New ‘multi-omics’ approach and its contribution to hepatocellular carcinoma in China

Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan

Correspondence to: Dr. Wei Tang, MD, PhD. Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, the University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan. Email: TANG-SUR@h.u-tokyo.ac.jp.

New ‘multi-omics’ approach and its contribution to hepatocellular carcinoma in China

Yoshinori Inagaki, Peipei Song, Norihiro Kokudo, Wei Tang

Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan

Correspondence to: Dr. Wei Tang, MD, PhD. Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, the University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan. Email: TANG-SUR@h.u-tokyo.ac.jp.

Submitted Nov 12, 2014. Accepted for publication Nov 21, 2014.

View this article at:http://dx.doi.org/10.3978/j.issn.1000-9604.2014.11.07

Hepatocellular carcinoma (HCC) is one of the most common liver neoplasms worldwide, and 70-80% cases are accounted in Asian countries (1). Etiological background of HCC patients is different in each country or area. In China, infection of hepatitis B virus (HBV) is a main etiological factor of increased incidence of HCC. In fact, 93 million HBV carriers are Chinese, accounting for 2/3 of such patients worldwide, and about 20 million of these people have chronic HBV infection (2). Chronic HBV infection is a high risk factor for development of HCC. Therefore, the follow-up of those chronic viral hepatitis type B patients and the early-detection of HCC in those patients are pressing tasks to reduce the incidence of HCC in China (3).

Recent years, various omics analyses have rapidly advanced with the development of next generation sequencing technology. Those omics analyses including genomic, transcriptomic and proteomic analyses can provide the huge amount of data regarding genetic alteration and gene or protein expression level. The combination of those omics analyses can overview the perturbed systems in the cell or tissue. Furthermore, the advanced technologies of bioinformatics enable construction of reliable and signifcant dataset. The combination of omics analyses and bioinformatics can contribute to the personalized medicine and the discovery of new diagnostic or therapeutic target, but the difficulty still remains in integration of those dataset, delineation of physiological pathway that affect signifcantly in disordered specimen (4,5).

The study of multi-omics analysis performed by Miao et al., entitled “Identi fi cation of prognostic biomarkers in hepatitis B virusrelated hepatocellular carcinoma and strati fi cation by integrative multi-omics analysis” can provide the foundation of genetic and transcriptomic analyses against individual patients’ HCC tissues (6). Whole-genome sequencing analysis of HBV-related HCC patients revealed the different HBV integration pattern and mutations in coding sequence, suggesting the different tumor clonality in the primarymetastatic tumor tissues or the synchronous tumor tissues. This analysis can be used for the evaluation of HCC characteristics from the genomic similarities of all tumors in the individual patient and contribute to the decision-making of treatment strategy. They also perform the transcriptomic analysis and revealed that genes related to cytoskeleton organization and extracellular matrix organization were upregulated in patient who had cirrhosis and multifocal, poorly differentiated HCC (died of recurrence) but not in patient who had non-cirrhosis and multifocal, well differentiated HCC (no recurrence). In addition, 21 genes related to cell cycle, p53 signaling pathway and histidine metabolism were found to be enriched in HCC of patient who had bad prognosis. Comparative analysis of gene expression level to clinicopathological characteristics in 174 HBV-related HCC patients showed expression level of SFN, TTK, BUB1 and MCM4 were signifcantly related to Edmondson tumor grade. Although further validation study is necessary, these results suggested that multi-mics approach can contribute to the characterization of individual HCC and the discovery of clinicopathologically signifcant genes.

Altered expression of those identified genes had partly studied and suggested the relationship with the role of carcinogenesis and cancer progression in HCC or other cancers (7-9). In the study of drug resistance using HCC cell lines, increased TTK expression induced the sorafenibresistance as well as up-regulation of cell proliferation in HCC cells (8). In addition, TTK overexpression was detected in 86.8% (46/53) of HCC tissue specimens. Thisrate coincides with the rate of high TTK gene expression in the result of transcriptomic analysis performed by Miao et al. (6). To perform further biological study to clarify the functional role of TTK in HCC, TTK can be developed as a diagnostic marker and a therapeutic target.

Serological detection of tumor marker is easy and effective as a diagnostic and follow-up method of HCC. Currently, simultaneous evaluation of two tumor markers [e.g., alphafetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP)] is recommended in J-HCC guideline (10,11). In contrast, only AFP has been recommended and widely used for the diagnosis of HCC in China. Our research group demonstrated a multi-center case-controlled study in China to investigate the clinical utility of simultaneous evaluation of AFP and DCP (12). As results, we found that simultaneous measurement of AFP and DCP could achieve a better sensitivity in diagnosing Chinese HCC patients, even for small tumors. We consider improvement of the diagnostic ability of serum biomarkers for HCC contributes to reduce the current high incidence of HCC patients in China.

Systematic medical care for HCC is being advanced in China. Introduction of effective tools (e.g., tumor marker) and the standardization of medical care (e.g., construction of guideline) are considered to be important for improving HCC patients’ prognosis (13). Novel factors discovered by multi-omics analysis of HBV-related HCC specimens are expected to develop new effective method of diagnosis and therapeutics for HCC.

Acknowledgements

Disclosure: The authors declare no confict of interest.

1. Huang J, Zeng Y. Current clinical uses of the biomarkers for hepatocellular carcinoma. Drug Discov Ther 2014;8:98-9.

2. Zhang K, Song P, Gao J, et al. Perspectives on a combined test of multi serum biomarkers in China: Towards screening for and diagnosing hepatocellular carcinoma at an earlier stage. Drug Discov Ther 2014;8:102-9.

3. Song P, Feng X, Zhang K, et al. Screening for and surveillance of high-risk patients with HBV-related chronic liver disease: promoting the early detection of hepatocellular carcinoma in China. Biosci Trends 2013;7:1-6.

4. Rosenblum D, Peer D. Omics-based nanomedicine: the future of personalized oncology. Cancer Lett 2014;352:126-36.

5. Weaver JM, Ross-Innes CS, Fitzgerald RC. The ‘-omics’revolution and oesophageal adenocarcinoma. Nat Rev Gastroenterol Hepatol 2014;11:19-27.

6. Miao R, Luo H, Zhou H, et al. Identifcation of prognostic biomarkers in hepatitis B virus-related hepatocellular carcinoma and stratifcation by integrative multi-omics analysis. J Hepatol 2014;61:840-9.

7. Shiba-Ishii A, Noguchi M. Aberrant stratifn overexpression is regulated by tumor-associated CpG demethylation in lung adenocarcinoma. Am J Pathol 2012;180:1653-62.

8. Liang XD, Dai YC, Li ZY, et al. Expression and function analysis of mitotic checkpoint genes identifes TTK as a potential therapeutic target for human hepatocellular carcinoma. PLoS One 2014;9:e97739.

9. Ricke RM, Jeganathan KB, van Deursen JM. Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivation. J Cell Biol 2011;193:1049-64.

10. Song P, Tang W, Hasegawa K, et al. Systematic evidencebased clinical practice guidelines are ushering in a new stage of standardized management of hepatocellular carcinoma in Japan. Drug Discov Ther 2014;8:64-70.

11. Song P, Gao J, Inagaki Y, et al. Biomarkers: evaluation of screening for and early diagnosis of hepatocellular carcinoma in Japan and china. Liver Cancer 2013;2:31-39. 12. Song P, Feng X, Inagaki Y, et al. Clinical utility of simultaneous measurement of alpha-fetoprotein and des-γ-carboxy prothrombin for diagnosis of patients with hepatocellular carcinoma in China: A multi-center case-controlled study of 1,153 subjects. Biosci Trends 2014;8:266-73.

13. Song P. Standardizing management of hepatocellular carcinoma in China: devising evidence-based clinical practice guidelines. Biosci Trends 2013;7:250-2.

Cite this article as:Inagaki Y, Song P, Kokudo N, Tang W. New ‘multi-omics’ approach and its contribution to hepatocellular carcinoma in China. Chin J Cancer Res 2014;26(6):639-640. doi: 10.3978/j.issn.1000-9604.2014.11.07

99mTc-labeled diethylenetriamine penta-acetic acid galactosyl human serum albumin (GSA) is an analogue ligand that binds to asialoglycoprotein receptors on the hepatocyte cell membranes (1). Therefore,99mTc-GSA scintigraphy is reported to be useful to evaluate function and functional reserve of the liver. There are various models and methods for assessing hepatic function when using99mTc-GSA scintigraphy. Recently, the uptake index (UI) and UI values calculated from99mTc-GSA scintigraphy were reported as a novel index in the Annals of Surgical Oncology on Oct 2014 (2,3). UI values were described as being useful to evaluate the liver function. UI values are obtained by combining UI and99mTc-GSA SPECT and contrast enhanced CT (CE-CT) fused imaging. UI values can correctly reflect the regional function of the liver because of the additional information provided by the CT imaging. Receiver operating characteristic curve analysis demonstrate that the UI values have almost perfect diagnostic performance for predicting the risk of liver failure (area under curve is 0.95). In a previous study, R max calculated from99mTc-GSA scintigraphy is also reported to be useful to predict the postoperative liver failure (4). Both of these indices display almost a perfect diagnostic performance for postoperative liver failure. Although the calculating method for Rmaxis highly complex, the UI is based on a simple 2-compartment model.

The UI values are reported to be useful to evaluate not only the regional function but also postoperative hepatic function. The correlation coeffcient between the predicted UI and actual postoperative UI is 0.95. Moreover, there is a correlation between the predicted UI and laboratory and clinical variables such as the presence of ascites, total bilirubin, and prothrombin time. Therefore, we suggested that UI values refect not only preoperative hepatic function but also hepatic functional reserve of the future remnant liver, and UI values are an ideal index for hepatectomy planning.

For accurate assessment of the hepatic function by using99mTc-GSA scintigraphy, the quality of the scintigraphic images is essential to maintain the quantitative nature of the indexes. There are various indices including UI calculated from99mTc-GSA scintigraphy that are reported to be useful to evaluate function and functional reserve of the whole liver and regional liver. However, the methods for obtaining the scintigraphic images and the reconstruction methods of scintigraphic images are not the same. Therefore, it is

10.3978/j.issn.1000-9604.2014.11.07