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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 1

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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 I-Chin Wu and Lee, {Yen Chien} and Lin, {Chih Peng} and Cheng, {Ji Hong} and Yih-Jyh Lin and Chia-Jui Yen and Pin-Nan Cheng 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 Kung-Chao Chang and Ho, {Cheng Hsun} and Tseng, {Vincent S.} and Chang, {Bill Chia Han} and Wu, {Jaw Ching} and Ting-Tsung Chang",
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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, 01.10.2017, 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

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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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