Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma

Torrecilla, Sara; Sia, Daniela; Harrington, Andrew N.; Zhang, Zhongyang; Cabellos, Laia; Cornellà, Helena; Moeini, Agrin; Campreciós, Genís; Leow, Wei Qiang; Fiel, M. Isabel; Hao, Ke; Bassaganyas, Laia; Mahajan, Milind; Thung, Swan N.; Villanueva, Augusto; Florman, Sander; Schwartz, Myron; Llovet, Josep M.

doi:10.1016/j.jhep.2017.08.013

Cited by 137 publications

(133 citation statements)

References 35 publications

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“…We confirmed a clonal distribution of known drivers, such as TERT promoter, CTNNB1, and TP53 ( Supplementary Fig. 3c, Supplementary Table 2), with only one tumor region (H4.a) depicting a subclonal mutation of CTNNB1 19 . Using DNA Sanger sequencing, we validated 11 expressed mutations predicted as damaging (Supplementary Table 3).…”

Section: Resultssupporting

confidence: 70%

Intratumoral heterogeneity and clonal evolution in liver cancer

et al. 2020

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Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCRseq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves singlebiopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how the different components of the HCC ecosystem interact during cancer evolution.

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Section: Resultssupporting

confidence: 70%

Intratumoral heterogeneity and clonal evolution in liver cancer

et al. 2020

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“…required in the early step of carcinogenesis in cirrhosis and TERT promoter mutations are the only recurrent mutations in the driver genes observed in both low-grade and high-grade dysplastic nodules (between 5 to 20% of mutations) and up to 60% of early HCCs. 52,53 These results indicate that TERT is a gatekeeper gene which is mutated very early in liver carcinogenesis, reactivating telomerase in order to bypass senescence of hepatocytes in cirrhosis. Moreover, transcriptomic analysis of premalignant nodules in cirrhosis and early HCCs have highlighted that activation of MYC, early in the course, could be involved in the process of malignant transformation 54 whereas activation of other signalling pathways such as transforming growth factor-b (TGFb), WNT or NOTCH occurred later during hepatocarcinogenesis.…”

Section: Mechanisms Of Malignant Transformation On Cirrhosismentioning

confidence: 93%

“…89,90 Preliminary data in HCC have suggested that the main driver genes such as CTNNB1, TP53 and TERT are clonal trunk mutations and are consequently ideal therapeutic targets. 53,[90][91][92] However, more data are required to clarify this using ultradeep sequencing in combination with methylation and transcriptomic analysis, in order to capture the complexity of intratumor heterogeneity in large cohorts of HCC. Another type of genomic heterogeneity observed in HCC is inter-tumour heterogeneity that can be related to de novo independent carcinogenesis on a background of cirrhosis and/or intrahepatic metastasis (Fig.…”

Section: Key Pointsmentioning

confidence: 99%

Advances in molecular classification and precision oncology in hepatocellular carcinoma

Rebouissou

Nault

2020

Journal of Hepatology

379

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Hepatocellular carcinoma (HCC) arises from hepatocytes through the sequential accumulation of multiple genomic and epigenomic alterations resulting from Darwinian selection. Genes from various signalling pathways such as telomere maintenance, Wnt/b-catenin, P53/cell cycle regulation, oxidative stress, epigenetic modifiers, AKT/mTOR and MAP kinase are frequently mutated in HCC. Several subclasses of HCC have been identified based on transcriptomic dysregulation and genetic alterations that are closely related to risk factors, pathological features and prognosis. Undoubtedly, integration of data obtained from both preclinical models and human studies can help to accelerate the identification of robust predictive biomarkers of response to targeted biotherapy and immunotherapy. The aim of this review is to describe the main advances in HCC in terms of molecular biology and to discuss how this knowledge could be used in clinical practice in the future.

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“…4 In this regard, the impact of intratumor heterogeneity in single-biopsy predictions is still debated despite recent studies showing that driver gene mutations are common between different regions of the tumour. 77,78 Traditionally, new therapies were compared with standard of care or placebo to demonstrate greater efficacy of the new drug. Despite this being the recommended trial design in HCC, 4,33 some studies after SHARP used non-inferiority designs to challenge sorafenib in first-line.…”

Section: Positive Phase III Clinical Trialsmentioning

confidence: 99%

Randomized trials and endpoints in advanced HCC: Role of PFS as a surrogate of survival

Llovet

Montal

Villanueva

2019

Journal of Hepatology

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171

167

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Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Around half of patients with HCC will receive systemic therapies during their life span. The pivotal positive sorafenib trial and regulatory approval in 2007 was followed by a decade of negative studies with drugs leading to marginal antitumoral efficacy, toxicity, or trials with a lack of enrichment strategies. This trend has changed over the last 2 years with several compounds, such as lenvatinib (in first-line) and regorafenib, cabozantinib, ramucirumab and nivolumab (in second-line), showing clinical benefit. These successes came at a cost of increasing the complexity of decision-making, and ultimately, impacting the design of future clinical trials. Nowadays, life expectancy with single active agents has surpassed the threshold of 1 year and sequential strategies have provided encouraging outcomes. Overall survival (OS) remains the main endpoint in phase III investigations, but as in other solid tumours, there is a clear need to define surrogate endpoints that both reliably recapitulate survival benefits and can be assessed before additional efficacious drugs are administered. A thorough analysis of 21 phase III trials published in advanced HCC demonstrated a moderate correlation between progression-free survival (PFS) or time to progression (TTP) and OS (R = 0.84 and R = 0.83, respectively). Nonetheless, the significant differences in PFS identified in 7 phase III studies only correlated with differences in OS in 3 cases. In these cases, the hazard ratio (HR) for PFS was ≤0.6. Thus, this threshold is herein proposed as a potential surrogate endpoint of OS in advanced HCC. Conversely, PFS with an HR between 0.6-0.7, despite significance, was not associated with better survival, and thus these magnitudes are considered uncertain surrogates. In the current review, we discuss the reasons for positive or negative phase III trials in advanced HCC, and the strengths and limitations of surrogate endpoints (PFS, TTP and objective response rate [ORR]) to predict survival.

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Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma

Cited by 137 publications

References 35 publications

Intratumoral heterogeneity and clonal evolution in liver cancer

Intratumoral heterogeneity and clonal evolution in liver cancer

Advances in molecular classification and precision oncology in hepatocellular carcinoma

Randomized trials and endpoints in advanced HCC: Role of PFS as a surrogate of survival

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