Non-invasive Analysis of Genomic Copy Number Variation in Patients with Hepatocellular Carcinoma by Next Generation DNA Sequencing

Xu, Huji; Zhu, Xia; Xu, Zhennan; Hu, Yue; Bo, Shiping; Xing, Tongjing; Zhu, Kuichun

doi:10.7150/jca.10747

Cited by 56 publications

(39 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Gene amplification, similar to gene mutation, plays a significant role in tumorigenesis in many types of cancer, such as gastric cancer, ovarian cancer, hepatocellular carcinoma, colon cancer, and others [22,23]. Thus, targeting the "driver genes" that are amplified may provide novel opportunities for precision medicine [20].…”

Section: Discussionmentioning

confidence: 99%

NTRK gene amplification in patients with metastatic cancer

et al. 2017

View full text Add to dashboard Cite

Purpose: Neurotropic tropomyosin receptor kinase (NTRK) fusions have been identified in a variety of cancers, and tyrosine kinase inhibitors targeting the tropomyosin receptor kinase (TRK) receptor are currently in clinical trials. However, no reports are available on the effects of NTRK gene amplification. Methods: Samples from patients enrolled in the sequencing program were analyzed using a next-generation sequencing (NGS) cancer panel. For cases in which NTRK amplification (defined as ≥ 4.0 copies) was identified, panTRK immunohistochemical (IHC) staining of tissue microarrays was performed. Results: A total of 1,250 tumor specimens collected between February 2014 and January 2016 were analyzed using the NGS cancer panel. NTRK amplification was detected in 28 cases of various types of cancer. Among 27 cases, only four were positive for pan-TRK IHC. These four cases were melanoma, sarcoma, lung cancer, and gastric cancer. We found that 2.2% of cancer patients showed NTRK amplification using NGS cancer panel and NTRK amplification resulted in protein overexpression in 14.8% of these patients. Conclusion: Patients with NTRK amplification and increased TRK protein expression may be considered for inclusion in clinical trials for NTRK inhibitors.

show abstract

Section: Discussionmentioning

confidence: 99%

NTRK gene amplification in patients with metastatic cancer

et al. 2017

View full text Add to dashboard Cite

show abstract

“…12 DNA CNVs include gene amplification, gain, loss and deletion. In addition to gene mutation, CNV has a significant role in tumorigenesis in many cancers, such as GC, 13 ovarian cancer, 14 hepatocellular carcinoma, 15 testicular germ cell tumors, 16 colorectal carcinoma, 17 bladder cancer 18 and so on. The accumulation of CNVs during gastric oncogenesis may be a result of preferential selection by which transforming cells gain evolutionary advantage.…”

Section: Introductionmentioning

confidence: 99%

Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

2015

View full text Add to dashboard Cite

Gastric cancer (GC) is among the most common malignancy in the world with poor prognosis and limited treatment options. It has been established that gastric carcinogenesis is caused by a complex interaction between host and environmental factors. Copy number variation (CNV) refers to a form of genomic structural variation that results in abnormal gene copy numbers, including gene amplification, gain, loss and deletion. DNA CNV is an important influential factor for the expression of both protein-coding and non-coding genes, affecting the activity of various signaling pathways. CNV arises as a result of preferential selection that favors cancer development, and thus, targeting the amplified 'driver genes' in GC may provide novel opportunities for personalized therapy. The detection of CNVs in chromosomal or mitochondrial DNA from tissue or blood samples may assist the diagnosis, prognosis and targeted therapy of GC. In this review, we discuss the recent CNV discoveries that shed light on the molecular pathogenesis of GC, with a specific emphasis on CNVs that display diagnostic, prognostic or therapeutic significances in GC.

show abstract

“…Z scores were calculated for each gene by comparing the test sample and WBC controls, , where X is the normalized copy number of the test sample, is the average copy number from the universal WBC reference, and S is the standard deviation from the universal reference. The single cell level cut-off for gene amplification is Z score >3; for deletion it is Z score <-3 [36]. At the patient level, amplification or deletion of a single gene needed to be observed on at least two CTCs for classification as alteration.…”

Section: Methodsmentioning

confidence: 99%

Chromosomal Instability Estimation Based on Next Generation Sequencing and Single Cell Genome Wide Copy Number Variation Analysis

et al. 2016

View full text Add to dashboard Cite

Genomic instability is a hallmark of cancer often associated with poor patient outcome and resistance to targeted therapy. Assessment of genomic instability in bulk tumor or biopsy can be complicated due to sample availability, surrounding tissue contamination, or tumor heterogeneity. The Epic Sciences circulating tumor cell (CTC) platform utilizes a non-enrichment based approach for the detection and characterization of rare tumor cells in clinical blood samples. Genomic profiling of individual CTCs could provide a portrait of cancer heterogeneity, identify clonal and sub-clonal drivers, and monitor disease progression. To that end, we developed a single cell Copy Number Variation (CNV) Assay to evaluate genomic instability and CNVs in patient CTCs. For proof of concept, prostate cancer cell lines, LNCaP, PC3 and VCaP, were spiked into healthy donor blood to create mock patient-like samples for downstream single cell genomic analysis. In addition, samples from seven metastatic castration resistant prostate cancer (mCRPC) patients were included to evaluate clinical feasibility. CTCs were enumerated and characterized using the Epic Sciences CTC Platform. Identified single CTCs were recovered, whole genome amplified, and sequenced using an Illumina NextSeq 500. CTCs were then analyzed for genome-wide copy number variations, followed by genomic instability analyses. Large-scale state transitions (LSTs) were measured as surrogates of genomic instability. Genomic instability scores were determined reproducibly for LNCaP, PC3, and VCaP, and were higher than white blood cell (WBC) controls from healthy donors. A wide range of LST scores were observed within and among the seven mCRPC patient samples. On the gene level, loss of the PTEN tumor suppressor was observed in PC3 and 5/7 (71%) patients. Amplification of the androgen receptor (AR) gene was observed in VCaP cells and 5/7 (71%) mCRPC patients. Using an in silico down-sampling approach, we determined that DNA copy number and genomic instability can be detected with as few as 350K sequencing reads. The data shown here demonstrate the feasibility of detecting genomic instabilities at the single cell level using the Epic Sciences CTC Platform. Understanding CTC heterogeneity has great potential for patient stratification prior to treatment with targeted therapies and for monitoring disease evolution during treatment.

show abstract

Non-invasive Analysis of Genomic Copy Number Variation in Patients with Hepatocellular Carcinoma by Next Generation DNA Sequencing

Cited by 56 publications

References 16 publications

NTRK gene amplification in patients with metastatic cancer

NTRK gene amplification in patients with metastatic cancer

Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

Chromosomal Instability Estimation Based on Next Generation Sequencing and Single Cell Genome Wide Copy Number Variation Analysis

Contact Info

Product

Resources

About