating frameshift/nonsense mutations in 10.6% of periampullary tumors overall; a duodenal adenoma with intraepithelial neoplasia carried an ELF3 mutation, supporting an early-driver role across periampullary sites including DA PMID:26804919.
  • MSI enriched in DUOAC relative to AMPCA and EHCH; MSI tumors show dramatically elevated mutation rates (~108/Mb vs. 4.7/Mb MSS median); all MSI cases had better survival (p < 0.0021 across all three periampullary sites) PMID:26804919.
  • KRAS — major RAS-pathway oncogene across all periampullary types including DA; RTK/RAS/PI3K activation in 84–94% of tumors PMID:26804919.

Subtypes

  • Intestinal-subtype IHC: 44% of DUOAC in the APGI/BCM cohort (vs. 22% pancreatobiliary); intestinal IHC correlates with higher WNT-pathway mutation frequency PMID:26804919.
  • MSI-high subset: most enriched among the three periampullary sites; MSI confers dramatically elevated mutational burden and favorable prognosis PMID:26804919.

Therapeutic landscape

  • WNT pathway inhibitors: DA harbors the highest WNT-mutation rate among periampullary tumors (72%); authors propose that DA, AMPCA, and EHCH should be classified as a single “WNT+/–” entity for therapeutic stratification, given small-molecule β-catenin inhibitors in clinical trials at time of publication PMID:26804919.
  • Molecular subtyping over histology: Pancreatobiliary vs. intestinal IHC subtyping agreed with molecular alteration patterns only 53–77% of the time; molecular profiling (including WNT status and MSI) is recommended over anatomic/IHC classification for treatment decisions PMID:26804919.

Sources

  • PMID:26804919 — Gingras et al. (2016), whole-exome sequencing of 160 periampullary tumors including 18 duodenal adenocarcinomas.

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