Project description:Background & Aims: Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer usually developed in non-cirrhotic livers of children and young adults with unknown etiology. Treatment is limited to surgical intervention. To date, molecular pathogenesis of FLC has been poorly characterized. Herein, we aim to provide an integrative genomic analysis from a large series of FLC patients. Methods: A clinically annotated cohort of 77 FLCs was analyzed through wholetranscriptome, SNP-array and whole-exome sequencing. Non-negative matrix factorization was performed for class discovery, and GSEA, NTP, IPA and immunohistochemistry for functional annotation. GISTIC algorithm identified chromosomal aberrations; Mutect and VarScan2, somatic mutations, and Random survival forest the prognostic signature, validated in an independent cohort. Results: Unsupervised gene expression clustering revealed 3 robust molecular classes: Proliferation-51%, enriched with liver cancer proliferation signatures and mTOR signaling activation, Inflammation-26%, with pro-inflammatory cytokines signatures, and Unannotated-23%, with non-liver-related cancer signatures. Neuroendocrine genes and cholangiocyte and hepatocyte histological markers were present in all classes. FLC showed few copy number variations, being the most frequent: focal amplification at 8q24.3(12.5%), and deletions at 19p13(28%) and 22q13.32(25%). DNAJB1-PRKACA fusion transcript was observed in 79% of cases. FLC tumors had 32 damaging mutations on average, affecting uncommon genes in liver neoplasms (BRCA2, U2AF1). An 8-gene prognostic signature predicted survival in FLC patients. Conclusions: FLC genomic analysis reveals a unique molecular portrait characterized by uncommon damaging mutations and chromosomal aberrations, and a highly prevalent fusion protein. Three molecular classes, including Proliferation and Inflammation, define the biological behavior. Prognostic signature will allow better patient stratification. Gene-expression profiles of fresh frozen human fibrolamellar hepatocellular carcinoma

Project description:Background & Aims: Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer usually developed in non-cirrhotic livers of children and young adults with unknown etiology. Treatment is limited to surgical intervention. To date, molecular pathogenesis of FLC has been poorly characterized. Herein, we aim to provide an integrative genomic analysis from a large series of FLC patients. Methods: A clinically annotated cohort of 77 FLCs was analyzed through whole transcriptome, SNP-array and whole-exome sequencing. Non-negative matrix factorization was performed for class discovery, and GSEA, NTP, IPA and immunohistochemistry for functional annotation. GISTIC algorithm identified chromosomal aberrations; Mutect and VarScan2, somatic mutations, and Random survival forest the prognostic signature, validated in an independent cohort. Results: Unsupervised gene expression clustering revealed 3 robust molecular classes: Proliferation-51%, enriched with liver cancer proliferation signatures and mTOR signaling activation, Inflammation-26%, with pro-inflammatory cytokines signatures, and Unannotated-23%, with non-liver-related cancer signatures. Neuroendocrine genes and cholangiocyte and hepatocyte histological markers were present in all classes. FLC showed few copy number variations, being the most frequent: focal amplification at 8q24.3(12.5%), and deletions at 19p13(28%) and 22q13.32(25%). DNAJB1-PRKACA fusion transcript was observed in 79% of cases. FLC tumors had 32 damaging mutations on average, affecting uncommon genes in liver neoplasms (BRCA2, U2AF1). An 8-gene prognostic signature predicted survival in FLC patients. Conclusions: FLC genomic analysis reveals a unique molecular portrait characterized by uncommon damaging mutations and chromosomal aberrations, and a highly prevalent fusion protein. Three molecular classes, including Proliferation and Inflammation, define the biological behavior. Prognostic signature will allow better patient stratification. Gene-expression profiles of formalin-fixed, paraffin-embedded human fibrolamellar hepatocellular carcinoma

Project description:Background & Aims: Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer usually developed in non-cirrhotic livers of children and young adults with unknown etiology. Treatment is limited to surgical intervention. To date, molecular pathogenesis of FLC has been poorly characterized. Herein, we aim to provide an integrative genomic analysis from a large series of FLC patients. Methods: A clinically annotated cohort of 77 FLCs was analyzed through wholetranscriptome, SNP-array and whole-exome sequencing. Non-negative matrix factorization was performed for class discovery, and GSEA, NTP, IPA and immunohistochemistry for functional annotation. GISTIC algorithm identified chromosomal aberrations; Mutect and VarScan2, somatic mutations, and Random survival forest the prognostic signature, validated in an independent cohort. Results: Unsupervised gene expression clustering revealed 3 robust molecular classes: Proliferation-51%, enriched with liver cancer proliferation signatures and mTOR signaling activation, Inflammation-26%, with pro-inflammatory cytokines signatures, and Unannotated-23%, with non-liver-related cancer signatures. Neuroendocrine genes and cholangiocyte and hepatocyte histological markers were present in all classes. FLC showed few copy number variations, being the most frequent: focal amplification at 8q24.3(12.5%), and deletions at 19p13(28%) and 22q13.32(25%). DNAJB1-PRKACA fusion transcript was observed in 79% of cases. FLC tumors had 32 damaging mutations on average, affecting uncommon genes in liver neoplasms (BRCA2, U2AF1). An 8-gene prognostic signature predicted survival in FLC patients. Conclusions: FLC genomic analysis reveals a unique molecular portrait characterized by uncommon damaging mutations and chromosomal aberrations, and a highly prevalent fusion protein. Three molecular classes, including Proliferation and Inflammation, define the biological behavior. Prognostic signature will allow better patient stratification.

Project description:BACKGROUND & AIMS: Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic (ICC) or extrahepatic. We performed an integrative genomic analysis of ICC samples from a large series of patients. METHODS: We performed gene expression profile, high-density single nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinico-pathological 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 (CNV) were identified by 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. CNV-based clustering was able to further refine these molecular groups. 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<0.001). CONCLUSIONS: We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, many features of the poor-prognosis signatures for HCC, and is associated with worse outcome. Different classes of ICC, based on molecular features, might therefore require different treatment approaches. Gene-expression profiling was performed using formalin-fixed, paraffin-embedded intrahepatic cholangiocarcinoma tissues obtained at the time of surgical resection.

Project description:BACKGROUND & AIMS: Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic (ICC) or extrahepatic. We performed an integrative genomic analysis of ICC samples from a large series of patients. METHODS: We performed gene expression profile, high-density single nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinico-pathological 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 (CNV) were identified by 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. CNV-based clustering was able to further refine these molecular groups. 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<0.001). CONCLUSIONS: We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, many features of the poor-prognosis signatures for HCC, and is associated with worse outcome. Different classes of ICC, based on molecular features, might therefore require different treatment approaches. DNA copy number profiling was performed using formalin-fixed, paraffin-embedded intrahepatic cholangiocarcinoma tissues obtained at the time of surgical resection.

Project description:BACKGROUND & AIMS: Cholangiocarcinoma, the second most common liver cancer, can be classified as intrahepatic (ICC) or extrahepatic. We performed an integrative genomic analysis of ICC samples from a large series of patients. METHODS: We performed gene expression profile, high-density single nucleotide polymorphism array, and mutation analyses using formalin-fixed ICC samples from 149 patients. Associations with clinico-pathological 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 (CNV) were identified by 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. CNV-based clustering was able to further refine these molecular groups. 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<0.001). CONCLUSIONS: We used an integrative genomic analysis to identify 2 classes of ICC. The proliferation class has specific copy number alterations, many features of the poor-prognosis signatures for HCC, and is associated with worse outcome. Different classes of ICC, based on molecular features, might therefore require different treatment approaches. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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Genomic analysis of Fibrolammellar Hepatocellular Carcinoma reveals an unique molecular profile [Training set]

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