Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes

Sebastian Mueller, Thomas Engleitner, Roman Maresch, Magdalena Zukowska, Sebastian Lange, Thorsten Kaltenbacher, Björn Konukiewitz, Rupert Öllinger, Maximilian Zwiebel, Alex Strong, Hsi-Yu Yen, Ruby Banerjee, Sandra Louzada, Beiyuan Fu, Barbara Seidler, Juliana Götzfried, Kathleen Schuck, Zonera Hassan, Andreas Arbeiter, Nina Schönhuber, Sabine Klein, Christian Veltkamp, Mathias Friedrich, Lena Rad, Maxim Barenboim, Christoph Ziegenhain, Julia Hess, Oliver M. Dovey, Stefan Eser, Swati Parekh, Fernando Constantino-Casas, Jorge de la Rosa, Marta I. Sierra, Mario Fraga, Julia Mayerle, Günter Klöppel, Juan Cadiñanos, Pentao Liu, George Vassiliou, Wilko Weichert, Katja Steiger, Wolfgang Enard, Roland M. Schmid, Fengtang Yang, Kristian Unger, Günter Schneider, Ignacio Varela, Allan Bradley, Dieter Saur and Roland Rad ()
Additional contact information
Sebastian Mueller: Center for Translational Cancer Research (TranslaTUM), Technische Universität München
Thomas Engleitner: Center for Translational Cancer Research (TranslaTUM), Technische Universität München
Roman Maresch: Center for Translational Cancer Research (TranslaTUM), Technische Universität München
Magdalena Zukowska: Center for Translational Cancer Research (TranslaTUM), Technische Universität München
Sebastian Lange: Center for Translational Cancer Research (TranslaTUM), Technische Universität München
Thorsten Kaltenbacher: Center for Translational Cancer Research (TranslaTUM), Technische Universität München
Björn Konukiewitz: Institute of Pathology, Technische Universität München
Rupert Öllinger: Center for Translational Cancer Research (TranslaTUM), Technische Universität München
Maximilian Zwiebel: Klinikum rechts der Isar, Technische Universität München
Alex Strong: The Wellcome Trust Sanger Institute, Genome Campus
Hsi-Yu Yen: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Ruby Banerjee: The Wellcome Trust Sanger Institute, Genome Campus
Sandra Louzada: The Wellcome Trust Sanger Institute, Genome Campus
Beiyuan Fu: The Wellcome Trust Sanger Institute, Genome Campus
Barbara Seidler: Center for Translational Cancer Research (TranslaTUM), Technische Universität München
Juliana Götzfried: Klinikum rechts der Isar, Technische Universität München
Kathleen Schuck: Klinikum rechts der Isar, Technische Universität München
Zonera Hassan: Klinikum rechts der Isar, Technische Universität München
Andreas Arbeiter: Klinikum rechts der Isar, Technische Universität München
Nina Schönhuber: Center for Translational Cancer Research (TranslaTUM), Technische Universität München
Sabine Klein: Center for Translational Cancer Research (TranslaTUM), Technische Universität München
Christian Veltkamp: Center for Translational Cancer Research (TranslaTUM), Technische Universität München
Mathias Friedrich: The Wellcome Trust Sanger Institute, Genome Campus
Lena Rad: Klinikum rechts der Isar, Technische Universität München
Maxim Barenboim: Klinikum rechts der Isar, Technische Universität München
Christoph Ziegenhain: Anthropology & Human Genomics, Ludwig-Maximilians Universität
Julia Hess: Helmholtz Zentrum München, Research Unit Radiation Cytogenetics
Oliver M. Dovey: The Wellcome Trust Sanger Institute, Genome Campus
Stefan Eser: Klinikum rechts der Isar, Technische Universität München
Swati Parekh: Anthropology & Human Genomics, Ludwig-Maximilians Universität
Fernando Constantino-Casas: University of Cambridge
Jorge de la Rosa: The Wellcome Trust Sanger Institute, Genome Campus
Marta I. Sierra: Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo
Mario Fraga: Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo
Julia Mayerle: Medizinische Klinik und Poliklinik II, Klinikum der LMU München-Grosshadern
Günter Klöppel: Institute of Pathology, Technische Universität München
Juan Cadiñanos: The Wellcome Trust Sanger Institute, Genome Campus
Pentao Liu: The Wellcome Trust Sanger Institute, Genome Campus
George Vassiliou: The Wellcome Trust Sanger Institute, Genome Campus
Wilko Weichert: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
Katja Steiger: Institute of Pathology, Technische Universität München
Wolfgang Enard: Anthropology & Human Genomics, Ludwig-Maximilians Universität
Roland M. Schmid: Klinikum rechts der Isar, Technische Universität München
Fengtang Yang: The Wellcome Trust Sanger Institute, Genome Campus
Kristian Unger: Helmholtz Zentrum München, Research Unit Radiation Cytogenetics
Günter Schneider: Klinikum rechts der Isar, Technische Universität München
Ignacio Varela: Instituto de Biomedicina y Biotecnología de Cantabria (UC-CSIC)
Allan Bradley: The Wellcome Trust Sanger Institute, Genome Campus
Dieter Saur: Center for Translational Cancer Research (TranslaTUM), Technische Universität München
Roland Rad: Center for Translational Cancer Research (TranslaTUM), Technische Universität München

Nature, 2018, vol. 554, issue 7690, 62-68

Abstract: 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.

Date: 2018
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DOI: 10.1038/nature25459

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