Hepatocellular carcinoma-associated single-nucleotide variants and deletions identified by the use of genome-wide high-throughput analysis of hepatitis B virus

Wen Chun Liu, I. Chin Wu, Yen Chien Lee, Chih Peng Lin, Ji Hong Cheng, Yih Jyh Lin, Chia Jui Yen, Pin Nan Cheng, Pei Fu Li, Yi Ting Cheng, Pei Wen Cheng, Koun Tem Sun, Shu Ling Yan, Jia Jhen Lin, Jui Chu Yang, Kung Chao Chang, Cheng Hsun Ho, Vincent S. Tseng, Bill Chia Han Chang, Jaw Ching WuTing Tsung Chang

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Abstract

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.

Original languageEnglish
Pages (from-to)176-192
Number of pages17
JournalJournal of Pathology
Volume243
Issue number2
DOIs
Publication statusPublished - 2017 Oct

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Hepatitis B virus
Hepatocellular Carcinoma
Nucleotides
Genome
Meta-Analysis
Genotype
Carcinoma
Endoplasmic Reticulum Stress
Sequence Deletion
DNA Repair
Transfection
Publications
Real-Time Polymerase Chain Reaction
Western Blotting
Odds Ratio
Confidence Intervals

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

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. / Hepatocellular carcinoma-associated single-nucleotide variants and deletions identified by the use of genome-wide high-throughput analysis of hepatitis B virus. In: Journal of Pathology. 2017 ; Vol. 243, No. 2. pp. 176-192.
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abstract = "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.",
author = "Liu, {Wen Chun} and Wu, {I. Chin} and Lee, {Yen Chien} and Lin, {Chih Peng} and Cheng, {Ji Hong} and Lin, {Yih Jyh} and Yen, {Chia Jui} and Cheng, {Pin Nan} and Li, {Pei Fu} and Cheng, {Yi Ting} and Cheng, {Pei Wen} and Sun, {Koun Tem} and Yan, {Shu Ling} and Lin, {Jia Jhen} and Yang, {Jui Chu} and Chang, {Kung Chao} and Ho, {Cheng Hsun} and Tseng, {Vincent S.} and Chang, {Bill Chia Han} and Wu, {Jaw Ching} and Chang, {Ting Tsung}",
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Hepatocellular carcinoma-associated single-nucleotide variants and deletions identified by the use of genome-wide high-throughput analysis of hepatitis B virus. / 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.

In: Journal of Pathology, Vol. 243, No. 2, 10.2017, p. 176-192.

Research output: Contribution to journalArticle

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T1 - Hepatocellular carcinoma-associated single-nucleotide variants and deletions identified by the use of genome-wide high-throughput analysis of hepatitis B virus

AU - Liu, Wen Chun

AU - Wu, I. Chin

AU - Lee, Yen Chien

AU - Lin, Chih Peng

AU - Cheng, Ji Hong

AU - Lin, Yih Jyh

AU - Yen, Chia Jui

AU - Cheng, Pin Nan

AU - Li, Pei Fu

AU - Cheng, Yi Ting

AU - Cheng, Pei Wen

AU - Sun, Koun Tem

AU - Yan, Shu Ling

AU - Lin, Jia Jhen

AU - Yang, Jui Chu

AU - Chang, Kung Chao

AU - Ho, Cheng Hsun

AU - Tseng, Vincent S.

AU - Chang, Bill Chia Han

AU - Wu, Jaw Ching

AU - Chang, Ting Tsung

PY - 2017/10

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N2 - 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.

AB - 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.

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