Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/125670
Title: Unique genomic profile of fibrolamellar hepatocellular carcinoma
Author: Cornella, Helena
Alsinet, Clara
Sayols, Sergi
Zhang, Zhongyang
Hao, Ke
Cabellos, Laia
Hoshida, Yujin
Vila Casadesús, Maria
Villanueva, Augusto
Thung, Swan
Ward, Stephen C.
Rodríguez Carunchio, Leonardo.
Imbeaud, Sandrine
Lachenmayer, Anja
Quaglia, Alberto
Nagorney David M.
Minguez, Beatriz
Carrilho, Flair
Robert, Lewis R.
Mazzaferro, Vincenzo
Schwartz, Myron
Esteller, Manel
Heaton, Nigel D.
Zucman-Rossi, Jessica
Llovet i Bayer, Josep Maria
Keywords: Càncer de fetge
Oncologia
Genoma humà
Liver cancer
Oncology
Human genome
Issue Date: 1-Apr-2015
Publisher: Elsevier
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.
Note: Versió postprint del document publicat a: https://doi.org/10.1053/j.gastro.2014.12.028
It is part of: Gastroenterology, 2015, vol. 148, num. 4, p. 806-818.e10
URI: http://hdl.handle.net/2445/125670
Related resource: https://doi.org/10.1053/j.gastro.2014.12.028
ISSN: 0016-5085
Appears in Collections:Articles publicats en revistes (Medicina)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

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