We integrated clinical, genomic and transcriptomic data from 217 primaries and 101 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma. Driver genes alterations, mutational and expression-based signatures were mostly preserved, and discordances implied Halstedian tumour spread. Cell cycle progression increased with sequential inactivation of tumour suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene mutations. Half of the cases were hypoxic by expression markers, overlapping with molecular subtypes. Inter-tumoural heterogeneity showed conserved truncations, inversions and translocations and therefore likely driver events. Multiple synchronous and metachronous PDAC arising in the same patients were actually intra-parenchymal metastases, and not independent primary tumours. Established clinical co-variates dominated survival analyses, though cell cycle progression, hypoxia and inter-tumoural heterogeneity may inform clinical practice.
Connor, Ashton A. and Denroche, Robert E. and Jang, Gun Ho and Lemire, Mathieu and Zhang, Amy and Chan-Seng-Yue, Michelle and Wilson, Gavin and Merico, Daniele and Lungu, Ilinca and Bartlett, John M. S. and Chadwick, Dianne and Liang, Sheng-Ben and Eagles, Jenna and Mbabaali, Faridah and Miller, Jessica K. and Krzyzanowski, Paul and Armstrong, Heather and Luo, Xuemei and Jorgensen, Lars G. T. and Romero, Joan M. and Bavi, Prashant and Fischer, Sandra E. and Serra, Stefano and Bakhtiari, Sara Hafezi and Caglar, Derin and Roehrl, Michael H. A. and Cleary, Sean and Hollingsworth, Michael A. and Petersen, Gloria and Thayer, Sarah and Law, Calvin H. L. and Nanji, Sulaiman and Golan, Talia and Smith, Alyssa L. and Borgida, Ayelet and Dodd, Anna and Hedley, David and Wouters, Bradly G. and O’Kane, Grainne M. and Wilson, Julie M. and Zogopoulos, George and Notta, Faiyaz and Knox, Jennifer J. and Gallinger, Steven, Integration of Genomic and Transcriptomic Features in Pancreatic Cancer Reveals Increased Cell Cycle Progression in Metastases (2018). Available at SSRN: https://ssrn.com/abstract=3188387 or http://dx.doi.org/10.2139/ssrn.3188387
This version of the paper has not been formally peer reviewed.
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