Genome-wide Analysis of Epstein-Barr Virus (EBV) Integration and Strain in C666-1 and Raji Cells

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Abstract

EBV is a key risk factor for many malignancy diseases such as nasopharyngeal carcinoma (NPC) and Burkitt lymphoma (BL). EBV integration has been reported, but its scale and impact to cancer development is remains unclear. C666-1 (NPC cell line) and Raji (BL cell line) are commonly studied EBV-positive cancer cells. A rare few EBV integration sites in Raji were found in previous research by traditional methods. To deeply survey EBV integration, we sequenced C666-1 and Raji whole genomes by the next generation sequencing (NGS) technology and a total of 909 breakpoints were detected in the two cell lines. Moreover, we observed that the number of integration sites was positive correlated with the total amount of chromosome structural variations (SVs) and copy number structural variations (CNVs), and most breakpoints located inside or nearby genome structural variations regions. It suggested that host genome instability provided an opportunity for EBV integration on one hand and the integration aggravated host genome instability on the other hand. Then, we respectively assembled the C666-1 and Raji EBV strains which would be useful resources for EBV-relative studies. Thus, we report the most comprehensive characterization of EBV integration in NPC cell and BL cell, and EBV shows the wide range and random integration to increase the tumorigenesis. The NGS provides an incomparable level of resolution on EBV integration and a convenient approach to obtain viral strain compared to any research technology before.

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Most cited references 49

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Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia.

Catherine Smith, Qi Wang, Chen-Shan Chin … (2012)

Effective targeted cancer therapeutic development depends upon distinguishing disease-associated 'driver' mutations, which have causative roles in malignancy pathogenesis, from 'passenger' mutations, which are dispensable for cancer initiation and maintenance. Translational studies of clinically active targeted therapeutics can definitively discriminate driver from passenger lesions and provide valuable insights into human cancer biology. Activating internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) are detected in approximately 20% of acute myeloid leukaemia (AML) patients and are associated with a poor prognosis. Abundant scientific and clinical evidence, including the lack of convincing clinical activity of early FLT3 inhibitors, suggests that FLT3-ITD probably represents a passenger lesion. Here we report point mutations at three residues within the kinase domain of FLT3-ITD that confer substantial in vitro resistance to AC220 (quizartinib), an active investigational inhibitor of FLT3, KIT, PDGFRA, PDGFRB and RET; evolution of AC220-resistant substitutions at two of these amino acid positions was observed in eight of eight FLT3-ITD-positive AML patients with acquired resistance to AC220. Our findings demonstrate that FLT3-ITD can represent a driver lesion and valid therapeutic target in human AML. AC220-resistant FLT3 kinase domain mutants represent high-value targets for future FLT3 inhibitor development efforts.

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Derek Y Chiang, Gad Getz, David B. Jaffe … (2009)

Cancer results from somatic alterations in key genes, including point mutations, copy-number alterations and structural rearrangements. A powerful way to discover cancer-causing genes is to identify genomic regions that show recurrent copy-number alterations (gains and losses) in tumor genomes. Recent advances in sequencing technologies suggest that massively parallel sequencing may provide a feasible alternative to DNA microarrays for detecting copy-number alterations. Here we present: (i) a statistical analysis of the power to detect copy-number alterations of a given size; (ii) SegSeq, an algorithm to segment equal copy numbers from massively parallel sequence data; and (iii) analysis of experimental data from three matched pairs of tumor and normal cell lines. We show that a collection of approximately 14 million aligned sequence reads from human cell lines has comparable power to detect events as the current generation of DNA microarrays and has over twofold better precision for localizing breakpoints (typically, to within approximately 1 kilobase).

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Jianbin Wang, H. Christina Fan, Barry Behr … (2012)

Meiotic recombination and de novo mutation are the two main contributions toward gamete genome diversity, and many questions remain about how an individual human's genome is edited by these two processes. Here, we describe a high-throughput method for single-cell whole-genome analysis that was used to measure the genomic diversity in one individual's gamete genomes. A microfluidic system was used for highly parallel sample processing and to minimize nonspecific amplification. High-density genotyping results from 91 single cells were used to create a personal recombination map, which was consistent with population-wide data at low resolution but revealed significant differences from pedigree data at higher resolution. We used the data to test for meiotic drive and found evidence for gene conversion. High-throughput sequencing on 31 single cells was used to measure the frequency of large-scale genome instability, and deeper sequencing of eight single cells revealed de novo mutation rates with distinct characteristics. Copyright © 2012 Elsevier Inc. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): J Cancer

Journal ID (iso-abbrev): J Cancer

Journal ID (publisher-id): jca

Title: Journal of Cancer

Publisher: Ivyspring International Publisher (Sydney )

ISSN (Electronic): 1837-9664

Publication date Collection: 2016

Publication date (Electronic): 1 January 2016

Volume: 7

Issue: 2

Pages: 214-224

Affiliations

1. Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China.

2. Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410078, China.

3. Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China.

Author notes

✉ Corresponding author: Wei Xiong, Cancer Research Institute and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, Hunan, 410013, China. Telephone: +86-731-8480-5446. Fax: +86-731-8480-5383. Email: xiongwei@ 123456csu.edu.cn

Competing Interests: The authors have declared that no competing interest exists.

Article

Publisher ID: jcav07p0214

DOI: 10.7150/jca.13150

PMC ID: 4716855

PubMed ID: 26819646

SO-VID: f134201f-7f73-47dc-b437-0063f0c16634

Copyright © © Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. See http://ivyspring.com/terms for terms and conditions.

Genome-wide Analysis of Epstein-Barr Virus (EBV) Integration and Strain in C666-1 and Raji Cells

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Karger: Oncology

Most cited references 49

Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia.

High-resolution mapping of copy-number alterations with massively parallel sequencing.

Genome-wide single-cell analysis of recombination activity and de novo mutation rates in human sperm.

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