Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes

Daniela Sia, Yujin Hoshida, Augusto Villanueva, Sasan Roayaie, Joana Ferrer, Barbara Tabak, Judit Peix, Manel Sole, Victoria Tovar, Clara Alsinet, Helena Cornella, Brandy Klotzle, Jian Bing Fan, Christian Cotsoglou, Swan N. Thung, Josep Fuster, Samuel Waxman, Juan Carlos Garcia-Valdecasas, Jordi Bruix, Myron E. SchwartzRameen Beroukhim, Vincenzo Mazzaferro, Josep M. Llovet

Research output: Contribution to journalArticle

214 Citations (Scopus)

Abstract

Background & Aims: Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma. We performed an integrative genomic analysis of ICC samples from a large series of patients. Methods: We performed a gene expression profile, high-density single-nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinicopathologic traits and patient outcomes were examined for 119 cases. Class discovery was based on a non-negative matrix factorization algorithm and significant copy number variations were identified by Genomic Identification of Significant Targets in Cancer (GISTIC) analysis. Gene set enrichment analysis was used to identify signaling pathways activated in specific molecular classes of tumors, and to analyze their genomic overlap with hepatocellular carcinoma (HCC). Results: We identified 2 main biological classes of ICC. The inflammation class (38% of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. The proliferation class (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC. Copy number variation-based clustering was able to refine these molecular groups further. We identified high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumor suppressor). In a complementary approach, we identified a gene expression signature that was associated with reduced survival times of patients with ICC; this signature was enriched in the proliferation class (P <.001). Conclusions: We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, activation of oncogenic pathways, and is associated with worse outcome. Different classes of ICC, based on molecular features, therefore might require different treatment approaches.

Original languageEnglish (US)
Pages (from-to)829-840
Number of pages12
JournalGastroenterology
Volume144
Issue number4
DOIs
StatePublished - Apr 2013
Externally publishedYes

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Cholangiocarcinoma
Transcriptome
Hepatocellular Carcinoma
Neoplasms
Mutation
Liver Neoplasms
Mitogen-Activated Protein Kinases
Formaldehyde
Single Nucleotide Polymorphism
Cluster Analysis
Cytokines
Inflammation
Survival
DNA

Keywords

  • Liver Cancer
  • Molecular Classification
  • Prognosis
  • Whole-Genome Profiling

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. / Sia, Daniela; Hoshida, Yujin; Villanueva, Augusto; Roayaie, Sasan; Ferrer, Joana; Tabak, Barbara; Peix, Judit; Sole, Manel; Tovar, Victoria; Alsinet, Clara; Cornella, Helena; Klotzle, Brandy; Fan, Jian Bing; Cotsoglou, Christian; Thung, Swan N.; Fuster, Josep; Waxman, Samuel; Garcia-Valdecasas, Juan Carlos; Bruix, Jordi; Schwartz, Myron E.; Beroukhim, Rameen; Mazzaferro, Vincenzo; Llovet, Josep M.

In: Gastroenterology, Vol. 144, No. 4, 04.2013, p. 829-840.

Research output: Contribution to journalArticle

Sia, D, Hoshida, Y, Villanueva, A, Roayaie, S, Ferrer, J, Tabak, B, Peix, J, Sole, M, Tovar, V, Alsinet, C, Cornella, H, Klotzle, B, Fan, JB, Cotsoglou, C, Thung, SN, Fuster, J, Waxman, S, Garcia-Valdecasas, JC, Bruix, J, Schwartz, ME, Beroukhim, R, Mazzaferro, V & Llovet, JM 2013, 'Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes', Gastroenterology, vol. 144, no. 4, pp. 829-840. https://doi.org/10.1053/j.gastro.2013.01.001
Sia, Daniela ; Hoshida, Yujin ; Villanueva, Augusto ; Roayaie, Sasan ; Ferrer, Joana ; Tabak, Barbara ; Peix, Judit ; Sole, Manel ; Tovar, Victoria ; Alsinet, Clara ; Cornella, Helena ; Klotzle, Brandy ; Fan, Jian Bing ; Cotsoglou, Christian ; Thung, Swan N. ; Fuster, Josep ; Waxman, Samuel ; Garcia-Valdecasas, Juan Carlos ; Bruix, Jordi ; Schwartz, Myron E. ; Beroukhim, Rameen ; Mazzaferro, Vincenzo ; Llovet, Josep M. / Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. In: Gastroenterology. 2013 ; Vol. 144, No. 4. pp. 829-840.
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abstract = "Background & Aims: Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma. We performed an integrative genomic analysis of ICC samples from a large series of patients. Methods: We performed a gene expression profile, high-density single-nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinicopathologic traits and patient outcomes were examined for 119 cases. Class discovery was based on a non-negative matrix factorization algorithm and significant copy number variations were identified by Genomic Identification of Significant Targets in Cancer (GISTIC) analysis. Gene set enrichment analysis was used to identify signaling pathways activated in specific molecular classes of tumors, and to analyze their genomic overlap with hepatocellular carcinoma (HCC). Results: We identified 2 main biological classes of ICC. The inflammation class (38{\%} of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. The proliferation class (62{\%}) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC. Copy number variation-based clustering was able to refine these molecular groups further. We identified high-level amplifications in 5 regions, including 1p13 (9{\%}) and 11q13.2 (4{\%}), and several focal deletions, such as 9p21.3 (18{\%}) and 14q22.1 (12{\%} in coding regions for the SAV1 tumor suppressor). In a complementary approach, we identified a gene expression signature that was associated with reduced survival times of patients with ICC; this signature was enriched in the proliferation class (P <.001). Conclusions: We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, activation of oncogenic pathways, and is associated with worse outcome. Different classes of ICC, based on molecular features, therefore might require different treatment approaches.",
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T1 - Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes

AU - Sia, Daniela

AU - Hoshida, Yujin

AU - Villanueva, Augusto

AU - Roayaie, Sasan

AU - Ferrer, Joana

AU - Tabak, Barbara

AU - Peix, Judit

AU - Sole, Manel

AU - Tovar, Victoria

AU - Alsinet, Clara

AU - Cornella, Helena

AU - Klotzle, Brandy

AU - Fan, Jian Bing

AU - Cotsoglou, Christian

AU - Thung, Swan N.

AU - Fuster, Josep

AU - Waxman, Samuel

AU - Garcia-Valdecasas, Juan Carlos

AU - Bruix, Jordi

AU - Schwartz, Myron E.

AU - Beroukhim, Rameen

AU - Mazzaferro, Vincenzo

AU - Llovet, Josep M.

PY - 2013/4

Y1 - 2013/4

N2 - Background & Aims: Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma. We performed an integrative genomic analysis of ICC samples from a large series of patients. Methods: We performed a gene expression profile, high-density single-nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinicopathologic traits and patient outcomes were examined for 119 cases. Class discovery was based on a non-negative matrix factorization algorithm and significant copy number variations were identified by Genomic Identification of Significant Targets in Cancer (GISTIC) analysis. Gene set enrichment analysis was used to identify signaling pathways activated in specific molecular classes of tumors, and to analyze their genomic overlap with hepatocellular carcinoma (HCC). Results: We identified 2 main biological classes of ICC. The inflammation class (38% of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. The proliferation class (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC. Copy number variation-based clustering was able to refine these molecular groups further. We identified high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumor suppressor). In a complementary approach, we identified a gene expression signature that was associated with reduced survival times of patients with ICC; this signature was enriched in the proliferation class (P <.001). Conclusions: We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, activation of oncogenic pathways, and is associated with worse outcome. Different classes of ICC, based on molecular features, therefore might require different treatment approaches.

AB - Background & Aims: Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma. We performed an integrative genomic analysis of ICC samples from a large series of patients. Methods: We performed a gene expression profile, high-density single-nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinicopathologic traits and patient outcomes were examined for 119 cases. Class discovery was based on a non-negative matrix factorization algorithm and significant copy number variations were identified by Genomic Identification of Significant Targets in Cancer (GISTIC) analysis. Gene set enrichment analysis was used to identify signaling pathways activated in specific molecular classes of tumors, and to analyze their genomic overlap with hepatocellular carcinoma (HCC). Results: We identified 2 main biological classes of ICC. The inflammation class (38% of ICCs) is characterized by activation of inflammatory signaling pathways, overexpression of cytokines, and STAT3 activation. The proliferation class (62%) is characterized by activation of oncogenic signaling pathways (including RAS, mitogen-activated protein kinase, and MET), DNA amplifications at 11q13.2, deletions at 14q22.1, mutations in KRAS and BRAF, and gene expression signatures previously associated with poor outcomes for patients with HCC. Copy number variation-based clustering was able to refine these molecular groups further. We identified high-level amplifications in 5 regions, including 1p13 (9%) and 11q13.2 (4%), and several focal deletions, such as 9p21.3 (18%) and 14q22.1 (12% in coding regions for the SAV1 tumor suppressor). In a complementary approach, we identified a gene expression signature that was associated with reduced survival times of patients with ICC; this signature was enriched in the proliferation class (P <.001). Conclusions: We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, activation of oncogenic pathways, and is associated with worse outcome. Different classes of ICC, based on molecular features, therefore might require different treatment approaches.

KW - Liver Cancer

KW - Molecular Classification

KW - Prognosis

KW - Whole-Genome Profiling

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