Genomic analyses identify molecular subtypes of pancreatic cancer

Australian Pancreatic Cancer Genome Initiative

Research output: Contribution to journalArticle

749 Citations (Scopus)

Abstract

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63ΔN transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

Original languageEnglish (US)
Pages (from-to)47-52
Number of pages6
JournalNature
Volume531
Issue number7592
DOIs
StatePublished - Mar 3 2016

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Pancreatic Neoplasms
Gene Regulatory Networks
Neoplasms
Up-Regulation
Genes
Molecular Evolution
DNA Repair
Chromatin
Adenocarcinoma
RNA
Mutation
Therapeutics

ASJC Scopus subject areas

  • General
  • Medicine(all)

Cite this

Australian Pancreatic Cancer Genome Initiative (2016). Genomic analyses identify molecular subtypes of pancreatic cancer. Nature, 531(7592), 47-52. https://doi.org/10.1038/nature16965

Genomic analyses identify molecular subtypes of pancreatic cancer. / Australian Pancreatic Cancer Genome Initiative.

In: Nature, Vol. 531, No. 7592, 03.03.2016, p. 47-52.

Research output: Contribution to journalArticle

Australian Pancreatic Cancer Genome Initiative 2016, 'Genomic analyses identify molecular subtypes of pancreatic cancer', Nature, vol. 531, no. 7592, pp. 47-52. https://doi.org/10.1038/nature16965
Australian Pancreatic Cancer Genome Initiative. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016 Mar 3;531(7592):47-52. https://doi.org/10.1038/nature16965
Australian Pancreatic Cancer Genome Initiative. / Genomic analyses identify molecular subtypes of pancreatic cancer. In: Nature. 2016 ; Vol. 531, No. 7592. pp. 47-52.
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abstract = "Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63ΔN transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.",
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