Decoding complex patterns of genomic rearrangement in hepatocellular carcinoma

Fernandez-Banet, Julio; Lee, Nikki P.; Chan, Kin; Gao, Huan; Liu, Xiao; Sung, Wing-Kin; Tan, Winnie; Fan, Sheung Tat; Poon, Ronnie Tung‐Ping; Li, Shiyong; Ching, Keith A.; Rejto, Paul A.; Mao, Mao; Kan, Zhengyan

doi:10.1016/j.ygeno.2014.01.003

Cited by 49 publications

(50 citation statements)

References 54 publications

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“…HCC stratified by low ALB and APOB expression were associated by Gene Set Enrichment Analysis (GSEA) with increased cell cycle progression, ribosome biogenesis and nucleotide synthesis, and reduced oxidative phosphorylation (data not shown). Because ALB expression accounts for 20% of cellular mRNA (Uhlen et al, 2015) and APOB consumes large amounts of cellular energy by facilitating VLDL secretion (Egusa et al, 1985), there may be selection for ALB or APOB inactivating mutations to divert energy into cancer-relevant metabolic pathways (Fernandez-Banet et al, 2014). …”

Section: Resultsmentioning

confidence: 99%

Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

Ally¹,

Balasundaram²,

Carlsen³

et al. 2017

Cell

1,826

1,195

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SUMMARY Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole exome sequencing and DNA copy number analyses, and 196 HCC also by DNA methylation, RNA, miRNA, and proteomic expression. DNA sequencing and mutation analysis identified significantly mutated genes including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or down-regulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.

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Section: Resultsmentioning

confidence: 99%

Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

Ally¹,

Balasundaram²,

Carlsen³

et al. 2017

Cell

1,826

1,195

View full text Add to dashboard Cite

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“…If this were the case, however, the mutants carrying mutations induced by Ar or Fe ion beams would be unique resources for the study of de novo epiallele formation, since details of the genomic rearrangements in the mutant genomes could be elucidated by NGS. Moreover, a gene fusion event could possibly result from the genomic rearrangements, and it has been reported that the fusion genes often present an aberrant expression pattern (Fernandez-Banet et al, 2014). The Ar-and Fe-ion beams have the potential to induce epiallele formation and gene fusion and thus extend a spectrum of mutant phenotypes beyond those generated by other mutagens.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive identification of mutations induced by heavy‐ion beam irradiation in Arabidopsis thaliana

et al. 2015

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SUMMARYHeavy-ion beams are widely used for mutation breeding and molecular biology. Although the mutagenic effects of heavy-ion beam irradiation have been characterized by sequence analysis of some restricted chromosomal regions or loci, there have been no evaluations at the whole-genome level or of the detailed genomic rearrangements in the mutant genomes. In this study, using array comparative genomic hybridization (array-CGH) and resequencing, we comprehensively characterized the mutations in Arabidopsis thaliana genomes irradiated with Ar or Fe ions. We subsequently used this information to investigate the mutagenic effects of the heavy-ion beams. Array-CGH demonstrated that the average number of deleted areas per genome were 1.9 and 3.7 following Ar-ion and Fe-ion irradiation, respectively, with deletion sizes ranging from 149 to 602 180 bp; 81% of the deletions were accompanied by genomic rearrangements. To provide a further detailed analysis, the genomes of the mutants induced by Ar-ion beam irradiation were resequenced, and total mutations, including base substitutions, duplications, in/dels, inversions, and translocations, were detected using three algorithms. All three resequenced mutants had genomic rearrangements. Of the 22 DNA fragments that contributed to the rearrangements, 19 fragments were responsible for the intrachromosomal rearrangements, and multiple rearrangements were formed in the localized regions of the chromosomes. The interchromosomal rearrangements were detected in the multiply rearranged regions. These results indicate that the heavy-ion beams led to clustered DNA damage in the chromosome, and that they have great potential to induce complicated intrachromosomal rearrangements. Heavy-ion beams will prove useful as unique mutagens for plant breeding and the establishment of mutant lines.

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“…To date, we are aware of only one study that investigated the role of chromothripsis in the incidence of HCC. In this study, chromothripsis and CIN were found to recurrently affect chromosomal arms 1q and 8q to create gene amplifications, suggesting that chromothripsis might contribute to hepatocarcinogenesis[33]. It seems that more attention should be paid to this concept.…”

Section: Genomic Instabilitymentioning

confidence: 99%

“…Although the distribution of aberrant chromosomal arms differs among HCCs, numerous studies have shown, using aCGH data and SNP arrays, that certain regions are frequently affected in HCC, including gains in chromosomes 1q, 5p, 6p, 7q, 8q, 17q, and 20q and losses in 1p, 4q, 6q, 8p, 9p, 13q, 14q, 16p-q, 17p, 21p-q, and 22q[28-33]. These findings reflect a high degree of CIN in HCC[34], contributing to hepatocarcinogenesis.…”

Section: Genomic Instabilitymentioning

confidence: 99%

Genetic alterations in hepatocellular carcinoma: An update

Niu¹,

Niu²,

Wang³

2016

WJG

130

108

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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC.

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Decoding complex patterns of genomic rearrangement in hepatocellular carcinoma

Cited by 49 publications

References 54 publications

Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

Comprehensive identification of mutations induced by heavy‐ion beam irradiation in Arabidopsis thaliana

Genetic alterations in hepatocellular carcinoma: An update

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