1. Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution.
- Author
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Chan-Seng-Yue M, Kim JC, Wilson GW, Ng K, Figueroa EF, O'Kane GM, Connor AA, Denroche RE, Grant RC, McLeod J, Wilson JM, Jang GH, Zhang A, Dodd A, Liang SB, Borgida A, Chadwick D, Kalimuthu S, Lungu I, Bartlett JMS, Krzyzanowski PM, Sandhu V, Tiriac H, Froeling FEM, Karasinska JM, Topham JT, Renouf DJ, Schaeffer DF, Jones SJM, Marra MA, Laskin J, Chetty R, Stein LD, Zogopoulos G, Haibe-Kains B, Campbell PJ, Tuveson DA, Knox JJ, Fischer SE, Gallinger S, and Notta F
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal mortality, Cohort Studies, Female, GATA6 Transcription Factor genetics, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genomic Instability, Humans, Male, Middle Aged, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms mortality, Phenotype, Proto-Oncogene Proteins p21(ras) genetics, Smad4 Protein genetics, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal pathology, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology
- Abstract
Pancreatic adenocarcinoma presents as a spectrum of a highly aggressive disease in patients. The basis of this disease heterogeneity has proved difficult to resolve due to poor tumor cellularity and extensive genomic instability. To address this, a dataset of whole genomes and transcriptomes was generated from purified epithelium of primary and metastatic tumors. Transcriptome analysis demonstrated that molecular subtypes are a product of a gene expression continuum driven by a mixture of intratumoral subpopulations, which was confirmed by single-cell analysis. Integrated whole-genome analysis uncovered that molecular subtypes are linked to specific copy number aberrations in genes such as mutant KRAS and GATA6. By mapping tumor genetic histories, tetraploidization emerged as a key mutational process behind these events. Taken together, these data support the premise that the constellation of genomic aberrations in the tumor gives rise to the molecular subtype, and that disease heterogeneity is due to ongoing genomic instability during progression.
- Published
- 2020
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