Genomic Perturbations Reveal Distinct Regulatory Networks in Intrahepatic Cholangiocarcinoma

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Genomic Perturbations Reveal Distinct Regulatory Networks in Intrahepatic Cholangiocarcinoma. / Nepal, Chirag; O'Rourke, Colm J; Oliveira, Douglas Vnp; Taranta, Andrzej; Shema, Steven; Gautam, Prson; Calderaro, Julien; Barbour, Andrew; Raggi, Chiara; Wennerberg, Krister; Wang, Xin W; Lautem, Anja; Roberts, Lewis R; Andersen, Jesper B.

I: Hepatology, Bind 68, Nr. 3, 09.2018, s. 949-963.

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

Harvard

Nepal, C, O'Rourke, CJ, Oliveira, DV, Taranta, A, Shema, S, Gautam, P, Calderaro, J, Barbour, A, Raggi, C, Wennerberg, K, Wang, XW, Lautem, A, Roberts, LR & Andersen, JB 2018, 'Genomic Perturbations Reveal Distinct Regulatory Networks in Intrahepatic Cholangiocarcinoma', Hepatology, bind 68, nr. 3, s. 949-963. https://doi.org/10.1002/hep.29764

APA

Nepal, C., O'Rourke, C. J., Oliveira, D. V., Taranta, A., Shema, S., Gautam, P., Calderaro, J., Barbour, A., Raggi, C., Wennerberg, K., Wang, X. W., Lautem, A., Roberts, L. R., & Andersen, J. B. (2018). Genomic Perturbations Reveal Distinct Regulatory Networks in Intrahepatic Cholangiocarcinoma. Hepatology, 68(3), 949-963. https://doi.org/10.1002/hep.29764

Vancouver

Nepal C, O'Rourke CJ, Oliveira DV, Taranta A, Shema S, Gautam P o.a. Genomic Perturbations Reveal Distinct Regulatory Networks in Intrahepatic Cholangiocarcinoma. Hepatology. 2018 sep.;68(3):949-963. https://doi.org/10.1002/hep.29764

Author

Nepal, Chirag ; O'Rourke, Colm J ; Oliveira, Douglas Vnp ; Taranta, Andrzej ; Shema, Steven ; Gautam, Prson ; Calderaro, Julien ; Barbour, Andrew ; Raggi, Chiara ; Wennerberg, Krister ; Wang, Xin W ; Lautem, Anja ; Roberts, Lewis R ; Andersen, Jesper B. / Genomic Perturbations Reveal Distinct Regulatory Networks in Intrahepatic Cholangiocarcinoma. I: Hepatology. 2018 ; Bind 68, Nr. 3. s. 949-963.

Bibtex

@article{7e73b4f0a4e349018e4e1a8a7f154fe0,
title = "Genomic Perturbations Reveal Distinct Regulatory Networks in Intrahepatic Cholangiocarcinoma",
abstract = "Intrahepatic cholangiocarcinoma (iCCA) 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, co-mutation 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 3 mutations ('undetermined') harbored the most extensive structural alterations while IDH mutant tumors displayed the most extensive DNA methylome dysregulation, consistent with previous findings.CONCLUSION: Stratification of iCCA patients based on occurrence of mutations in three classifier genes (IDH, KRAS, TP53) revealed unique oncogenic programs (mutational, structural, epi-mutational) 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. This article is protected by copyright. All rights reserved.",
keywords = "Journal Article",
author = "Chirag Nepal and O'Rourke, {Colm J} and Oliveira, {Douglas Vnp} and Andrzej Taranta and Steven Shema and Prson Gautam and Julien Calderaro and Andrew Barbour and Chiara Raggi and Krister Wennerberg and Wang, {Xin W} and Anja Lautem and Roberts, {Lewis R} and Andersen, {Jesper B}",
note = "{\textcopyright} 2017 by the American Association for the Study of Liver Diseases.",
year = "2018",
month = sep,
doi = "10.1002/hep.29764",
language = "English",
volume = "68",
pages = "949--963",
journal = "Hepatology",
issn = "0270-9139",
publisher = "JohnWiley & Sons, Inc.",
number = "3",

}

RIS

TY - JOUR

T1 - Genomic Perturbations Reveal Distinct Regulatory Networks in Intrahepatic Cholangiocarcinoma

AU - Nepal, Chirag

AU - O'Rourke, Colm J

AU - Oliveira, Douglas Vnp

AU - Taranta, Andrzej

AU - Shema, Steven

AU - Gautam, Prson

AU - Calderaro, Julien

AU - Barbour, Andrew

AU - Raggi, Chiara

AU - Wennerberg, Krister

AU - Wang, Xin W

AU - Lautem, Anja

AU - Roberts, Lewis R

AU - Andersen, Jesper B

N1 - © 2017 by the American Association for the Study of Liver Diseases.

PY - 2018/9

Y1 - 2018/9

N2 - Intrahepatic cholangiocarcinoma (iCCA) 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, co-mutation 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 3 mutations ('undetermined') harbored the most extensive structural alterations while IDH mutant tumors displayed the most extensive DNA methylome dysregulation, consistent with previous findings.CONCLUSION: Stratification of iCCA patients based on occurrence of mutations in three classifier genes (IDH, KRAS, TP53) revealed unique oncogenic programs (mutational, structural, epi-mutational) 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. This article is protected by copyright. All rights reserved.

AB - Intrahepatic cholangiocarcinoma (iCCA) 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, co-mutation 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 3 mutations ('undetermined') harbored the most extensive structural alterations while IDH mutant tumors displayed the most extensive DNA methylome dysregulation, consistent with previous findings.CONCLUSION: Stratification of iCCA patients based on occurrence of mutations in three classifier genes (IDH, KRAS, TP53) revealed unique oncogenic programs (mutational, structural, epi-mutational) 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. This article is protected by copyright. All rights reserved.

KW - Journal Article

U2 - 10.1002/hep.29764

DO - 10.1002/hep.29764

M3 - Journal article

C2 - 29278425

VL - 68

SP - 949

EP - 963

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 3

ER -

ID: 187583179