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Publication : Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes.

First Author	Mueller S	Year	2018
Journal	Nature	Volume	554
Issue	7690	Pages	62-68
PubMed ID	29364867	Mgi Jnum	J:257934
Mgi Id	MGI:6115581	Doi	10.1038/nature25459
Citation	Mueller S, et al. (2018) Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. Nature 554(7690):62-68

abstractText

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 Kras(MUT) levels underlying aggressive undifferentiated phenotypes. We also identify alternative oncogenic gains (Myc, Yap1 or Nfkb2), which collaborate with heterozygous Kras(MUT) 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, Tgfbeta-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.

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Publication : Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes.

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