Circumventing intratumoral heterogeneity to identify potential therapeutic targets in hepatocellular carcinoma

Huang, Ao; Zhao, Xin; Yang, Xin‐Rong; Li, Fuqiang; Zhou, Xinlan; Wu, Kui; Zhang, Xin; Sun, Qiqing; Cao, Yang; Zhu, Hongmei; Wang, Xiangdong; Yang, Huanming; Wang, Jian; Tang, Zhao–You; Hou, Yong; Fan, Jia; Zhou, Jian

doi:10.1016/j.jhep.2017.03.005

Cited by 88 publications

(110 citation statements)

References 51 publications

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“…A major technical issue is the generally low sequencing coverage used for WES resulting in false-negative results for cfDNA variants present below the limit of detection. This is supported by the comparison of WES (coverage 226X) with targeted deep sequencing (coverage 1806X) on the same sample [5], demonstrating that some variants with low MAFs (< 5%) were detected by targeted deep sequencing only [5]. However, with the introduction of unique molecular identifiers and Elimination of Recurrent Artefacts and Stochastic Errors (ERASE-Seq) [42] discrimination of sequencing artefacts from true variants can be improved, enabling detection DNA variants at ultralow frequency.…”

Section: Discussionmentioning

confidence: 87%

“…Furthermore, SNVs indicated as subclonal in cfDNA might be of clonal origin in tumor tissue from other metastatic sites. Studies comparing cfDNA to multiple tumor region sampling support this hypothesis [5,25]. Huang et al found that nearly all exclusively detected SNVs in plasma by WES were also detected in tumor samples from different liver lesions using targeted deep sequencing (average 98.7%, range: 69.3-100%) [5].…”

Section: Discussionmentioning

confidence: 99%

“…In total, 20 studies were included in this review of which the individual patient data of 12 studies were included for the meta-analyses of SNV sensitivity and agreement ( Fig. 1) [5,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33].…”

Section: Data Retrieval and Study Characteristicsmentioning

confidence: 99%

“…CfDNA consists of short fragments of DNA derived from normal-and tumor cells (ctDNA). Contrary to a single tumor tissue biopsy, ctDNA might give a more accurate representation of the entire mutational profile present across the different lesions within an individual cancer patient [5][6][7]. Although significant progress has been made for tracking previously detected tumor mutations using targeted gene panels or single gene assays [8], whole exome sequencing (WES) enables a more comprehensive analysis covering the complex landscape of somatic alterations.…”

Section: Introductionmentioning

confidence: 99%

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Whole exome sequencing of cell-free DNA – A systematic review and Bayesian individual patient data meta-analysis

Bos

Angus

Nasserinejad

et al. 2020

Cancer Treatment Reviews

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A B S T R A C TMolecular profiling of tumor derived cell free DNA (cfDNA) is gaining ground as a prognostic and predictive biomarker. However to what extent cfDNA reflects the full metastatic landscape as currently determined by tumor tissue analysis remains controversial. Though technically challenging, whole exome sequencing (WES) of cfDNA enables thorough evaluation of somatic alterations. Here, we review the feasibility of WES of cfDNA and determine the sensitivity of WES-detected single nucleotide variants (SNVs) in cfDNA on individual patient data level using paired tumor tissue as reference ( × 100%shared SNVs All tissue SNVs ). The pooled sensitivity was 50% (95% credible interval (CI): 29-72%). The tissue mutant allele frequency (MAF) of variants exclusively identified in tissue was significantly lower (12.5%, range: 0.5-18%) than the tissue MAF of variants identified in both tissue and cfDNA (23.9%, range: 17-38%), p = 0.004. The overall agreement ( × 100%)shared SNVs All SNVs between SNVs in cfDNA and tumor tissue was 31% (95% CI: 15-49%). The number of detected SNVs was positively correlated with circulating tumor DNA (ctDNA) fraction (p = 0.016). A sub analysis of samples with ctDNA fractions ≥ 25% improved the sensitivity to 69% (95% CI: 46-89%) and agreement to 46% (95% CI: 36-59%), suggesting that WES is mainly feasible for patients with high ctDNA fractions. Pre-and post-analytical procedures were highly variable between studies rendering comparisons problematic. In conclusion, various aspects of WES of cfDNA are largely in its investigative phase, standardization of methodologies is highly needed to bring this promising technique to its clinical potential.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Data Retrieval and Study Characteristicsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Whole exome sequencing of cell-free DNA – A systematic review and Bayesian individual patient data meta-analysis

Bos

Angus

Nasserinejad

et al. 2020

Cancer Treatment Reviews

View full text Add to dashboard Cite

show abstract

“…In addition to methylation-based assays of ctDNA, genetic alterations such as mutations, deletions, epigenetic changes can also be used as tumor biomarkers in HCC. Until recently, many studies have confirmed that tumor-specific mutations in TP53 [95], ITH [96], HCK [97], CTNNB1 and TERT [98] are common in the peripheral blood of patients with HCC. Jiang P et al [99] applied the established CAZA mathematical model to calculate CNVs in tumors by sequencing DNA.…”

Section: Introductionmentioning

confidence: 99%

Clinical applications of liquid biopsy as prognostic and predictive biomarkers in hepatocellular carcinoma: circulating tumor cells and circulating tumor DNA

Han

et al. 2018

J Exp Clin Cancer Res

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Hepatocellular carcinoma (HCC) is a highly malignant disease with a poor prognosis and high mortality due to a low early diagnosis rate, resistance to systemic treatments and progression to late-stage liver disease. Owing to limitations in the detection of HCC and the lack of awareness of healthcare systems, fewer than 40% of HCC patients are eligible for surgery due to advanced stages of the disease at the time of diagnosis and the occurrence of multiple lesions in the cirrhotic or fibrotic liver. At present, the updated American Association for the Study of Liver Disease (AASLD) guidelines no longer recommend alpha-fetoprotein (AFP) testing as a part of diagnostic evaluation. Thus, it is imperative to establish a novel diagnostic strategy with high sensitivity and reliability to monitor risk factors to detect HCC at an early stage. In recent years, “liquid biopsy,” (including circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA)), has emerged as a technique for the characterization of circulating cells, providing a strong basis for the individualized treatment of patients. As a noninvasive detection method, liquid biopsy is expected to play an important role in the early diagnosis, dynamic monitoring of cancer patients and drug screening. In this review, we will focus on the clinical applications, recent studies and future prospects of liquid biopsy, particularly focusing on HCC.

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IDH Mutation Subgroup Status Associates with Intratumor Heterogeneity and the Tumor Microenvironment in Intrahepatic Cholangiocarcinoma

et al. 2021

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Intrahepatic cholangiocarcinoma (ICC) is highly heterogeneous. Here, the authors perform exome sequencing and bulk RNA sequencing on 73 tumor regions from 14 ICC patients to portray the multi-faceted intratumor heterogeneity (ITH) landscape of ICC. The authors show that ITH is highly concordant across genomic, transcriptomic, and immune levels. Comparison of these data to 8 published datasets reveals significantly higher degrees of ITH in ICC than hepatocellular carcinoma. Remarkably, the authors find that high-ITH tumors highly overlap with the IDH (isocitrate dehydrogenase)-mutant subgroup (IDH-SG), comprising of IDH-mutated tumors and IDH-like tumors, that is, those IDH-wildtype tumors that exhibit similar molecular profiles to the IDH-mutated ones. Furthermore, IDH-SG exhibits less T cell infiltration and lower T cell cytotoxicity, indicating a colder tumor microenvironment (TME). The higher ITH and colder TME of IDH-SG are successfully validated by single-cell RNA sequencing on 17 503 cells from 4 patients. Collectively, the study shows that IDH mutant subgroup status, rather than IDH mutation alone, is associated with ITH and the TME of ICC tumors. The results highlight that IDH-like patients may also benefit from IDH targeted therapies and provide important implications for the diagnosis and treatment of ICC.

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Circumventing intratumoral heterogeneity to identify potential therapeutic targets in hepatocellular carcinoma

Cited by 88 publications

References 51 publications

Whole exome sequencing of cell-free DNA – A systematic review and Bayesian individual patient data meta-analysis

Whole exome sequencing of cell-free DNA – A systematic review and Bayesian individual patient data meta-analysis

Clinical applications of liquid biopsy as prognostic and predictive biomarkers in hepatocellular carcinoma: circulating tumor cells and circulating tumor DNA

IDH Mutation Subgroup Status Associates with Intratumor Heterogeneity and the Tumor Microenvironment in Intrahepatic Cholangiocarcinoma

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