Mutation profiling in cholangiocarcinoma: Prognostic and therapeutic implications

Chaitanya R. Churi; Rachna Shroff; Ying Wang; Asif Rashid; Hyun Seon C. Kang; Jacqueline Weatherly; Mingxin Zuo; Ralph Zinner; David Hong; Funda Meric-Bernstam; Filip Janku; Christopher H. Crane; Lopa Mishra; Jean Nicholas Vauthey; Robert A. Wolff; Gordon Mills; Milind Javle; Chad Creighton

doi:10.1371/journal.pone.0115383

Mutation profiling in cholangiocarcinoma: Prognostic and therapeutic implications

Chaitanya R. Churi, Rachna Shroff, Ying Wang, Asif Rashid, Hyun Seon C. Kang, Jacqueline Weatherly, Mingxin Zuo, Ralph Zinner, David Hong, Funda Meric-Bernstam, Filip Janku, Christopher H. Crane, Lopa Mishra, Jean Nicholas Vauthey, Robert A. Wolff, Gordon Mills, Milind Javle, Chad Creighton

Research output: Contribution to journal › Article › peer-review

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Abstract

Background: Cholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics.

Methods: We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a) NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials.

Results: There were significant differences between intrahepatic (n555) and extrahepatic CCA (n520) in regard to the nature and frequency of the genetic aberrations (GAs). IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). Most frequent GAs in extrahepatic CCA (n520) were TP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4 (25%), FBXW7 (15%) and CDKN2A (15%). In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors.

Conclusion: There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications.

Original language	English (US)
Article number	e115383
Journal	PloS one
Volume	9
Issue number	12
DOIs	https://doi.org/10.1371/journal.pone.0115383
State	Published - Dec 23 2014
Externally published	Yes

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Churi, C. R., Shroff, R., Wang, Y., Rashid, A., Kang, H. S. C., Weatherly, J., Zuo, M., Zinner, R., Hong, D., Meric-Bernstam, F., Janku, F., Crane, C. H., Mishra, L., Vauthey, J. N., Wolff, R. A., Mills, G., Javle, M., & Creighton, C. (2014). Mutation profiling in cholangiocarcinoma: Prognostic and therapeutic implications. PloS one, 9(12), Article e115383. https://doi.org/10.1371/journal.pone.0115383

Churi, CR, Shroff, R, Wang, Y, Rashid, A, Kang, HSC, Weatherly, J, Zuo, M, Zinner, R, Hong, D, Meric-Bernstam, F, Janku, F, Crane, CH, Mishra, L, Vauthey, JN, Wolff, RA, Mills, G, Javle, M & Creighton, C 2014, 'Mutation profiling in cholangiocarcinoma: Prognostic and therapeutic implications', PloS one, vol. 9, no. 12, e115383. https://doi.org/10.1371/journal.pone.0115383

@article{af9dae8a146b4d1f9a455f2bcfd81690,

title = "Mutation profiling in cholangiocarcinoma: Prognostic and therapeutic implications",

abstract = "Background: Cholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics.Methods: We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a) NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials.Results: There were significant differences between intrahepatic (n555) and extrahepatic CCA (n520) in regard to the nature and frequency of the genetic aberrations (GAs). IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). Most frequent GAs in extrahepatic CCA (n520) were TP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4 (25%), FBXW7 (15%) and CDKN2A (15%). In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors.Conclusion: There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications.",

author = "Churi, {Chaitanya R.} and Rachna Shroff and Ying Wang and Asif Rashid and Kang, {Hyun Seon C.} and Jacqueline Weatherly and Mingxin Zuo and Ralph Zinner and David Hong and Funda Meric-Bernstam and Filip Janku and Crane, {Christopher H.} and Lopa Mishra and Vauthey, {Jean Nicholas} and Wolff, {Robert A.} and Gordon Mills and Milind Javle and Chad Creighton",

note = "Publisher Copyright: {\textcopyright} 2014 Churi et al.",

year = "2014",

month = dec,

day = "23",

doi = "10.1371/journal.pone.0115383",

language = "English (US)",

volume = "9",

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T1 - Mutation profiling in cholangiocarcinoma

T2 - Prognostic and therapeutic implications

AU - Churi, Chaitanya R.

AU - Shroff, Rachna

AU - Wang, Ying

AU - Rashid, Asif

AU - Kang, Hyun Seon C.

AU - Weatherly, Jacqueline

AU - Zuo, Mingxin

AU - Zinner, Ralph

AU - Hong, David

AU - Meric-Bernstam, Funda

AU - Janku, Filip

AU - Crane, Christopher H.

AU - Mishra, Lopa

AU - Vauthey, Jean Nicholas

AU - Wolff, Robert A.

AU - Mills, Gordon

AU - Javle, Milind

AU - Creighton, Chad

PY - 2014/12/23

Y1 - 2014/12/23

N2 - Background: Cholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics.Methods: We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a) NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials.Results: There were significant differences between intrahepatic (n555) and extrahepatic CCA (n520) in regard to the nature and frequency of the genetic aberrations (GAs). IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). Most frequent GAs in extrahepatic CCA (n520) were TP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4 (25%), FBXW7 (15%) and CDKN2A (15%). In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors.Conclusion: There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications.

AB - Background: Cholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics.Methods: We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a) NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials.Results: There were significant differences between intrahepatic (n555) and extrahepatic CCA (n520) in regard to the nature and frequency of the genetic aberrations (GAs). IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). Most frequent GAs in extrahepatic CCA (n520) were TP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4 (25%), FBXW7 (15%) and CDKN2A (15%). In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors.Conclusion: There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications.

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Mutation profiling in cholangiocarcinoma: Prognostic and therapeutic implications

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