Next-Generation Sequencing: Path for Driver Discovery in Hepatocellular Carcinoma

Toffanin, Sara; Cornellà, Helena; Harrington, Andrew N.; Llovet, Josep M.

doi:10.1053/j.gastro.2012.09.026

Cited by 8 publications

(9 citation statements)

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“…ARID1A and ARID2 are components of the SWItch/Sucrose Non-Fermentable (SWI/SNF)-related chromatin remodeling complex. Better comprehension of the network of molecules involved in the SWI/SNF complex is required [ 40 ].…”

Section: Signaling Pathwaysmentioning

confidence: 99%

“…In part by modulating mTOR signaling, RPS6KA3 mediates stress-induced and mitogenic activation of transcription factors and cellular differentiation, growth, and survival [ 23 ]. In addition, RPS6KA3 (RSK2) is a kinase enzyme that acts downstream of the MAPK/ERK pathway [ 40 ]. RPS6KA3 tends to be altered in poorly differentiated HCC [ 54 ].…”

Section: Signaling Pathwaysmentioning

confidence: 99%

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The biology of Hepatocellular carcinoma: implications for genomic and immune therapies

Khemlina

Ikeda

Kurzrock³

2017

Mol Cancer

362

250

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Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is a leading cause of cancer-related death worldwide. It is highly refractory to most systemic therapies. Recently, significant progress has been made in uncovering genomic alterations in HCC, including potentially targetable aberrations. The most common molecular anomalies in this malignancy are mutations in the TERT promoter, TP53, CTNNB1, AXIN1, ARID1A, CDKN2A and CCND1 genes. PTEN loss at the protein level is also frequent. Genomic portfolios stratify by risk factors as follows: (i) CTNNB1 with alcoholic cirrhosis; and (ii) TP53 with hepatitis B virus-induced cirrhosis. Activating mutations in CTNNB1 and inactivating mutations in AXIN1 both activate WNT signaling. Alterations in this pathway, as well as in TP53 and the cell cycle machinery, and in the PI3K/Akt/mTor axis (the latter activated in the presence of PTEN loss), as well as aberrant angiogenesis and epigenetic anomalies, appear to be major events in HCC. Many of these abnormalities may be pharmacologically tractable. Immunotherapy with checkpoint inhibitors is also emerging as an important treatment option. Indeed, 82% of patients express PD-L1 (immunohistochemistry) and response rates to anti-PD-1 treatment are about 19%, and include about 5% complete remissions as well as durable benefit in some patients. Biomarker-matched trials are still limited in this disease, and many of the genomic alterations in HCC remain challenging to target. Future studies may require combination regimens that include both immunotherapies and molecularly matched targeted treatments.

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Section: Signaling Pathwaysmentioning

confidence: 99%

Section: Signaling Pathwaysmentioning

confidence: 99%

The biology of Hepatocellular carcinoma: implications for genomic and immune therapies

Khemlina

Ikeda

Kurzrock³

2017

Mol Cancer

362

250

View full text Add to dashboard Cite

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“…The massively parallel sequencing ability of NGS technologies has made high throughput and multiplexed sequencing of specific panels of genes or whole exomes/genomes feasible. [13][14][15] These technologies are currently being applied extensively to characterize genomic alterations in cancer [16][17][18][19] and are highly relevant for diagnostic purposes as alternatives to first-generation sequencing techniques. 20 However, inclusion of NGS technologies into the diagnostic arena has been delayed due to the lack of adequate guidelines and rigorous validation.…”

mentioning

confidence: 99%

Next-generation sequencing-based multigene mutational screening for acute myeloid leukemia using MiSeq: applicability for diagnostics and disease monitoring

et al. 2013

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“…Overall, 16 to 24% of HCCs and 7.5 to 25% of iCCAs showed genetic alterations in pathways related to chromatin regulation (e.g., ARID1A, ARID2, BAP1, MLL and PBRM1 ), suggesting a causative association with hepatocyte transformation and highlighting recent evidence for the key role of epigenetics in hepatocarcinogenesis [72]. HDACs are important mediators of epigenetic transcriptional regulation.…”

Section: New Durgable Tragets On the Horizonmentioning

confidence: 99%

Liver Cancer Oncogenomics: Opportunities and Dilemmas for Clinical Applications

Marquardt

Andersen

2015

Hepat. Oncol.

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SUMMARY Primary liver cancers are among the most rapidly evolving malignant tumors worldwide. An underlying chronic inflammatory liver disease, which precedes liver cancer development for several decades and frequently creates a pro-oncogenic microenvironment, impairs progress in therapeutic approaches. Molecular heterogeneity of liver cancer is potentiated by a crosstalk between epithelial tumor and stromal cells that complicate translational efforts to unravel molecular mechanisms of hepatocarcinogenesis with a drugable intend. Next-generation sequencing has greatly advanced our understanding of cancer development. With regards to liver cancer, the unprecedented coverage of next-generation sequencing has created a detailed map of genetic alterations and identified key somatic changes such as CTNNB1 and TP53 as well as several previously unrecognized recurrent disease-causing alterations that could contribute to new therapeutic approaches. Importantly, these investigations indicate that a classical oncogene addiction cannot be assumed for primary liver cancer. Therefore, hepatocarcinogenesis can be considered a paradigm suitable for individualized medicine.

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Next-Generation Sequencing: Path for Driver Discovery in Hepatocellular Carcinoma

Cited by 8 publications

References 0 publications

The biology of Hepatocellular carcinoma: implications for genomic and immune therapies

The biology of Hepatocellular carcinoma: implications for genomic and immune therapies

Next-generation sequencing-based multigene mutational screening for acute myeloid leukemia using MiSeq: applicability for diagnostics and disease monitoring

Liver Cancer Oncogenomics: Opportunities and Dilemmas for Clinical Applications

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