Ampullary Carcinoma (Baylor College of Medicine, Cell Reports 2016)

Overview

Multi-institutional cohort of 160 periampullary tumors collected by the Australian Pancreatic Cancer Genome Initiative (APGI), Baylor College of Medicine, MD Anderson, and TU Dresden. All patients underwent curative-intent pancreatoduodenectomy. The cohort encompasses three anatomically distinct but biologically related tumor types arising at the junction of the pancreatic duct, common bile duct, and duodenum: 98 ampullary adenocarcinomas (AMPCA), 44 distal bile duct / cholangiocarcinomas (CAC), and 18 duodenal adenocarcinomas (DUOAC). Sequence data are deposited in dbGaP under accession PRJNA280134. PMID:26804919

Composition

  • 98 ampullary adenocarcinomas (AMPCA): 51% pancreatobiliary IHC subtype, 34% intestinal, remainder mixed.
  • 44 distal bile duct / cholangiocarcinomas (EHCH): 86% pancreatobiliary, 11% intestinal.
  • 18 duodenal adenocarcinomas (DA): 44% intestinal, 22% pancreatobiliary.
  • All samples from patients undergoing curative-intent surgery; no recurrent or metastatic biopsies. PMID:26804919

Assays / panels (linked)

  • whole-exome-seq: Illumina HiSeq 2000 at ~120× average coverage on 152 samples.
  • targeted-deep-amplicon-seq: 71-gene panel for an 8-sample addendum; ultra-deep validation of all called mutations.
  • SNP arrays: Illumina HumanOmni2.5-8 for copy-number profiling.
  • rna-seq: TruSeq Stranded Total RNA, 100 bp paired-end, ≥50 M reads, on 28/98 AMPAC and 2/18 DUOAC samples.
  • Reference genome: hg19 (GRCh37). PMID:26804919

Papers using this cohort

  • PMID:26804919 — Gingras et al. 2016, Cell Reports: Primary study; molecular taxonomy of 160 periampullary tumors revealing WNT-pathway dominance and ELF3 as a novel tumor suppressor.

Notable findings derived from this cohort

  • ELF3 mutated in 10.6% of periampullary tumors with predominantly inactivating frameshift/nonsense mutations — approximately 3× higher than any other cancer in cBioPortal at the time. PMID:26804919
  • WNT pathway mutated in 46% of all periampullary tumors; rates differ significantly by site: DUOAC 72%, AMPAC 49%, CAC 30% (ChiSq p<0.05); intestinal IHC subtype 67% WNT-altered vs 30% pancreatobiliary. PMID:26804919
  • MSI present in 12/160 patients (8% overall); all 6 MSI-AMPCA patients alive 2–8 years post-diagnosis (p=0.04); MSI associated with dramatically elevated mutation rates (median 68–127 mutations/Mb vs 3.8–4.7/Mb MSS). PMID:26804919
  • PMS2 mutated in half of MSI patients — markedly higher than the <5% frequency in the general Lynch-syndrome population. PMID:26804919
  • TGF-β pathway mutations independently predicted better OS (HR=0.42, p=0.0059); PI3K pathway mutations similarly predicted better OS (HR=0.43, p=0.036). PMID:26804919
  • Five mutational signatures prominent; signature #1 (C>T at CpG) independently associated with worse outcome (multivariate Cox p=0.02). PMID:26804919

Sources

  • cBioPortal study: ampca_bcm_2016 — https://www.cbioportal.org/study/summary?id=ampca_bcm_2016
  • dbGaP accession: PRJNA280134
  • PMID:26804919 — Gingras et al. 2016, Cell Reports, DOI 10.1016/j.celrep.2015.12.005.

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