Hepatitis B virus surface gene pre-S2 mutant as a high-risk serum marker for hepatoma recurrence after curative hepatic resection

Chia Jui Yen, Yu Lin Ai, Hung Wen Tsai, Shih Huang Chan, Chia Sheng Yen, Kuang Hsiung Cheng, Yun Ping Lee, Chia Wei Kao, Yu Chun Wang, Yi Lin Chen, Cheng Han Lin, Tsunglin Liu, Huey Pin Tsai, Jen Ren Wang, Ih Jen Su, Wenya Huang

Research output: Contribution to journalArticle

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Abstract

Chronic hepatitis B virus (HBV) infection is the major cause of hepatocellular carcinoma (HCC). The pre-S2 mutant large HBV surface antigen (LHBS) is highly associated with HCC. This study analyzed the expression of the large form of surface protein in tumors and evaluated the LHBS with mutations within the pre-S2 region as a high-risk recurrence marker in HCC patients after curative hepatic resection. By analyses using immunohistochemical staining (n = 12) and western blotting (n = 22), the HBV surface protein, which is mainly comprised of the major form of HBV surface antigen, was greatly diminished in the tumors. However, LHBS was not significantly decreased in tumorous regions, suggesting that LHBS maintains its expression in cancer development. A cohort of 175 patients with HBV-related HCC who underwent curative hepatic resection was analyzed for pre-S gene mutations using Pre-S Gene Chip. Results of the multivariate regression analysis showed that the serum pre-S2 mutant level and the American Joint Committee on Cancer stage were the two main independent high-risk factors for recurrence. A Cox proportional hazards analysis also revealed a prediction model, which indicated the recurrence-free survival rate along with the time after surgery; this was developed and further validated in an independent HCC cohort. Receiver operating characteristic curve analysis revealed that the model showed close sensitivities in the main and validation cohorts (area under the curve values, 0.741 and 0.704, respectively). Conclusion: Unlike the major HBV surface antigen, LHBS is mostly expressed in the tumorous regions of HBV-induced HCC, indicating that it plays a unique role in tumor progression; the relative level of pre-S2 mutant in serum is, independently of tumor stage, an important high-risk marker for HCC recurrence after primary hepatic resection. (Hepatology 2018).

Original languageEnglish
Pages (from-to)815-826
Number of pages12
JournalHepatology
Volume68
Issue number3
DOIs
Publication statusPublished - 2018 Sep

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Hepatitis B virus
Hepatocellular Carcinoma
Biomarkers
Recurrence
Surface Antigens
Liver
Genes
Hepatitis B Surface Antigens
Neoplasms
Membrane Proteins
Mutation
Chronic Hepatitis B
Gastroenterology
Virus Diseases
Oligonucleotide Array Sequence Analysis
Serum
ROC Curve
Area Under Curve
Multivariate Analysis
Survival Rate

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Yen, Chia Jui ; Ai, Yu Lin ; Tsai, Hung Wen ; Chan, Shih Huang ; Yen, Chia Sheng ; Cheng, Kuang Hsiung ; Lee, Yun Ping ; Kao, Chia Wei ; Wang, Yu Chun ; Chen, Yi Lin ; Lin, Cheng Han ; Liu, Tsunglin ; Tsai, Huey Pin ; Wang, Jen Ren ; Su, Ih Jen ; Huang, Wenya. / Hepatitis B virus surface gene pre-S2 mutant as a high-risk serum marker for hepatoma recurrence after curative hepatic resection. In: Hepatology. 2018 ; Vol. 68, No. 3. pp. 815-826.
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title = "Hepatitis B virus surface gene pre-S2 mutant as a high-risk serum marker for hepatoma recurrence after curative hepatic resection",
abstract = "Chronic hepatitis B virus (HBV) infection is the major cause of hepatocellular carcinoma (HCC). The pre-S2 mutant large HBV surface antigen (LHBS) is highly associated with HCC. This study analyzed the expression of the large form of surface protein in tumors and evaluated the LHBS with mutations within the pre-S2 region as a high-risk recurrence marker in HCC patients after curative hepatic resection. By analyses using immunohistochemical staining (n = 12) and western blotting (n = 22), the HBV surface protein, which is mainly comprised of the major form of HBV surface antigen, was greatly diminished in the tumors. However, LHBS was not significantly decreased in tumorous regions, suggesting that LHBS maintains its expression in cancer development. A cohort of 175 patients with HBV-related HCC who underwent curative hepatic resection was analyzed for pre-S gene mutations using Pre-S Gene Chip. Results of the multivariate regression analysis showed that the serum pre-S2 mutant level and the American Joint Committee on Cancer stage were the two main independent high-risk factors for recurrence. A Cox proportional hazards analysis also revealed a prediction model, which indicated the recurrence-free survival rate along with the time after surgery; this was developed and further validated in an independent HCC cohort. Receiver operating characteristic curve analysis revealed that the model showed close sensitivities in the main and validation cohorts (area under the curve values, 0.741 and 0.704, respectively). Conclusion: Unlike the major HBV surface antigen, LHBS is mostly expressed in the tumorous regions of HBV-induced HCC, indicating that it plays a unique role in tumor progression; the relative level of pre-S2 mutant in serum is, independently of tumor stage, an important high-risk marker for HCC recurrence after primary hepatic resection. (Hepatology 2018).",
author = "Yen, {Chia Jui} and Ai, {Yu Lin} and Tsai, {Hung Wen} and Chan, {Shih Huang} and Yen, {Chia Sheng} and Cheng, {Kuang Hsiung} and Lee, {Yun Ping} and Kao, {Chia Wei} and Wang, {Yu Chun} and Chen, {Yi Lin} and Lin, {Cheng Han} and Tsunglin Liu and Tsai, {Huey Pin} and Wang, {Jen Ren} and Su, {Ih Jen} and Wenya Huang",
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Hepatitis B virus surface gene pre-S2 mutant as a high-risk serum marker for hepatoma recurrence after curative hepatic resection. / Yen, Chia Jui; Ai, Yu Lin; Tsai, Hung Wen; Chan, Shih Huang; Yen, Chia Sheng; Cheng, Kuang Hsiung; Lee, Yun Ping; Kao, Chia Wei; Wang, Yu Chun; Chen, Yi Lin; Lin, Cheng Han; Liu, Tsunglin; Tsai, Huey Pin; Wang, Jen Ren; Su, Ih Jen; Huang, Wenya.

In: Hepatology, Vol. 68, No. 3, 09.2018, p. 815-826.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Hepatitis B virus surface gene pre-S2 mutant as a high-risk serum marker for hepatoma recurrence after curative hepatic resection

AU - Yen, Chia Jui

AU - Ai, Yu Lin

AU - Tsai, Hung Wen

AU - Chan, Shih Huang

AU - Yen, Chia Sheng

AU - Cheng, Kuang Hsiung

AU - Lee, Yun Ping

AU - Kao, Chia Wei

AU - Wang, Yu Chun

AU - Chen, Yi Lin

AU - Lin, Cheng Han

AU - Liu, Tsunglin

AU - Tsai, Huey Pin

AU - Wang, Jen Ren

AU - Su, Ih Jen

AU - Huang, Wenya

PY - 2018/9

Y1 - 2018/9

N2 - Chronic hepatitis B virus (HBV) infection is the major cause of hepatocellular carcinoma (HCC). The pre-S2 mutant large HBV surface antigen (LHBS) is highly associated with HCC. This study analyzed the expression of the large form of surface protein in tumors and evaluated the LHBS with mutations within the pre-S2 region as a high-risk recurrence marker in HCC patients after curative hepatic resection. By analyses using immunohistochemical staining (n = 12) and western blotting (n = 22), the HBV surface protein, which is mainly comprised of the major form of HBV surface antigen, was greatly diminished in the tumors. However, LHBS was not significantly decreased in tumorous regions, suggesting that LHBS maintains its expression in cancer development. A cohort of 175 patients with HBV-related HCC who underwent curative hepatic resection was analyzed for pre-S gene mutations using Pre-S Gene Chip. Results of the multivariate regression analysis showed that the serum pre-S2 mutant level and the American Joint Committee on Cancer stage were the two main independent high-risk factors for recurrence. A Cox proportional hazards analysis also revealed a prediction model, which indicated the recurrence-free survival rate along with the time after surgery; this was developed and further validated in an independent HCC cohort. Receiver operating characteristic curve analysis revealed that the model showed close sensitivities in the main and validation cohorts (area under the curve values, 0.741 and 0.704, respectively). Conclusion: Unlike the major HBV surface antigen, LHBS is mostly expressed in the tumorous regions of HBV-induced HCC, indicating that it plays a unique role in tumor progression; the relative level of pre-S2 mutant in serum is, independently of tumor stage, an important high-risk marker for HCC recurrence after primary hepatic resection. (Hepatology 2018).

AB - Chronic hepatitis B virus (HBV) infection is the major cause of hepatocellular carcinoma (HCC). The pre-S2 mutant large HBV surface antigen (LHBS) is highly associated with HCC. This study analyzed the expression of the large form of surface protein in tumors and evaluated the LHBS with mutations within the pre-S2 region as a high-risk recurrence marker in HCC patients after curative hepatic resection. By analyses using immunohistochemical staining (n = 12) and western blotting (n = 22), the HBV surface protein, which is mainly comprised of the major form of HBV surface antigen, was greatly diminished in the tumors. However, LHBS was not significantly decreased in tumorous regions, suggesting that LHBS maintains its expression in cancer development. A cohort of 175 patients with HBV-related HCC who underwent curative hepatic resection was analyzed for pre-S gene mutations using Pre-S Gene Chip. Results of the multivariate regression analysis showed that the serum pre-S2 mutant level and the American Joint Committee on Cancer stage were the two main independent high-risk factors for recurrence. A Cox proportional hazards analysis also revealed a prediction model, which indicated the recurrence-free survival rate along with the time after surgery; this was developed and further validated in an independent HCC cohort. Receiver operating characteristic curve analysis revealed that the model showed close sensitivities in the main and validation cohorts (area under the curve values, 0.741 and 0.704, respectively). Conclusion: Unlike the major HBV surface antigen, LHBS is mostly expressed in the tumorous regions of HBV-induced HCC, indicating that it plays a unique role in tumor progression; the relative level of pre-S2 mutant in serum is, independently of tumor stage, an important high-risk marker for HCC recurrence after primary hepatic resection. (Hepatology 2018).

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U2 - 10.1002/hep.29790

DO - 10.1002/hep.29790

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