Unique genomic profile of fibrolamellar hepatocellular carcinoma

Helena Cornella, Clara Alsinet, Sergi Sayols, Zhongyang Zhang, Ke Hao, Laia Cabellos, Yujin Hoshida, Augusto Villanueva, Swan Thung, Stephen C. Ward, Leonardo Rodriguez-Carunchio, Maria Vila-Casadesús, Sandrine Imbeaud, Anja Lachenmayer, Alberto Quaglia, David M. Nagorney, Beatriz Minguez, Flair Carrilho, Lewis Rowland Roberts, Samuel WaxmanVincenzo Mazzaferro, Myron Schwartz, Manel Esteller, Nigel D. Heaton, Jessica Zucman-Rossi, Josep M. Llovet

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Background Aims Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer that develops in children and young adults without cirrhosis. Little is known about its pathogenesis, and it can be treated only with surgery. We performed an integrative genomic analysis of a large series of patients with FLC to identify associated genetic factors. Methods By using 78 clinically annotated FLC samples, we performed whole-transcriptome (n = 58), single-nucleotide polymorphism array (n = 41), and next-generation sequencing (n = 48) analyses; we also assessed the prevalence of the DNAJB1-PRKACA fusion transcript associated with this cancer (n = 73). We performed class discovery using non-negative matrix factorization, and functional annotation using gene-set enrichment analyses, nearest template prediction, ingenuity pathway analyses, and immunohistochemistry. The genomic identification of significant targets in a cancer algorithm was used to identify chromosomal aberrations, MuTect and VarScan2 were used to identify somatic mutations, and the random survival forest was used to determine patient prognoses. Findings were validated in an independent cohort. Results Unsupervised gene expression clustering showed 3 robust molecular classes of tumors: the proliferation class (51% of samples) had altered expression of genes that regulate proliferation and mammalian target of rapamycin signaling activation; the inflammation class (26% of samples) had altered expression of genes that regulate inflammation and cytokine enriched production; and the unannotated class (23% of samples) had a gene expression signature that was not associated previously with liver tumors. Expression of genes that regulate neuroendocrine function, as well as histologic markers of cholangiocytes and hepatocytes, were detected in all 3 classes. FLCs had few copy number variations; the most frequent were focal amplification at 8q24.3 (in 12.5% of samples), and deletions at 19p13 (in 28% of samples) and 22q13.32 (in 25% of samples). The DNAJB1-PRKACA fusion transcript was detected in 79% of samples. FLC samples also contained mutations in cancer-related genes such as BRCA2 (in 4.2% of samples), which are uncommon in liver neoplasms. However, FLCs did not contain mutations most commonly detected in liver cancers. We identified an 8-gene signature that predicted survival of patients with FLC. Conclusions In a genomic analysis of 78 FLC samples, we identified 3 classes based on gene expression profiles. FLCs contain mutations and chromosomal aberrations not previously associated with liver cancer, and almost 80% contain the DNAJB1-PRKACA fusion transcript. By using this information, we identified a gene signature that is associated with patient survival time.

Original languageEnglish (US)
Pages (from-to)806-818.e10
JournalGastroenterology
Volume148
Issue number4
DOIs
StatePublished - Apr 1 2015

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Liver Neoplasms
Transcriptome
Gene Expression
Mutation
Chromosome Aberrations
Survival
Neoplasms
Inflammation
Molecular Sequence Annotation
Neoplasm Genes
Sirolimus
Genes
Single Nucleotide Polymorphism
Cluster Analysis
Fibrolamellar hepatocellular carcinoma
Young Adult
Hepatocytes
Fibrosis
Immunohistochemistry
Cytokines

Keywords

  • Genomic Profiling
  • Molecular Classification
  • Outcome
  • Targeted Therapies

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Cornella, H., Alsinet, C., Sayols, S., Zhang, Z., Hao, K., Cabellos, L., ... Llovet, J. M. (2015). Unique genomic profile of fibrolamellar hepatocellular carcinoma. Gastroenterology, 148(4), 806-818.e10. https://doi.org/10.1053/j.gastro.2014.12.028

Unique genomic profile of fibrolamellar hepatocellular carcinoma. / Cornella, Helena; Alsinet, Clara; Sayols, Sergi; Zhang, Zhongyang; Hao, Ke; Cabellos, Laia; Hoshida, Yujin; Villanueva, Augusto; Thung, Swan; Ward, Stephen C.; Rodriguez-Carunchio, Leonardo; Vila-Casadesús, Maria; Imbeaud, Sandrine; Lachenmayer, Anja; Quaglia, Alberto; Nagorney, David M.; Minguez, Beatriz; Carrilho, Flair; Roberts, Lewis Rowland; Waxman, Samuel; Mazzaferro, Vincenzo; Schwartz, Myron; Esteller, Manel; Heaton, Nigel D.; Zucman-Rossi, Jessica; Llovet, Josep M.

In: Gastroenterology, Vol. 148, No. 4, 01.04.2015, p. 806-818.e10.

Research output: Contribution to journalArticle

Cornella, H, Alsinet, C, Sayols, S, Zhang, Z, Hao, K, Cabellos, L, Hoshida, Y, Villanueva, A, Thung, S, Ward, SC, Rodriguez-Carunchio, L, Vila-Casadesús, M, Imbeaud, S, Lachenmayer, A, Quaglia, A, Nagorney, DM, Minguez, B, Carrilho, F, Roberts, LR, Waxman, S, Mazzaferro, V, Schwartz, M, Esteller, M, Heaton, ND, Zucman-Rossi, J & Llovet, JM 2015, 'Unique genomic profile of fibrolamellar hepatocellular carcinoma', Gastroenterology, vol. 148, no. 4, pp. 806-818.e10. https://doi.org/10.1053/j.gastro.2014.12.028
Cornella H, Alsinet C, Sayols S, Zhang Z, Hao K, Cabellos L et al. Unique genomic profile of fibrolamellar hepatocellular carcinoma. Gastroenterology. 2015 Apr 1;148(4):806-818.e10. https://doi.org/10.1053/j.gastro.2014.12.028
Cornella, Helena ; Alsinet, Clara ; Sayols, Sergi ; Zhang, Zhongyang ; Hao, Ke ; Cabellos, Laia ; Hoshida, Yujin ; Villanueva, Augusto ; Thung, Swan ; Ward, Stephen C. ; Rodriguez-Carunchio, Leonardo ; Vila-Casadesús, Maria ; Imbeaud, Sandrine ; Lachenmayer, Anja ; Quaglia, Alberto ; Nagorney, David M. ; Minguez, Beatriz ; Carrilho, Flair ; Roberts, Lewis Rowland ; Waxman, Samuel ; Mazzaferro, Vincenzo ; Schwartz, Myron ; Esteller, Manel ; Heaton, Nigel D. ; Zucman-Rossi, Jessica ; Llovet, Josep M. / Unique genomic profile of fibrolamellar hepatocellular carcinoma. In: Gastroenterology. 2015 ; Vol. 148, No. 4. pp. 806-818.e10.
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abstract = "Background Aims Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer that develops in children and young adults without cirrhosis. Little is known about its pathogenesis, and it can be treated only with surgery. We performed an integrative genomic analysis of a large series of patients with FLC to identify associated genetic factors. Methods By using 78 clinically annotated FLC samples, we performed whole-transcriptome (n = 58), single-nucleotide polymorphism array (n = 41), and next-generation sequencing (n = 48) analyses; we also assessed the prevalence of the DNAJB1-PRKACA fusion transcript associated with this cancer (n = 73). We performed class discovery using non-negative matrix factorization, and functional annotation using gene-set enrichment analyses, nearest template prediction, ingenuity pathway analyses, and immunohistochemistry. The genomic identification of significant targets in a cancer algorithm was used to identify chromosomal aberrations, MuTect and VarScan2 were used to identify somatic mutations, and the random survival forest was used to determine patient prognoses. Findings were validated in an independent cohort. Results Unsupervised gene expression clustering showed 3 robust molecular classes of tumors: the proliferation class (51{\%} of samples) had altered expression of genes that regulate proliferation and mammalian target of rapamycin signaling activation; the inflammation class (26{\%} of samples) had altered expression of genes that regulate inflammation and cytokine enriched production; and the unannotated class (23{\%} of samples) had a gene expression signature that was not associated previously with liver tumors. Expression of genes that regulate neuroendocrine function, as well as histologic markers of cholangiocytes and hepatocytes, were detected in all 3 classes. FLCs had few copy number variations; the most frequent were focal amplification at 8q24.3 (in 12.5{\%} of samples), and deletions at 19p13 (in 28{\%} of samples) and 22q13.32 (in 25{\%} of samples). The DNAJB1-PRKACA fusion transcript was detected in 79{\%} of samples. FLC samples also contained mutations in cancer-related genes such as BRCA2 (in 4.2{\%} of samples), which are uncommon in liver neoplasms. However, FLCs did not contain mutations most commonly detected in liver cancers. We identified an 8-gene signature that predicted survival of patients with FLC. Conclusions In a genomic analysis of 78 FLC samples, we identified 3 classes based on gene expression profiles. FLCs contain mutations and chromosomal aberrations not previously associated with liver cancer, and almost 80{\%} contain the DNAJB1-PRKACA fusion transcript. By using this information, we identified a gene signature that is associated with patient survival time.",
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TY - JOUR

T1 - Unique genomic profile of fibrolamellar hepatocellular carcinoma

AU - Cornella, Helena

AU - Alsinet, Clara

AU - Sayols, Sergi

AU - Zhang, Zhongyang

AU - Hao, Ke

AU - Cabellos, Laia

AU - Hoshida, Yujin

AU - Villanueva, Augusto

AU - Thung, Swan

AU - Ward, Stephen C.

AU - Rodriguez-Carunchio, Leonardo

AU - Vila-Casadesús, Maria

AU - Imbeaud, Sandrine

AU - Lachenmayer, Anja

AU - Quaglia, Alberto

AU - Nagorney, David M.

AU - Minguez, Beatriz

AU - Carrilho, Flair

AU - Roberts, Lewis Rowland

AU - Waxman, Samuel

AU - Mazzaferro, Vincenzo

AU - Schwartz, Myron

AU - Esteller, Manel

AU - Heaton, Nigel D.

AU - Zucman-Rossi, Jessica

AU - Llovet, Josep M.

PY - 2015/4/1

Y1 - 2015/4/1

N2 - Background Aims Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer that develops in children and young adults without cirrhosis. Little is known about its pathogenesis, and it can be treated only with surgery. We performed an integrative genomic analysis of a large series of patients with FLC to identify associated genetic factors. Methods By using 78 clinically annotated FLC samples, we performed whole-transcriptome (n = 58), single-nucleotide polymorphism array (n = 41), and next-generation sequencing (n = 48) analyses; we also assessed the prevalence of the DNAJB1-PRKACA fusion transcript associated with this cancer (n = 73). We performed class discovery using non-negative matrix factorization, and functional annotation using gene-set enrichment analyses, nearest template prediction, ingenuity pathway analyses, and immunohistochemistry. The genomic identification of significant targets in a cancer algorithm was used to identify chromosomal aberrations, MuTect and VarScan2 were used to identify somatic mutations, and the random survival forest was used to determine patient prognoses. Findings were validated in an independent cohort. Results Unsupervised gene expression clustering showed 3 robust molecular classes of tumors: the proliferation class (51% of samples) had altered expression of genes that regulate proliferation and mammalian target of rapamycin signaling activation; the inflammation class (26% of samples) had altered expression of genes that regulate inflammation and cytokine enriched production; and the unannotated class (23% of samples) had a gene expression signature that was not associated previously with liver tumors. Expression of genes that regulate neuroendocrine function, as well as histologic markers of cholangiocytes and hepatocytes, were detected in all 3 classes. FLCs had few copy number variations; the most frequent were focal amplification at 8q24.3 (in 12.5% of samples), and deletions at 19p13 (in 28% of samples) and 22q13.32 (in 25% of samples). The DNAJB1-PRKACA fusion transcript was detected in 79% of samples. FLC samples also contained mutations in cancer-related genes such as BRCA2 (in 4.2% of samples), which are uncommon in liver neoplasms. However, FLCs did not contain mutations most commonly detected in liver cancers. We identified an 8-gene signature that predicted survival of patients with FLC. Conclusions In a genomic analysis of 78 FLC samples, we identified 3 classes based on gene expression profiles. FLCs contain mutations and chromosomal aberrations not previously associated with liver cancer, and almost 80% contain the DNAJB1-PRKACA fusion transcript. By using this information, we identified a gene signature that is associated with patient survival time.

AB - Background Aims Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer that develops in children and young adults without cirrhosis. Little is known about its pathogenesis, and it can be treated only with surgery. We performed an integrative genomic analysis of a large series of patients with FLC to identify associated genetic factors. Methods By using 78 clinically annotated FLC samples, we performed whole-transcriptome (n = 58), single-nucleotide polymorphism array (n = 41), and next-generation sequencing (n = 48) analyses; we also assessed the prevalence of the DNAJB1-PRKACA fusion transcript associated with this cancer (n = 73). We performed class discovery using non-negative matrix factorization, and functional annotation using gene-set enrichment analyses, nearest template prediction, ingenuity pathway analyses, and immunohistochemistry. The genomic identification of significant targets in a cancer algorithm was used to identify chromosomal aberrations, MuTect and VarScan2 were used to identify somatic mutations, and the random survival forest was used to determine patient prognoses. Findings were validated in an independent cohort. Results Unsupervised gene expression clustering showed 3 robust molecular classes of tumors: the proliferation class (51% of samples) had altered expression of genes that regulate proliferation and mammalian target of rapamycin signaling activation; the inflammation class (26% of samples) had altered expression of genes that regulate inflammation and cytokine enriched production; and the unannotated class (23% of samples) had a gene expression signature that was not associated previously with liver tumors. Expression of genes that regulate neuroendocrine function, as well as histologic markers of cholangiocytes and hepatocytes, were detected in all 3 classes. FLCs had few copy number variations; the most frequent were focal amplification at 8q24.3 (in 12.5% of samples), and deletions at 19p13 (in 28% of samples) and 22q13.32 (in 25% of samples). The DNAJB1-PRKACA fusion transcript was detected in 79% of samples. FLC samples also contained mutations in cancer-related genes such as BRCA2 (in 4.2% of samples), which are uncommon in liver neoplasms. However, FLCs did not contain mutations most commonly detected in liver cancers. We identified an 8-gene signature that predicted survival of patients with FLC. Conclusions In a genomic analysis of 78 FLC samples, we identified 3 classes based on gene expression profiles. FLCs contain mutations and chromosomal aberrations not previously associated with liver cancer, and almost 80% contain the DNAJB1-PRKACA fusion transcript. By using this information, we identified a gene signature that is associated with patient survival time.

KW - Genomic Profiling

KW - Molecular Classification

KW - Outcome

KW - Targeted Therapies

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