標題: Hepatocellular carcinoma-associated single-nucleotide variants and deletions identified by the use of genome-wide high-throughput analysis of hepatitis B virus
作者: Liu, Wen-Chun
Wu, I-Chin
Lee, Yen-Chien
Lin, Chih-Peng
Cheng, Ji-Hong
Lin, Yih-Jyh
Yen, Chia-Jui
Cheng, Pin-Nan
Li, Pei-Fu
Cheng, Yi-Ting
Cheng, Pei-Wen
Sun, Koun-Tem
Yan, Shu-Ling
Lin, Jia-Jhen
Yang, Jui-Chu
Chang, Kung-Chao
Ho, Cheng-Hsun
Tseng, Vincent S.
Chang, Bill Chia-Han
Wu, Jaw-Ching
Chang, Ting-Tsung
資訊工程學系
Department of Computer Science
關鍵字: deletion index;hepatocarcinogenesis;meta-analysis;next-generation sequencing;U-shaped distribution
公開日期: 1-Oct-2017
摘要: This study investigated hepatitis B virus (HBV) single-nucleotide variants (SNVs) and deletion mutations linked with hepatocellular carcinoma (HCC). Ninety-three HCC patients and 108 non-HCC patients were enrolled for HBV genome-wide next-generation sequencing (NGS) analysis. A systematic literature review and a meta-analysis were performed to validate NGS-defined HCC-associated SNVs and deletions. The experimental results identified 60 NGS-defined HCC-associated SNVs, including 41 novel SNVs, and their pathogenic frequencies. Each SNV was specific for either genotype B (n = 24) or genotype C (n = 34), except for nt53C, which was present in both genotypes. The pathogenic frequencies of these HCC-associated SNVs showed a distinct U-shaped distribution pattern. According to the meta-analysis and literature review, 167 HBV variants from 109 publications were categorized into four levels (A-D) of supporting evidence that they are associated with HCC. The proportion of NGS-defined HCC-associated SNVs among these HBV variants declined significantly from 75% of 12 HCC-associated variants by meta-analysis (Level A) to 0% of 10 HCC-unassociated variants by meta-analysis (Level D) (P < 0.0001). PreS deletions were significantly associated with HCC, in terms of deletion index, for both genotypes B (P = 0.030) and C (P = 0.049). For genotype C, preS deletions involving a specific fragment (nt2977-3013) were significantly associated with HCC (HCC versus non-HCC, 6/34 versus 0/32, P = 0.025). Meta-analysis of preS deletions showed significant association with HCC (summary odds ratio 3.0; 95% confidence interval 2.3-3.9). Transfection of Huh7 cells showed that all of the five novel NGS-defined HCC-associated SNVs in the small surface region influenced hepatocarcinogenesis pathways, including endoplasmic reticulum-stress and DNA repair systems, as shown by microarray, real-time polymerase chain reaction and western blot analysis. Their carcinogenic mechanisms are worthy of further research. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
URI: http://dx.doi.org/10.1002/path.4938
http://hdl.handle.net/11536/146092
ISSN: 0022-3417
DOI: 10.1002/path.4938
期刊: JOURNAL OF PATHOLOGY
Volume: 243
起始頁: 176
結束頁: 192
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