Allelic imbalance with increased KrasG12D gene dosage drives key PDAC characteristics.
Major finding: Allelic imbalance with increased KrasG12D gene dosage drives key PDAC characteristics.
Approach: Integrated multi-omic approaches characterize mouse PDAC cell culture resources with human data sets.
Impact: Oncogene dosage gain is critical for early PDAC progression and influences the evolutionary tumor route.
Pancreatic ductal adenocarcinoma (PDAC) exhibits a complex genome, and so far mutational landscapes have not been linked to biological or clinical phenotypes. To better understand the genomics underlying PDAC phenotypic diversification and progression, Mueller, Engleitner, Maresch, and colleagues characterized primary PDAC cell cultures from KRASG12D-driven pancreatic cancer mouse models using exome sequencing, comparative genomic hybridization, and advanced cytogenetics. Amplifications affecting the KrasG12D allele occurred frequently and were also observed in human PDAC precursor lesions, suggesting that upon KRAS mutation, additional oncogenic dosage gain is required for early cancer progression. Altogether, two thirds of tumors had allelic imbalances that increased the KrasG12D gene dosage (KrasG12D-iGD); these occurred through focal gain, arm-level gain, or copy number–neutral loss of heterozygosity. KrasG12D gene dosage gain was not only linked to early progression, but also associated with metastasis, which may provide a mechanism for early dissemination of human PDAC. Tumors without increased KrasG12D-iGD frequently showed amplification of alternative oncogenes such as Myc, Yap1, or Nfkb2, suggesting that they may drive early PDAC progression when KrasG12D is not amplified. Further, the type and level of oncogenic gain affected multiple disease characteristics including cellular histopathologic phenotypes; the most aggressive undifferentiated cancers were linked to the highest KrasG12D-iGD dosages. Major PDAC tumor suppressor gene pathways were involved in acquisition of different types of oncogenic gains. For example, homozygous inactivation of Cdkn2a or Trp53 predisposed cancers to acquire KrasG12D-iGD whereas heterozygous loss of Cdkn2a allowed for amplification of the alternative oncogenes. Taken together, these findings indicate that oncogenic dosage gain is critical for early PDAC progression and can evolve along distinct evolutionary routes. The resulting dosage variation subsequently affects multiple aspects of PDAC biology. Further, these findings may extend to other KRAS-driven tumor types.
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