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.
In: Hepatology, Vol. 68, No. 3, 09.2018, p. 949-963.Research output: Contribution to journal › Journal article › Research › peer-review
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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