Chirag Nepal1, Colm J O'Rourke1, Douglas V N P Oliveira1, Andrzej Taranta1, Steven Shema2, Prson Gautam3, Julien Calderaro4,5,6, Andrew Barbour7, Chiara Raggi8, Krister Wennerberg1,3, Xin W Wang9, Anja Lautem10, Lewis R Roberts11, Jesper B Andersen1. 1. Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 2. Center for Cancer Research Genomics Core, National Cancer Institute, National Institutes of Health, Bethesda, MD. 3. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. 4. Assistance Publique-Hôpitaux de Paris, Department of Pathology, CHU Henri Mondor, Créteil, France. 5. Faculté de Médecine, Université Paris-Est Créteil, Créteil, France. 6. Inserm U955 Equipe 18, Institut Mondor de Recherche Biomédicale, Créteil, France. 7. University of Queensland, Brisbane, Australia. 8. Center for Autoimmune Liver Diseases, IRCCS Istituto Clinico Humanitas, Rozzano (MI), Italy. 9. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD. 10. Department of General, Visceral and Transplantation Surgery, University Medical Center Mainz, Mainz, Germany. 11. Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN.
Abstract
Intrahepatic cholangiocarcinoma remains a highly heterogeneous malignancy that has eluded effective patient stratification to date. The extent to which such heterogeneity can be influenced by individual driver mutations remains to be evaluated. Here, we analyzed genomic (whole-exome sequencing, targeted exome sequencing) and epigenomic data from 496 patients and used the three most recurrently mutated genes to stratify patients (IDH, KRAS, TP53, "undetermined"). Using this molecular dissection approach, each subgroup was determined to possess unique mutational signature preferences, comutation profiles, and enriched pathways. High-throughput drug repositioning in seven patient-matched cell lines, chosen to reflect the genetic alterations specific for each patient group, confirmed in silico predictions of subgroup-specific vulnerabilities linked to enriched pathways. Intriguingly, patients lacking all three mutations ("undetermined") harbored the most extensive structural alterations, while isocitrate dehydrogenase mutant tumors displayed the most extensive DNA methylome dysregulation, consistent with previous findings. CONCLUSION: Stratification of intrahepatic cholangiocarcinoma patients based on occurrence of mutations in three classifier genes (IDH, KRAS, TP53) revealed unique oncogenic programs (mutational, structural, epimutational) that influence pharmacologic response in drug repositioning protocols; this genome dissection approach highlights the potential of individual mutations to induce extensive molecular heterogeneity and could facilitate advancement of therapeutic response in this dismal disease. (Hepatology 2018).
Intrahepatic cholangiocarcinoma remains a highly heterogeneous malignancy that has eluded effective patient stratification to date. The extent to which such heterogeneity can be influenced by individual driver mutations remains to be evaluated. Here, we analyzed genomic (whole-exome sequencing, targeted exome sequencing) and epigenomic data from 496 patients and used the three most recurrently mutated genes to stratify patients (IDH, KRAS, TP53, "undetermined"). Using this molecular dissection approach, each subgroup was determined to possess unique mutational signature preferences, comutation profiles, and enriched pathways. High-throughput drug repositioning in seven patient-matched cell lines, chosen to reflect the genetic alterations specific for each patient group, confirmed in silico predictions of subgroup-specific vulnerabilities linked to enriched pathways. Intriguingly, patients lacking all three mutations ("undetermined") harbored the most extensive structural alterations, while isocitrate dehydrogenase mutant tumors displayed the most extensive DNA methylome dysregulation, consistent with previous findings. CONCLUSION: Stratification of intrahepatic cholangiocarcinomapatients based on occurrence of mutations in three classifier genes (IDH, KRAS, TP53) revealed unique oncogenic programs (mutational, structural, epimutational) that influence pharmacologic response in drug repositioning protocols; this genome dissection approach highlights the potential of individual mutations to induce extensive molecular heterogeneity and could facilitate advancement of therapeutic response in this dismal disease. (Hepatology 2018).
Authors: Michael R O'Dell; Jing Li Huang; Christa L Whitney-Miller; Vikram Deshpande; Paul Rothberg; Valerie Grose; Randall M Rossi; Andrew X Zhu; Hartmut Land; Nabeel Bardeesy; Aram F Hezel Journal: Cancer Res Date: 2012-01-20 Impact factor: 12.701
Authors: Juan Valle; Harpreet Wasan; Daniel H Palmer; David Cunningham; Alan Anthoney; Anthony Maraveyas; Srinivasan Madhusudan; Tim Iveson; Sharon Hughes; Stephen P Pereira; Michael Roughton; John Bridgewater Journal: N Engl J Med Date: 2010-04-08 Impact factor: 91.245
Authors: Jesper B Andersen; Bart Spee; Boris R Blechacz; Itzhak Avital; Mina Komuta; Andrew Barbour; Elizabeth A Conner; Matthew C Gillen; Tania Roskams; Lewis R Roberts; Valentina M Factor; Snorri S Thorgeirsson Journal: Gastroenterology Date: 2011-12-13 Impact factor: 22.682
Authors: Marian M H Claessen; Frank P Vleggaar; Kristien M A J Tytgat; Peter D Siersema; Henk R van Buuren Journal: J Hepatol Date: 2008-10-14 Impact factor: 25.083
Authors: E Andrés Houseman; Brock C Christensen; Margaret R Karagas; Margaret R Wrensch; Heather H Nelson; Joseph L Wiemels; Shichun Zheng; John K Wiencke; Karl T Kelsey; Carmen J Marsit Journal: Bioinformatics Date: 2009-06-19 Impact factor: 6.937
Authors: Darrell R Borger; Kenneth K Tanabe; Kenneth C Fan; Hector U Lopez; Valeria R Fantin; Kimberly S Straley; David P Schenkein; Aram F Hezel; Marek Ancukiewicz; Hannah M Liebman; Eunice L Kwak; Jeffrey W Clark; David P Ryan; Vikram Deshpande; Dora Dias-Santagata; Leif W Ellisen; Andrew X Zhu; A John Iafrate Journal: Oncologist Date: 2011-12-16 Impact factor: 5.837
Authors: Jesus M Banales; Jose J G Marin; Angela Lamarca; Pedro M Rodrigues; Shahid A Khan; Lewis R Roberts; Vincenzo Cardinale; Guido Carpino; Jesper B Andersen; Chiara Braconi; Diego F Calvisi; Maria J Perugorria; Luca Fabris; Luke Boulter; Rocio I R Macias; Eugenio Gaudio; Domenico Alvaro; Sergio A Gradilone; Mario Strazzabosco; Marco Marzioni; Cédric Coulouarn; Laura Fouassier; Chiara Raggi; Pietro Invernizzi; Joachim C Mertens; Anja Moncsek; Sumera Rizvi; Julie Heimbach; Bas Groot Koerkamp; Jordi Bruix; Alejandro Forner; John Bridgewater; Juan W Valle; Gregory J Gores Journal: Nat Rev Gastroenterol Hepatol Date: 2020-06-30 Impact factor: 46.802