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Nature. 2018 Feb 1;554(7690):62-68. doi: 10.1038/nature25459. Epub 2018 Jan 24.

Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes.

Author information

1
Center for Translational Cancer Research (TranslaTUM), Technische Universität München, 81675 Munich, Germany.
2
Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
3
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
4
Institute of Pathology, Technische Universität München, 81675 Munich, Germany.
5
The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
6
Comparative Experimental Pathology, Technische Universität München, 81675 Munich, Germany.
7
Anthropology & Human Genomics, Department of Biology II, Ludwig-Maximilians Universität, 82152 Martinsried, Germany.
8
Helmholtz Zentrum München, Research Unit Radiation Cytogenetics, 85764 Neuherberg, Germany.
9
Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK.
10
Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), 33193 Oviedo, Spain.
11
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.
12
Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, 33011 Oviedo, Spain.
13
Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo, 33940 El Entrego, Spain.
14
Medizinische Klinik und Poliklinik II, Klinikum der LMU München-Grosshadern, 81377 Munich, Germany.
15
Instituto de Biomedicina y Biotecnología de Cantabria (UC-CSIC), 39012 Santander, Spain.

Abstract

The poor correlation of mutational landscapes with phenotypes limits our understanding of the pathogenesis and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here we show that oncogenic dosage-variation has a critical role in PDAC biology and phenotypic diversification. We find an increase in gene dosage of mutant KRAS in human PDAC precursors, which drives both early tumorigenesis and metastasis and thus rationalizes early PDAC dissemination. To overcome the limitations posed to gene dosage studies by the stromal richness of PDAC, we have developed large cell culture resources of metastatic mouse PDAC. Integration of cell culture genomes, transcriptomes and tumour phenotypes with functional studies and human data reveals additional widespread effects of oncogenic dosage variation on cell morphology and plasticity, histopathology and clinical outcome, with the highest KrasMUT levels underlying aggressive undifferentiated phenotypes. We also identify alternative oncogenic gains (Myc, Yap1 or Nfkb2), which collaborate with heterozygous KrasMUT in driving tumorigenesis, but have lower metastatic potential. Mechanistically, different oncogenic gains and dosages evolve along distinct evolutionary routes, licensed by defined allelic states and/or combinations of hallmark tumour suppressor alterations (Cdkn2a, Trp53, Tgfβ-pathway). Thus, evolutionary constraints and contingencies direct oncogenic dosage gain and variation along defined routes to drive the early progression of PDAC and shape its downstream biology. Our study uncovers universal principles of Ras-driven oncogenesis that have potential relevance beyond pancreatic cancer.

PMID:
29364867
PMCID:
PMC6097607
DOI:
10.1038/nature25459
[Indexed for MEDLINE]
Free PMC Article

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