Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution

• Published in: Nature genetics Vol. 52; no. 2; pp. 231 - 240
• Main Authors: Chan-Seng-Yue, Michelle, Kim, Jaeseung C., Wilson, Gavin W., Ng, Karen, Figueroa, Eugenia Flores, O’Kane, Grainne M., Connor, Ashton A., Denroche, Robert E., Grant, Robert C., McLeod, Jessica, Wilson, Julie M., Jang, Gun Ho, Zhang, Amy, Dodd, Anna, Liang, Sheng-Ben, Borgida, Ayelet, Chadwick, Dianne, Kalimuthu, Sangeetha, Lungu, Ilinca, Bartlett, John M. S., Krzyzanowski, Paul M., Sandhu, Vandana, Tiriac, Hervé, Froeling, Fieke E. M., Karasinska, Joanna M., Topham, James T., Renouf, Daniel J., Schaeffer, David F., Jones, Steven J. M., Marra, Marco A., Laskin, Janessa, Chetty, Runjan, Stein, Lincoln D., Zogopoulos, George, Haibe-Kains, Benjamin, Campbell, Peter J., Tuveson, David A., Knox, Jennifer J., Fischer, Sandra E., Gallinger, Steven, Notta, Faiyaz
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2020; Nature Publishing Group
• Subjects: 38/91; 45; 45/23; 631/208/212/2019; 631/67/1504/1713; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Agriculture; Animal Genetics and Genomics; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - mortality; Carcinoma, Pancreatic Ductal - pathology; Chemotherapy; Classification; Cohort Studies; Constellations; Copy number; Epithelium; Female; GATA6 Transcription Factor - genetics; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Function; Gene mapping; Genes; Genetic aspects; Genetic transcription; Genomes; Genomic Instability; Genomics; Heterogeneity; Human Genetics; Humans; Male; Mapping; Metastases; Metastasis; Middle Aged; Mutants; Mutation; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - mortality; Pancreatic Neoplasms - pathology; Patients; Phenotype; Phenotypes; Proto-Oncogene Proteins p21(ras) - genetics; Smad4 Protein - genetics; Subpopulations; Transcription; Tumors; Canada; Ontario
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-019-0566-9

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. Whole-genome sequencing, transcriptome sequencing and single-cell analysis of primary and metastatic pancreatic adenocarcinoma identify molecular subtypes and intratumor heterogeneity.