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Molecular Pathological Epidemiology in Diabetes Mellitus and Risk of Hepatocellular Carcinoma

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Molecular Pathological Epidemiology in Diabetes Mellitus and Risk of Hepatocellular Carcinoma Submit a Manuscript: http://www.wjgnet.com/esps/ World J Hepatol 2016 September 28; 8(27): 1119-1127 Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx ISSN 1948-5182 (online) DOI: 10.4254/wjh.v8.i27.1119 © 2016 Baishideng Publishing Group Inc. All rights reserved. REVIEW Molecular pathological epidemiology in diabetes mellitus and risk of hepatocellular carcinoma Chun Gao Chun Gao, Department of Gastroenterology, China-Japan logy and epidemiology, and investigates the relationship Friendship Hospital, Ministry of Health, Beijing 100029, China between exogenous and endogenous exposure factors, tumor molecular signatures, and tumor initiation, progres- Author contributions: Gao C conceived the topic, performed sion, and response to treatment. Molecular epidemiology research, retrieved concerned literatures and wrote the paper. broadly encompasses MPE and conventional-type mole- cular epidemiology. Hepatocellular carcinoma (HCC) Supported by Beijing NOVA Programme of Beijing Municipal is the third most common cause of cancer-associated Science and Technology Commission, No. Z13110.7000413067. death worldwide and remains as a major public health Conflict-of-interest statement: No conflict of interest. challenge. Over the past few decades, a number of epidemiological studies have demonstrated that diabetes Open-Access: This article is an open-access article which was mellitus (DM) is an established independent risk factor selected by an in-house editor and fully peer-reviewed by external for HCC. However, how DM affects the occurrence and reviewers. It is distributed in accordance with the Creative development of HCC remains as yet unclearly under- Commons Attribution Non Commercial (CC BY-NC 4.0) license, stood. MPE may be a promising approach to investigate which permits others to distribute, remix, adapt, build upon this the molecular mechanisms of carcinogenesis of DM in work non-commercially, and license their derivative works on HCC, and provide some useful insights for this patho- different terms, provided the original work is properly cited and logical process, although a few challenges must be the use is non-commercial. See: http://creativecommons.org/ overcome. This review highlights the recent advances licenses/by-nc/4.0/ in this field, including: (1) introduction of MPE; (2) HCC, risk factors, and DM as an established independent Manuscript source: Invited manuscript risk factor for HCC; (3) molecular pathology, molecular Correspondence to: Chun Gao, MD, Department of Gastro- epidemiology, and MPE in DM and HCC; and (4) MPE enterology, China-Japan Friendship Hospital, Ministry of Health, studies in DM and risk of HCC. More MPE studies are No. 2 Yinghua East Road, Beijing 100029, expected to be performed in future and I believe that China. [email protected] this field can provide some very important insights on Telephone: +86-10-84205313 the molecular mechanisms, diagnosis, personalized Fax: +86-10-64481924 prevention and treatment for DM and risk of HCC. Received: April 2, 2016 Key words: Diabetes mellitus; Molecular pathological Peer-review started: April 7, 2016 epidemiology; Hepatocellular carcinoma; Risk factor; First decision: June 6, 2016 Molecular mechanism Revised: June 28, 2016 Accepted: August 6, 2016 © The Author(s) 2016. Published by Baishideng Publishing Article in press: August 8, 2016 Published online: September 28, 2016 Group Inc. All rights reserved. Core tip: Diabetes mellitus (DM) is an established in- dependent risk factor for hepatocellular carcinoma (HCC); however, how DM affects the occurrence and Abstract development of HCC remains as yet unclearly understood. Molecular pathological epidemiology (MPE) is a multi- Molecular pathological epidemiology (MPE) may be a pro- disciplinary and transdisciplinary study field, which has mising approach to investigate the molecular mechanisms emerged as an integrated approach of molecular patho- of carcinogenesis of DM in HCC, and provide some WJH|www.wjgnet.com 1119 September 28, 2016|Volume 8|Issue 27| Gao C. MPE in diabetes and risk of HCC useful insights for this pathological process. This review MPE addresses two questions: (1) the association highlights the recent advances in this field and more MPE of particular exposure factors with specific molecular studies are expected to be performed for this question in changes; and (2) the interaction of particular exposure future. factors with specific molecular changes to affect deve­ lopment, progression and prognosis of tumors. The typical research of cancer MPE is used to examine the Gao C. Molecular pathological epidemiology in diabetes mellitus relationship between exposure factors and risk of tumors and risk of hepatocellular carcinoma. World J Hepatol 2016; according to the status of tumor signatures[9,10]. Cancer 8(27): 1119-1127 Available from: URL: http://www.wjgnet. MPE techniques and studies can help us understand com/1948-5182/full/v8/i27/1119.htm DOI: http://dx.doi. the carcinogenesis of certain exposure factors, through org/10.4254/wjh.v8.i27.1119 the examination of molecular pathological signatures associated with initiation and progression of tumors, and the exposures[5,6]. INTRODUCTION Molecular pathology examines the expression of mole­ HEPATOCELLULAR CARCINOMA AND cular markers within bodily fluids, tissues or organs, RISK FACTORS and focuses on the diagnosis and studies of diseases, Hepatocellular carcinoma (HCC) has been confirmed as such as tumors[1,2]. Epidemiology is focused upon the the third leading cause globally, among all the cancer­ studies of distributions and determinants of diseases and [10­12] related deaths . For primary liver cancers, more than health conditions in specific populations[3,4]. Molecular 80% are HCC and the incidence rate annually of HCC is pathological epidemiology (MPE) is a multidisciplinary 4.9 per 100000 persons. Although some advances have and transdisciplinary study field, which has emerged been gained in the diagnosis and treatment of HCC, as an integrated approach of molecular pathology and the prognosis remains very poor. Similarly, the annual epidemiology, and investigates the relationship between mortality rate remains very high and HCC has also been tumour molecular markers, exposure of endogenous and [13] ranked as one of the most lethal cancers . exogenous factors, and development, progression and With the using and popularization of hepatitis B virus prognosis of tumors[5­8]. Molecular epidemiology broadly (HBV) vaccination, the improvement of people’s living encompasses MPE and conventional­type molecular standard and life style, and advancement of early diagnosis epidemiology. and treatment of premalignant lesions, the incidence of In MPE, researchers investigate the relationships HCC had been anticipated to be decreased. However, between: (1) changes of extracellular or cellular molecules the incidence rate of HCC has already been found to (disease molecular signatures); (2) genetic, dietary, be increased significantly in the past thirty years in environmental and lifestyle factors; and (3) development [6] some countries, including the United States, China and and progression of diseases, such as tumors . In 2010, [14,15] Japan . For example, during the period of 1981­1983 Professor Shuji Ogino and Professor Meir Stampfer[5] in the United States, the age adjusted incidence rate were the first to introduce the concept of MPE. They was 1.3 per 100000; however, this rate increased to 3.0 consolidated this concept mainly based on the researches per 100000 during the period of 1996­1998[14,15]. Although of colorectal cancer (CRC), particularly the prototypical more than fifty percent of this increase has been attri­ study in the evolving field of MPE, which was conducted buted to hepatitis virus C (HCV), other hepatitis viruses by Professor Peter T Campbell and others[9]. and alcoholic liver disease[16], the reason remains as This case­control study of Campbell et al[9] was unclear. conducted to determine the relationships between CRC The identified risk factors of HCC include liver cirrhosis, microsatellite instability (MSI) status, risk of CRC, and HBV, HCV, heavy alcoholic consumption, alfatoxin ex­ human body mass index (BMI). The results showed that posure, non­alcoholic steatohepatitis, positive family an increased CRC risk was found in those patients with a history, male sex, and increasing age[17­19]. Over the high BMI; however, this risk of CRC was associated with past few decades, a number of epidemiological studies the MSI status. For patients with MS­stable, the adjusted have demonstrated that diabetes mellitus (DM) is an odds ratio (OR) was 1.38 and 95%CI was 1.24­1.54, established independent risk factor for HCC[12,20­23]. for an increment of 5 kg/m2 of BMI; for patients with MSI­low, the OR was 1.33 and 95%CI was 1.04­1.72; however, for patients with MSI­high tumours, the value of DM AS AN ESTABLISHED INDEPENDENT OR and 95%CI were 1.05 and 0.84­1.31, respectively[9]. The authors concluded that the relationship between the RISK FACTOR FOR HCC high BMI and increased CRC risk was related to the tumor In the year of 1986, for the first time, Lawson et al[24] MSI status[9]. According to the concept and principle of proposed accidentally the positive association of DM with MPE, this prototypical study addressed the relationship HCC. The authors observed that, in Western Europe, the between exposure factor (high BMI), molecular change incidence rate of primary liver cancers was increased, and (CRC MSI status) and tumor initiation
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