Skip to main content

Investigating genetic characteristics of hepatitis B virus-associated and -non-associated hepatocellular carcinoma

  • XI-HUA FU (a1), MIN LI (a2), HAI-BO LOU (a1), MING-SHOU HUANG (a1) and CHUN-LONG LIU (a3)...
Summary Background:

Hepatocellular carcinoma (HCC) is a primary liver malignancy that mainly occurs in patients with chronic liver disease and cirrhosis. Risk factors for HCC include hepatitis B virus (HBV) infection. However, the specific role of HBV infection in HCC development is not yet completely understood. In order to reveal the effects of HBV on HCC, we compare the genes of HCC patients infected with HBV with those who are not infected.


We encoded the genes of these two types of HCC in databases using enrichment scores of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway terms. A random forest algorithm was employed in order to distinguish these two types in the classifier, and a series of feature selection approaches was used in order to select their optimal features. Novel HBV-associated and -non-associated HCC genes were predicted, respectively, based on their optimal features in the classifier. A shortest-path algorithm was also employed in order to find all of the shortest-paths genes connecting the known related genes.


A total of 54 different features between HBV-associated and -non-associated HCC genes were identified. In total, 1236 and 881 novel related genes were predicted for HBV-associated and -non-associated HCC, respectively. By integrating the predicted genes and shortest path genes in their gene interaction network, we identified 679 common genes involved in the two types of HCC.


We identified the significantly different genetic features between two types of HCC. We also predicted related genes for the two types based on their specific features. Finally, we determined the common genes and features that were involved in both of these two types of HCC.

Corresponding author
*Corresponding author: Dr. Chun-Long Liu, Department of Rehabilitation, Clinical Medicine College of Acupuncture and Rehabilitation, Guangzhou University of Chinese Medicine, College Town, Panyu District, Guangzhou 510000, China. Tel: +86 13632313146. Fax: +86 02039358431. E-mail:
Hide All
Andrisani O. M., Studach L. & Merle P. (2011). Gene signatures in hepatocellular carcinoma (HCC). Seminars in Cancer Biolpgy 21, 49.
Arlia-Ciommo A., Piano A., Svistkova V., Mohtashami S. & Titorenko V. I. (2014). Mechanisms underlying the anti-aging and anti-tumor effects of lithocholic bile acid. International Journal of Moleclar Science 15, 1652216543.
Arzumanyan A., Reis H. M. & Feitelson M. A. (2013). Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nature Reviews Cancer 13, 123135.
Baenke F., Peck B., Miess H. & Schulze A. (2013). Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development. Disease Models & Mechanisms 6, 13531363.
Balkwill F. (2006). TNF-alpha in promotion and progression of cancer. Cancer Metastasis Review 25, 409416.
Bauvois B., Durant L., Laboureau J., Barthelemy E., Rouillard D., Boulla G., et al. (1999). Upregulation of CD38 gene expression in leukemic B cells by interferon types I and II. Journal of Interferon & Cytokine Research 19, 10591066.
Bouckaert R. R., Frank E., Hall M. A., Holmes G., Pfahringer B., Reutemann P., et al. (2010). WEKA – experiences with a Java open-source project. The Journal of Machine Learning Research 11, 25332541.
Cairns R. A., Harris I. S. & Mak T. W. (2011). Regulation of cancer cell metabolism. Nature Reviews Cancer 11, 8595.
Capece D., Fischietti M., Verzella D., Gaggiano A., Cicciarelli G., Tessitore A., et al. (2013). The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumor-associated macrophages. BioMed Research International 2013, 187204.
Carmona-Saez P., Chagoyen M., Tirado F., Carazo J. M. & Pascual-Montano A. (2007). GENECODIS: a web-based tool for finding significant concurrent annotations in gene lists. Genome Biology 8, R3.
Chen Y., Wei H., Sun R. & Tian Z. (2005). Impaired function of hepatic natural killer cells from murine chronic HBsAg carriers. International Immunopharmacology 5, 18391852.
Chu C. M. & Liaw Y. F. (2006). Hepatitis B virus-related cirrhosis: natural history and treatment. Semininars in Liver Disease 26, 142152.
de Groot M. E., Dukel L., Chadha-Ajwani S., Metselaar H. J., Tilanus H. W. & Huikeshoven F. J. (2000). Massive solitary metastasis of hepatocellular carcinoma in the ovary two years after liver transplantation. European Journal of Obstetrics, Gynecology, and Reproductive Biology 90, 109111.
Deng M., Zhang K., Mehta S., Chen T. & Sun F. (2003). Prediction of protein function using protein–protein interaction data. Journal of Computational Biology 10, 947960.
El-Serag H. B. (2011). Hepatocellular carcinoma. New England Journal of Medicine 365, 11181127.
El-Serag H. B. (2012). Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 142, 12641273.e1.
El-Serag H. B. & Rudolph K. L. (2007). Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132, 25572576.
Feitelson M. A. (2006). Parallel epigenetic and genetic changes in the pathogenesis of hepatitis virus-associated hepatocellular carcinoma. Cancer Letters 239, 1020.
Floyd R. W. (1962). Algorithm 97: shortest path. Communications of the ACM 5, 345.
Forbes S. A., Bindal N., Bamford S., Cole C., Kok C. Y., Beare D., et al. (2011). COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Research 39, D945D950.
Ge H., Zhang G. (2014). RETRACTED: identifying halophilic proteins based on random forests with preprocessing of the pseudo-amino acid composition. Journal of Theoretical Biology 361, 175181.
Goldberg A. A., Beach A., Davies G. F., Harkness T. A., Leblanc A. & Titorenko V. I. (2011). Lithocholic bile acid selectively kills neuroblastoma cells, while sparing normal neuronal cells. Oncotarget 2, 761782.
Grivennikov S. I., Greten F. R. & Karin M. (2010). Immunity, inflammation, and cancer. Cell 140, 883899.
Grossman S. R. (2001). p300/CBP/p53 interaction and regulation of the p53 response. European Journal of Biochemistry 268, 27732778.
Ha H. L. & Yu D. Y. (2010). HBx-induced reactive oxygen species activates hepatocellular carcinogenesis via dysregulation of PTEN/Akt pathway. World Journal of Gastroenterology 16, 49324937.
Hsieh Y. H., Su I. J., Wang H. C., Chang W. W., Lei H. Y., Lai M. D., et al. (2004). Pre-S mutant surface antigens in chronic hepatitis B virus infection induce oxidative stress and DNA damage. Carcinogenesis 25, 20232032.
Hu L., Huang T., Liu X. J. & Cai Y. D. (2011). Predicting protein phenotypes based on protein–protein interaction network. PLoS One 6, e17668.
Jensen L. J., Kuhn M., Stark M., Chaffron S., Creevey C., Muller J., et al. (2009). STRING 8 – a global view on proteins and their functional interactions in 630 organisms. Nucleic Acids Research 37, D412D416.
Jump D. B., Depner C. M., Tripathy S. & Lytle K. A. (2015). Potential for dietary omega-3 fatty acids to prevent nonalcoholic fatty liver disease and reduce the risk of primary liver cancer. Advances in Nutrition 6, 694702.
Katoh Y. & Katoh M. (2007). Comparative genomics on PROM1 gene encoding stem cell marker CD133. International Journal of Molecular Medicine 19, 967970.
Lambert M. P., Paliwal A., Vaissiere T., Chemin I., Zoulim F., Tommasino M., et al. (2011). Aberrant DNA methylation distinguishes hepatocellular carcinoma associated with HBV and HCV infection and alcohol intake. Journal of Hepatology 54, 705715.
Levesque M. C., Hobbs M. R., Anstey N. M., Chancellor J. A., Misukonis M. A., Granger D. L., et al. (2001). A review of polymorphisms in the human gene for inducible nitric oxide synthase (NOS2) in patients with malaria. Sepsis 4, 217231.
Lin S., Hoffmann K. & Schemmer P. (2012). Treatment of hepatocellular carcinoma: a systematic review. Liver Cancer 1, 144158.
Mantych G., Devaskar U., deMello D. & Devaskar S. (1991). GLUT 1-glucose transporter protein in adult and fetal mouse lung. Biochemical and Biophysical Research Communications 180, 367373.
Mao R., Raj Kumar P. K., Guo C., Zhang Y. & Liang C. (2014). Comparative analyses between retained introns and constitutively spliced introns in Arabidopsis thaliana using random forest and support vector machine. PLoS One 9, e104049.
Mathews L. A., Cabarcas S. M., Hurt E. M., Zhang X., Jaffee E. M. & Farrar W. L. (2011). Increased expression of DNA repair genes in invasive human pancreatic cancer cells. Pancreas 40, 730739.
Montella M., Crispo A. & Giudice A. (2011). HCC, diet and metabolic factors: diet and HCC. Hepatitis Monthly 11, 159162.
Mullighan C. G., Zhang J., Kasper L. H., Lerach S., Payne-Turner D., Phillips L. A., et al. (2011). CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 471, 235239.
Ng K. L., Ciou J. S. & Huang C. H. (2010). Prediction of protein functions based on function–function correlation relations. Computers in Biology and Medicine 40, 300305.
Papp B., Pal C. & Hurst L. D. (2003). Dosage sensitivity and the evolution of gene families in yeast. Nature 424, 194197.
Peng H., Long F. & Ding C. (2005). Feature selection based on mutual information: criteria of max-dependency, max-relevance, and min-redundancy. IEEE Transactions on Pattern Analysis and Machine Intelligence 27, 12261238.
Rawat S., Clippinger A. J. & Bouchard M. J. (2012). Modulation of apoptotic signaling by the hepatitis B virus X protein. Viruses 4, 29452972.
Raza A. & Sood G. K. (2014). Hepatocellular carcinoma review: current treatment, and evidence-based medicine. World Journal of Gastroenterology 20, 41154127.
Rhodes D. R. & Chinnaiyan A. M. (2005). Integrative analysis of the cancer transcriptome. Nat Genet 37(Suppl.), S31S37.
Roderburg C., Gautheron J. & Luedde T. (2012). TNF-dependent signaling pathways in liver cancer: promising targets for therapeutic strategies? Digestive Disease 30, 500507.
Shaw D. R., Ashbumer M., Blake J. A., Baldarelli R. M., Botstein D., Davis A. P., et al. (1999). Gene Ontology: a controlled vocabulary to describe the function, biological process and cellular location of gene products in genome databases. American Journal of Human Genetics 65, A419A419.
Sun B. & Karin M. (2008). NF-kappaB signaling, liver disease and hepatoprotective agents. Oncogene 27, 62286244.
Xiao E. H., Li J. Q. & Huang J. F. (2004). Effects of p53 on apoptosis and proliferation of hepatocellular carcinoma cells treated with transcatheter arterial chemoembolization. World Journal of Gastroenterology 10, 190194.
Yang J., Chen L., Kong X., Huang T. & Cai Y. D. (2014). Analysis of tumor suppressor genes based on gene ontology and the KEGG pathway. PLoS One 9, e107202.
Yoo N. J., Lee J. W., Jeong E. G., Soung Y. H., Nam S. W., Lee J. Y., et al. (2006). Expressional analysis of anti-apoptotic phospho-BAD protein and mutational analysis of pro-apoptotic BAD gene in hepatocellular carcinomas. Digestive and Liver Disease 38, 683687.
Zhang E. & Lu M. (2015). Toll-like receptor (TLR)-mediated innate immune responses in the control of hepatitis B virus (HBV) infection. Medical Microbiology and Immunology 204, 1120.
Zhang X., Zhang H. & Ye L. (2006). Effects of hepatitis B virus X protein on the development of liver cancer. The Journal of Laboratory and Clinical Medicine 147, 5866.
Zhou L., Wang Y., Tian D. A., Yang J. & Yang Y. Z. (2012). Decreased levels of nitric oxide production and nitric oxide synthase-2 expression are associated with the development and metastasis of hepatocellular carcinoma. Molecular Medicine Reports 6, 12611266.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Genetics Research
  • ISSN: 0016-6723
  • EISSN: 1469-5073
  • URL: /core/journals/genetics-research
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
Type Description Title
Supplementary Materials

Fu supplementary material
Supplementary Tables

 Unknown (364 KB)
364 KB


Full text views

Total number of HTML views: 5
Total number of PDF views: 39 *
Loading metrics...

Abstract views

Total abstract views: 307 *
Loading metrics...

* Views captured on Cambridge Core between 11th November 2016 - 17th November 2017. This data will be updated every 24 hours.