Gastrointestinal Oncology - World Journal of Gastroenterology

World Journal of 

Gastrointestinal Oncology 

World J Gastrointest Oncol 2012 August 15; 4(8): 187-201 

www.wjgnet.com 

ISSN 1948-5204 (online)

Editorial Board 

2009-2013 

The World Journal of Gastrointestinal Oncology Editorial Board consists of 404 members, representing a team of 

worldwide experts in gastrointestinal oncology. They are from 41 countries, including Argentina (1), Australia (9), 

Austria (1), Belgium (4), Brazil (2), Bulgaria (1), Canada (4), Chile (2), China (51), Czech Republic (1), Finland (3), 

France (5), Germany (18), Greece (12), Hungary (2), India (9), Iran (3), Ireland (2), Israel (4), Italy (34), Japan (47), 

Kuwait (2), Mexico (1), Netherlands (8), New Zealand (2), Norway (1), Poland (4), Portugal (5), Romania (1), Saudi 

Arabia (1), Serbia (2), Singapore (4), South Korea (27), Spain (11), Sweden (6), Switzerland (2), Syria (1), Thailand 

(1), Turkey (6), United Kingdom (13), and United States (91). 

EDITOR-IN-CHIEF 

Wasaburo Koizumi, Kanagawa 

Hsin-Chen Lee, Taipei 

Dimitrios H Roukos, Ioannina 

STRATEGY ASSOCIATE 

EDITORS-IN-CHIEF 

Jian-Yuan Chai, Long Beach 

Antonio Macrì, Messina 

Markus K Menges, Schwaebisch Hall 

GUEST EDITORIAL BOARD 

MEMBERS 

Da-Tian Bau, Taichung 

Jui-I Chao, Hsinchu 

Chiao-Yun Chen, Kaohsiung 

Shih-Hwa Chiou, Taipei 

Tzeon-Jye Chiou, Taipei 

Jing-Gung Chung, Taichung 

Yih-Gang Goan, Kaohsiung 

Li-Sung Hsu, Taichung 

Tsann-Long Hwang, Taipei 

Long-Bin Jeng, Taichung 

Kwang-Huei Lin, Taoyuan 

Joseph T Tseng, Tainan 

Jaw Y Wang, Kaohsiung 

Kenneth K Wu, Miaoli 

Tzu-Chen Yen, Taoyuan 

MEMBERS OF THE EDITORIAL 

BOARD 

Argentina 

Lydia Inés Puricelli, Buenos Aires 

Australia 

Ned Abraham, Coffs Harbour 

Stephen John Clarke, Concord 

Michael McGuckin, South Brisbane 

Muhammed A Memon, Queensland 

Liang Qiao, Westmead 

Rodney J Scott, New South Wales 

Joanne Patricia Young, Herston 

Xue-Qin Yu, Kings Cross 

Xu-Dong Zhang, Newcastle 

Austria 

Michael Gnant, Vienna 

Belgium 

Wim P Ceelen, Ghent 

Van Cutsem Eric, Leuven 

Xavier Sagaert, Leuven 

Jan B Vermorken, Edegem 

Brazil 

Raul A Balbinotti, Caxias do Sul RS 

Sonia Maria Oliani, São Paulo 

Bulgaria 

Krassimir Dimitrow Ivanov, Varna 

Canada 

Alan G Casson, Saskatoon 

Hans Chung, Toronto 

WJGO|www.wjgnet.com I 

Rami Kotb, Sherbrooke 

Sai Yi Pan, Ottawa 

Chile 

Alejandro H Corvalan, Santiago 

Juan Carlos Roa, Temuco 

China 

Feng Bi, Chengdu 

Yong-Chang Chen, Zhenjiang 

Chi-Hin Cho, Hong Kong 

Ming-Xu Da , Lanzhou 

Xiang-Wu Ding, Xiangfan 

Jin Gu, Beijing 

Qin-Long Gu, Shanghai 

Hai-Tao Guan, Xi’an 

Chun-Yi Hao, Beijing 

Yu-Tong He, Shijiazhuang 

Jian-Kun Hu, Chengdu 

Huang-Xian Ju, Nanjing 

Wai-Lun Law, Hong Kong 

Shao Li, Beijing 

Yu-Min Li, Lanzhou 

Ka-Ho Lok, Hong Kong 

Maria Li Lung, Hong Kong 

Simon Ng, Hong Kong 

Wei-Hao Sun, Nanjing 

Qian Tao, Hong Kong 

Bin Wang, Nanjing 

Kai-Juan Wang, Zhengzhou 

Wei-Hong Wang, Beijing 

Ya-Ping Wang, Nanjing 

Ai-Wen Wu, Beijing 

Zhao-Lin Xia, Shanghai 

Xue-Yuan Xiao, Beijing 

Dong Xie, Shanghai 

Yi-Zhuang Xu, Beijing 

August 15, 2012

Guo-Qiang Xu, Hangzhou 

Winnie Yeo, Hong Kong 

Ying-Yan Yu, Shanghai 

Siu Tsan Yuen, Hong Kong 

Wei-Hui Zhang, Harbin 

Li Zhou, Beijing 

Yong-Ning Zhou, Lanzhou 

Ondrej Slaby, Brno 

Czech Republic 

Finland 

Riyad Bendardaf, Turku 

Pentti Ilmari Sipponen, Helsinki 

Markku Voutilainen, Jyväskylä 

France 

Bouvier Anne-Marie, Cedex 

Stéphane Benoist, Boulogne 

Ouaissi Mehdi, Cedex 

Isabelle V Seuningen, Cedex 

Karem Slim, Clermont-Ferrand 

Germany 

Han-Xiang An, Marburg 

Karl-Friedrich Becker, München 

Stefan Boeck, Munich 

Dietrich Doll, Marburg 

Volker Ellenrieder, Marburg 

Joachim P Fannschmidt, Heidelberg 

Ines Gütgemann, Bonn 

Jakob R Izbicki, Hamburg 

Gisela Keller, München 

Jörg H Kleeff, Munich 

Axel Kleespies, Munich 

Hans-Joachim Meyer, Solingen 

Lars Mueller, Kiel 

Marc A Reymond, Bielefeld 

Robert Rosenberg, München 

Oliver Stoeltzing, Mainz 

Ludwig G Strauss, Heidelberg 

Greece 

Ekaterini Chatzaki, Alexandroupolis 

Eelco de Bree, Heraklion 

Maria Gazouli, Athens 

Vassilis Georgoulias, Crete 

John Griniatsos, Athens 

Ioannis D Kanellos, Thessaloniki 

Vaios Karanikas, Larissa 

Georgios Koukourakis, Athens 

Gregory Kouraklis, Athens 

Dimitrios H Roukos, Ioannina 

Konstantinos Nik Syrigos, Athens 

Ioannis A Voutsadakis, Larissa 

Hungary 

László Herszényi, Budapest 

Zsuzsa Schaff, Budapest 

India 

Uday Chand Ghoshal, Lucknow 

Ruchika Gupta, New Delhi 

Kalpesh Jani, Gujarat 

Ashwani Koul, Chandigarh 

Balraj Mittal, Lucknow 

Rama Devi Mittal, Lucknow 

Susanta Roychoudhury, Kolkata 

Yogeshwer Shukla, Lucknow 

Imtiaz Ahmed Wani, Kashmir 

Iran 

Mohammad R Abbaszadegan, Mashhad 

Reza Malekezdeh, Tehran 

Mohamad A Pourhoseingholi, Tehran 

Ireland 

Aileen Maria Houston, Cork 

Colm Ó’Moráin, Dublin 

Israel 

Nadir Arber, Tel Aviv 

Dan David Hershko, Haifa 

Eytan Domany, Rehovot 

Yaron Niv, Patch Tikva 

Italy 

Massimo Aglietta, Turin 

Azzariti Amalia, Bari 

Domenico Alvaro, Rome 

Marco Braga, Milan 

Federico Cappuzzo, Rozzano 

Fabio Carboni, Rome 

Vincenzo Cardinale, Rome 

Luigi Cavanna, Piacenza 

Riccardo Dolcetti, Aviano 

Pier Francesco Ferrucci, Milano 

Francesco Fiorica, Ferrara 

Gennaro Galizia, Naples 

Silvano Gallus, Milan 

Milena Gusella, Trecenta 

Roberto F Labianca, Bergamo 

Massimo Libra, Catania 

Roberto Manfredi, Bologna 

Gabriele Masselli, Roma 

Simone Mocellin, Padova 

Gianni Mura, Arezzo 

Gerardo Nardonen, Napoli 

Francesco Perri, San Benedetto del Tronto 

Francesco Recchia, Avezzano 

Vittorio Ricci, Pavia 

Fabrizio Romano, Monza 

Antonio Russo, Palermo 

Daniele Santini, Roma 

Claudio Sorio, Verona 

Cosimo Sperti, Padova 

Gianni Testino, Genova 

Giuseppe Tonini, Rome 

Bruno Vincenzi, Rome 

Angelo Zullo, Rome 

Japan 

Keishiro Aoyagi, Kurume 

Suminori Akiba, Kagoshima 

WJGO|www.wjgnet.com II 

Narikazu Boku, Kanagawa 

Yataro Daigo, Tokyo 

Itaru Endo, Yokohama 

Mitsuhiro Fujishiro, Tokyo 

Osamu Handa, Kyoto 

Kenji Hibi, Yokohama 

Asahi Hishida, Nagoya 

Eiso Hiyama, Hiroshima 

Atsushi Imagawa, Okayama 

Johji Inazawa, Tokyo 

Terumi Kamisawa, Tokyo 

Tatsuo Kanda, Niigata 

Masaru Katoh, Tokyo 

Takayoshi Kiba, Hyogo 

Hajime Kubo, Kyoto 

Yukinori Kurokawa, Osaka 

Chihaya Maesawa, Morioka 

Yoshinori Marunaka, Kyoto 

Hishairo Matsubara, Chiba 

Osam Mazda, Kyoto 

Shinichi Miyagawa, Matsumoto 

Eiji Miyoshi, Suita 

Toshiyuki Nakayama, Nagasaki 

Masahiko Nishiyama, Saitama 

Koji Oba, Kyoto 

Masayuki Ohtsukam, Chiba 

Masao Seto, Aichi 

Tomoyuki Shibata, Aichi 

Mitsugi Shimoda, Tochigi 

Haruhiko Sugimura, Hamamatsu 

Tomomitsu Tahara, Aichi 

Shinji Takai, Osaka 

Satoru Takayama, Nagoya 

Hiroya Takiuchi, Osaka 

Akio Tomoda, Tokyo 

Akihiko Tsuchida, Tokyo 

Yasuo Tsuchiya, Niigata 

Takuya Watanabe, Niigata 

Toshiaki Watanabe, Tokyo 

Hiroshi Yasuda, Kanagawa 

Yo-ichi Yamashita, Hiroshima 

Hiroki Yamaue, Wakayama 

Hiroshi Yokomizo, Kumamoto 

Yutaka Yonemura, Osaka 

Reigetsu Yoshikawa, Hyogo 

Kuwait 

Fahd Al-Mulla, Safat 

Salem Alshemmari, Safat 

Mexico 

Oscar GA Rodriguez, Mexico 

Netherlands 

Jan Paul De Boer, Amsterdam 

Bloemena Elisabeth, Amsterdam 

Peter JK Kuppen, Leiden 

Gerrit Albert Meijer, Hattem 

Anya N Milne, Utrecht 

Godefridus J Peters, Amsterdam 

Cornelis FM Sier, Leiden 

Peter Derk Siersema, Utrecht 

New Zealand 

Lynnette R Ferguson, Auckland 

Jonathan Barnes Koea, Auckland 

Norway 

Kjetil Søreide, Stavanger 

August 15, 2012

Contents Monthly Volume 4 Number 8 August 15, 2012 

EDITORIAL 

ORIGINAL ARTICLE 

187 Laparoscopic liver resection: Current role and limitations 

Mostaedi R, Milosevic Z, Han HS, Khatri VP 

193 Leukocyte DNA methylation and colorectal cancer among male 

smokers 

Gao Y, Killian K, Zhang H, Yu K, Li QZ, Weinstein S, Virtamo J, Tucker M, 

Taylor P, Albanes D, Meltzer P, Caporaso N 

WJGO|www.wjgnet.com August 15, 2012|Volume 4| ssue 8|

Contents 

ACKNOWLEDGMENTS 

APPENDIX 

ABOUT COVER 

AIM AND SCOPE 

FLYLEAF 

EDITORS FOR 

THIS ISSUE 

NAME OF JOURNAL 

World Journal of Gastrointestinal Oncology 

ISSN 

ISSN 1948-5204 (online) 

LAUNCH DATE 

October 15, 2009 

FREQUENCY 

Monthly 

EDITING 

Editorial Board of World Journal of Gastrointestinal Oncology 

Room 903, Building D, Ocean International Center, 

No. 62 Dongsihuan Zhonglu, Chaoyang District, 

Beijing 100025, China 

Telephone: +86-10-85381891 

Fax: +86-10-85381893 

E-mail: wjgo@wjgnet.com 

http://www.wjgnet.com 

EDITOR-IN-CHIEF 

Wasaburo Koizumi, MD, PhD, Professor, Chairman, 

Department of Gastroenterology, Gastrointestinal 

Oncology, School of Medicine, Kitasato University, 

2-1-1 Asamizodai Minamiku Sagamihara Kanagawa 

252-0380, Japan 

WJGO|www.wjgnet.com 


Volume 4 Number 8 August 15, 2012 

I Acknowledgments to reviewers of World Journal of Gastrointestinal Oncology 

I Meetings 

I-V Instructions to authors 

World Journal of Gastrointestinal Oncology Editorial Board, Vijay P Khatri, 

MBChB, FACS, Professor, Department of Surgery, University of California, Davis 

School of Medicine, 4501 X Street, Sacramento, CA 95817, United States 

World Journal of Gastrointestinal Oncology (World J Gastrointest Oncol, WJGO, online ISSN 

1948-5204, DOI: 10.4251) is a monthly peer-reviewed, online, open-access, journal 

supported by an editorial board consisting of 404 experts in gastrointestinal oncology 

from 41 countries. 

The major task of WJGO is to report rapidly the most recent advances in basic 

and clinical research on gastrointestinal oncology. The topics of WJGO cover the 

carcinogenesis, tumorigenesis, metastasis, diagnosis, prevention, prognosis, clinical 

manifestations, nutritional support, molecular mechanisms, and therapy of benign and 

malignant tumors of the digestive tract. This cover epidemiology, etiology, immunology, 

molecular oncology, cytology, pathology, genetics, genomics, proteomics, pharmacology, 

pharmacokinetics, nutrition, diagnosis and therapeutics. This journal will also provide 

extensive and timely review articles on oncology. 

I-III Editorial Board 

Responsible Assistant Editor: Jin-Lei Wang Responsible Science Editor: Jin-Lei Wang 

Responsible Electronic Editor: Xiao-Mei Zheng Proofing Editorial Office Director: Jin-Lei Wang 

Proofing Editor-in-Chief: Lian-Sheng Ma 

Hsin-Chen Lee, PhD, Professor, Institute of Pharmacology, 

School of Medicine, National Yang-Ming 

University, Taipei 112, Taiwan, China 

Dimitrios H Roukos, MD, PhD, Professor, Personalized 

Cancer Genomic Medicine, Human Cancer Biobank 

Center, Ioannina University, Metabatiko Ktirio 

Panepistimiou Ioanninon, Office 229, Ioannina, TK 

45110, Greece 

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wjgo@wjgnet.com 

doi:10.4251/wjgo.v4.i8.187 

Laparoscopic liver resection: Current role and limitations 

Rouzbeh Mostaedi, Zoran Milosevic, Ho-Seong Han, Vijay P Khatri 

Rouzbeh Mostaedi, Vijay P Khatri, Department of Surgery, University 

of California, Davis Cancer Center, University of California, 

Davis Medical Center, Sacramento, CA 95817, United States 

Zoran Milosevic, Clinic for Abdominal, Endocrine and Transplantation 

Surgery, Clinical Center Vojvodina, 21000 Novi Sad, Serbia 

Ho-Seong Han, Department of Surgery, Seoul National University 

Bundang Hospital, Seoul National University College of 

Medicine, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 

463-707, South Korea 

Author contributions: Mostaedi R and Khatri VP contributed 

to conception, writing, editing, and final approval of the version 

to be published; Milosevic Z reviewed the manuscript; Han HS 

critically reviewed the manuscript. 

Correspondence to: Vijay P Khatri, MBChB, FACS, Professor 

of Surgery, Department of Surgery, University of California, Davis 

School of Medicine, 4501 X Street, Sacramento, CA 95817, 

United States. vijay.khatri@ucdmc.ucdavis.edu 

Telephone: +1-916-7342172 Fax: +1-916-7035267 

Received: December 13, 2011 Revised: July 31, 2012 

Accepted: August 6, 2012 

Published online: August 15, 2012 

Abstract 

Laparoscopic liver resection (LLR) for the treatment of 

benign and malignant liver lesions is often performed 

at specialized centers. Technological advances, such as 

laparoscopic ultrasonography and electrosurgical tools, 

have afforded surgeons simultaneous improvements in 

surgical technique. The utilization of minimally invasive 

techniques for liver resection has been reported to reduce 

operative time, decrease blood loss, and shorten 

length of hospital stay with equivalent postoperative 

mortality and morbidity rates compared to open liver 

resection (OLR). Non-anatomic liver resection and left 

lateral sectionectomy are now routinely performed laparoscopically 

at many institutions. Furthermore, major 

hepatic resections are performed by pure laparoscopy, 

hand-assisted technique, and the hybrid method. In 

addition, robotic surgery and single port surgery are revealing 

early promising results. The consensus recommendation 

for the treatment of benign liver disease and 

malignant lesions remains unchanged when considering 



© 2012 Baishideng. All rights reserved. 

a laparoscopic approach, except when comorbidities 

and anatomic limitations of the liver lesion preclude this 

technique. Disease free and survival rates after LLR for 

hepatocellular carcinoma and metastatic colon cancer 

correspond to OLR. Patient selection is a significant 

factor for these favorable outcomes. The limitations 

include LLR of superior and posterior liver lesions; 

however, adjustments in technique may now consider 

a laparoscopic approach as a viable option. As growing 

data continue to reveal the feasibility and efficacy of 

laparoscopic liver surgery, this skill is increasingly being 

adopted by hepatobiliary surgeons. Although the full 

scope of laparoscopic liver surgery remains infrequently 

used by many general surgeons, this technique will become 

a standard in the treatment of liver diseases as 

studies continue to show favorable outcomes. 


Key words: Laparoscopic liver resection; Laparoscopic 

hepatectomy; Minimally invasive liver surgery; Handassisted 

technique; Hybrid technique 

Peer reviewers: Satoru Takayama, MD, Department of Gastroenterological 

Surgery, Nagoya City University, 1 Kawasumi, 

Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan; Simon Ng, 

Professor, Division of Colorectal Surgery, Department of Surgery, 

University of Hong Kong; Department of Surgery, Prince 

of Wales Hospital, Shatin, Room 64045, 4/F, Clinical Sciences 

Building, Hong Kong, China 

Mostaedi R, Milosevic Z, Han HS, Khatri VP. Laparoscopic liver 

resection: Current role and limitations. World J Gastrointest 

Oncol 2012; 4(8): 187-192 Available from: URL: http://www. 

wjgnet.com/1948-5204/full/v4/i8/187.htm DOI: http://dx.doi. 

org/10.4251/wjgo.v4.i8.187 

INTRODUCTION 

EDITORIAL 

The advent of laparoscopic cholecystectomy demonstrated 

an associated decrease in postoperative morbidity, 

decreased blood loss, and reduced length of hospital 

WJGO|www.wjgnet.com 187 

August 15, 2012|Volume 4|Issue 8|

Mostaedi R et al . Laparoscopic liver resection 

hepatectomies are performed at specialized centers by 

hepatobiliary surgeons skilled in minimally invasive 

techniques. A priority for the safe dissemination of the 

laparoscopic liver surgery has been addressed, yet there 

is no uniform consensus on the criteria for certification 

and credentialing [5] . However, the recommendation for 

surgeons with limited experience in complex laparoscopic 

liver surgery should begin with minor hepatectomies, 

such as the left lateral sectionectomy or minor non-anatomic 

hepatectomy [5,7] , and transition to major hepatectomies 

with the hybrid approach [17] . 

A risk-adjusted Cumulative Sum analysis determined 

that the learning curve for LLR is 60 cases [34] . LLRs during 

three consecutive periods were compared to open 

resections, and significant improvements were seen in 

conversion rates (15.5%, 10.3% and 3.4%, P < 0.005), 

operative time (210, 180 and 150 min, P < 0.05), and operative 

blood loss (300, 200 and 200 mL, P < 0.05) [34] . 

The results of LLR are promising, and presently show 

favorable outcomes in postoperative morbidity and mortality 

[35] . The role of LLR for difficultly located lesions, 

specifically in the posterior and centrally located regions, 

is becoming a viable option for many minimally invasive 

hepatobiliary surgeons [9,16,36] . These early single institution 

studies indicate that laparoscopic techniques are feasible 

with equivalent perioperative complication rates. One of 

the author, Han HS from Seoul National University Bundang 

Hospital, has been applying LLR for tumor located 

in posterosuperior segment. As laparoscopic approach 

for the lesion located in posterosuperior segment is technically 

difficult with the possibility of significant bleeding 

during operation, it is recommended to be performed by 

very experienced surgeons. 

The retrospective analysis by Cho et al [36] compared 

laparoscopic (n = 42) to open (n = 40) liver resection for 

lesions located on the right side of the liver. Their results 

did not show a significant difference in the rate of complications 

(27.5% vs 28.6%), operative time, estimated 

blood loss, or number of operative blood transfusions. 

Yoon et al [9] compared patients with lesions located in 

the anterolateral segments (AL group, n = 44) to posterosuperior 

segments (PS group, n = 25) undergoing 

LLR for HCC. The PS group had a longer operative time 

(P = 0.001), longer length of hospital stay (P = 0.039), 

higher rate of open conversion (P = 0.054), and greater 

estimated blood loss (P = 0.068). There were no statistical 

difference in postoperative complications (18.2% vs 

28.0%), recurrence rate (34.0% vs 24.0%), 3-year overall 

survival (84.6% vs 100.0%), or disease-free survival (58.5% 

vs 63.4%) between the two groups. 

These case series on LLR for lesions in the centrally 

located, superior and posterior segments are promising. 

However, further review needs to be done to confirm its 

feasibility and appropriateness in selected patients. 

COMPLICATIONS 

Safe laparoscopic principles have long been established, 

and the philosophy of open conversion should not be 

considered a complication, but as part of the planned 

procedure for difficult dissections, uncontrolled bleeding, 

and for the safety of the patient. However, the failure 

to convert and the associated consequences should still 

remain to be considered a complication. Expert understanding 

of liver anatomy and physiology, and extended 

experience in laparoscopic liver surgery is necessary for 

low complication rates similar to OLRs. 

The meta-analysis of laparoscopic hepatectomies 

by Nguyen et al [35] found that the overall morbidity rate 

was 10.5% (range 0% to 50%), and overall mortality 

rate was 0.3% (range 0% to 10%) in 2804 patients. The 

most common postoperative complication was a bile 

leak (1.5%) followed by transient hepatic insufficiency 

(1.0%). The most common general- and surgical-related 

complications were pleural effusions, incisional bleeding 

and wound infections-each less than 1%. In several 

large series, the overall morbidity rate ranges from 22% 

to 45%, and the overall mortality rate ranges from 3.1 to 

4.9% and decrease to 1.3% in the last decade reported by 

Jarnagin et al [37] for OLRs [37-39] . The overall morbidity and 

mortality rates for LLR are favorable compared to these 

large series on OLR. 

FUTURE 

Early results for the utilization of single port laparoscopy 

have shown to be feasible with minimal rates of complication 

similar to multiport laparoscopic liver surgery [40-43] . 

Patient selection was general limited to anterolateral segments 

and tumors < 3 cm [40,41] . In a recent case series, single 

port laparoscopic major hepatectomy was performed 

in 2 patients with HCC [43] . There were no reported complications 

and no cancer recurrence. These early experiences 

reported longer operative time and limitations due 

to instrumentation length and triangulation. 

There are case series on patients undergoing roboticassisted 

LLR and VATS-H [11-15] . These novel techniques 

have been shown to be successful in both minor and major 

hepatectomies, and for liver tumors located in difficult 

anatomic locations. 

Giulianotti et al [13] reported no deaths and the overall 

complication rate was 21.4% in 70 patients undergoing 

robotic-assisted laparoscopic liver surgery. Ji et al [14] 

reviewed 13 consecutive patients, and there were no reported 

deaths and the overall complication rate of 7.8%. 

Chan et al [12] also reported similar results performed in 27 

patients with no reported deaths and morbidity of 7.4%. 

Berber et al [11] reported a comparative analysis on 

robotic (n = 9) and laparoscopic (n = 23) liver resection. 

Operative time (234 ± 17 min vs 259 ± 28 min), blood 

loss (136 ± 61 mL vs 155 ± 54 mL), negative tumor margins 

and complication rates (11% vs 17%) were similar 

for both groups. 

Murakami et al [15] reported a small series of 5 patients 

undergoing VATS-H for subdiaphragmatic liver tumors. 

The procedure was performed with both thoracoscopic 



and laparoscopic ports, and intraoperative thoracoscopic 

ultrasound was used to localize the liver tumor over the 

diaphragm. The blood median blood loss was 43 g (0- 

200 g) and median total operating time was 137 min 

(95-185 min). There were no perioperative deaths or 

complications such as re-exploration, postoperative 

bleeding, biliary fistula, hydrothorax, or hepatic failure. 

The patients on follow-up did not show any evidence of 

recurrent disease. The VATS-H may thus provide another 

surgical option for the difficultly located liver tumors. 

CONCLUSION 

The associated risks for OLR have been well documented 

[37-39] . Belghiti et al [38] reported an overall in-hospital 

mortality rate of 4.4% (9.5% with an underlying liver 

disease and 1% without an underlying liver disease). The 

large meta-analysis of LLR by Nguyen et al [35] reported 

a total mortality rate of 0.3% and complication rate of 

10.5% 

Koffron et al [3] reported in a large, single-center experience 

of 300 LLRs which were compared to 100 contemporaneous, 

cohort-matched OLRs. The LLR group 

compared favorably to the OLR in operative times, blood 

loss, and length of hospital stay. The overall complications 

rate was less in the LLR group (9.3% vs 22%). 

As more hepatobiliary surgeons are adopting laparoscopic 

liver surgery into their practice, guidelines and 

consensus statements are now being established to provide 

a standard approach to the treatment of benign and 

malignant liver diseases with minimally invasive techniques. 

LLR of complex lesions and difficultly located 

lesions has shown to be feasible in case series, but should 

be reserved for minimally invasive hepatobiliary surgeons 

at specialized centers. Anterior and peripheral hepatic 

lesions should be evaluated for a minimally invasive approach, 

and left lateral sectionectomy is considered to be 

a standard surgical treatment option. Perioperative complication 

rates and long-term oncologic outcomes appear 

to be favorable, and continue to be a viable surgical option 

at specialized centers. Robotic-assisted laparoscopic 

hepatectomies and VATS-H show promising early results 

in the few small case series, but undoubtedly will become 

another option in selected patients. 

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S- Editor Wang JL L- Editor A E- Editor Zheng XM 





doi:10.4251/wjgo.v4.i8.193 

Leukocyte DNA methylation and colorectal cancer among 

male smokers 

Ying Gao, Keith Killian, Hong Zhang, Kai Yu, Qi-Zhai Li, Stephanie Weinstein, Jarmo Virtamo, Margaret Tucker, 

Philip Taylor, Demetrius Albanes, Paul Meltzer, Neil Caporaso 

Ying Gao, Kai Yu, Stephanie Weinstein, Margaret Tucker, 

Philip Taylor, Demetrius Albanes, Neil Caporaso, Division of 

Cancer Epidemiology and Genetics, National Cancer Institute, 

National Institutes of Health, Bethesda, MD 20852, United States 

Keith Killian, Paul Meltzer, Center for Cancer Research, National 

Cancer Institute, National Institutes of Health, Bethesda, MD 

20852, United States 

Hong Zhang, Institute of Biostatistics, School of Life Science, 

Fudan University, Shanghai 200433, China 

Qi-Zhai Li, Department of Statistics, Chinese Academy of Sciences, 


Jarmo Virtamo, National Public Health Institute, Helsinki 

FI-00271, Finland 

Author contributions: Gao Y and Caporaso N designed the 

study; Gao Y, Zhang H, Yu K and Li QZ analyzed the data; Gao 

Y and Caporaso N wrote the report; Killian K and Meltzer P conducted 

laboratory assays; all authors read, gave comments, and 

approved the final version of the manuscript; Gao Y had full access 

to all of the data in the study and take responsibility for the 

integrity of the data and the accuracy of the data analysis. 

Supported by Grants from the Intramural Research Program 

of the Division of Cancer Epidemiology and Genetics, National 

Cancer Institute, National Institutes of Health 

Correspondence to: Ying Gao, MD, PhD, Professor, Genetic 

Epidemiology Branch, Division of Cancer Epidemiology and 

Genetics, National Cancer Institute, 6120 Executive Boulevard, 

Bldg. EPS/Room 7110, NIH/NCI, Bethesda, MD 20892, 

United States. gaoying@mail.nih.gov 

Telephone: +1-301-4969249 Fax: +1-301-4024489 

Received: January 13, 2012 Revised: July 13, 2012 

Accepted: July 20, 2012 

Published online: August 15, 2012 

Abstract 

AIM: To explore the association between methylation 

in leukocyte DNA and colorectal cancer (CRC) risk in 

male smokers using the α-tocopherol, β-carotene cancer 

prevention study. 

METHODS: About 221 incident CRC cases, and 219 




controls, frequency-matched on age and smoking intensity 

were included. DNA methylation of 1505 CpG 

sites selected from 807 genes were evaluated using Illumina 

GoldenGate Methylation Cancer Panel I in prediagnostic 

blood leukocytes of study subjects. Tertiles 

of methylation level classified according to the distribution 

in controls for each CpG site were used to analyze 

the association between methylation level and CRC 

risk with logistic regression. The time between blood 

draw to cancer diagnosis (classifying cases according 

to latency) was incorporated in further analyses using 

proportional odds regression. 

RESULTS: We found that methylation changes of 

31 CpG sites were associated with CRC risk at P < 0.01 

level. Though none of these 31 sites remained statistically 

significant after Bonferroni correction, the most 

statistically significant CpG site associated with CRC 

risk achieved a P value of 1.0 × 10 -4 . The CpG site is 

located in DSP gene, and the risk estimate was 1.52 

(95% CI: 0.91-2.53) and 2.62 (95% CI: 1.65-4.17) for 

the second and third tertile comparing with the lowest 

tertile respectively. Taking the latency information into 

account strengthened some associations, suggesting 

that the methylation levels of corresponding sites might 

change over time with tumor progression. 

CONCLUSION: The results suggest that the methylation 

level of some genes were associated with cancer 

susceptibility and some were related to tumor development 

over time. Further studies are warranted to confirm 

and refine our results. 


ORIGINAL ARTICLE 

Key words: DNA methylation; Colorectal cancer; Susceptibility 

Peer reviewer: Haruhiko Sugimura, MD, PhD, Department of 

Investigative Pathology I, Hamamatsu University School of Med- 



Gao Y et al . DNA methylation and colorectal cancer 

icine, 1-20-1 Handayama, Higashi-ward, Hamamatsu 431-3192, 

Japan 

Gao Y, Killian K, Zhang H, Yu K, Li QZ, Weinstein S, Virtamo J, 

Tucker M, Taylor P, Albanes D, Meltzer P, Caporaso N. Leukocyte 

DNA methylation and colorectal cancer among male smokers. 

World J Gastrointest Oncol 2012; 4(8): 193-201 Available 

from: URL: http://www.wjgnet.com/1948-5204/full/v4/i8/193. 

htm DOI: http://dx.doi.org/10.4251/wjgo.v4.i8.193 

INTRODUCTION 

Although its incidence and mortality have declined in the 

past decades, colorectal cancer (CRC) remains the third 

most common cancer worldwide [1] . Epigenetic changes, 

which affect gene expression and subsequent phenotypes 

by mechanisms other than DNA sequence change, have 

been shown to play important roles in etiology of various 

cancers [2] . Studying the roles of epigenetic and genetic 

factors, as well as their interaction with environmental 

exposures, should lead to better understanding on the 

pathogenesis of CRC, and ultimately contribute to the 

prevention and treatment. 

DNA methylation, the covalent addition of a methyl 

group, is an epigenetic event that alters gene expression. 

It has a degree of dependence on host status, including 

age [3,4] and genetic background [5-7] , as well as environmental 

exposures, including dietary availability of methyl 

groups [8] , smoking [9] , and other factors. Variation in DNA 

methylation helps explain genetic diversity, which might 

mediate gene-environment interaction; mechanistically 

it might represent a key mechanism whereby changing 

environment modulates gene action. Alterations of the 

normal DNA methylation pattern, which is unique for 

each gene, have been considered an important step in 

many human diseases and been associated with all cancers 

examined to date, including CRC [2] . Promoter hypermethylation 

of many genes, associated with silencing 

(tumor suppressor genes) or activation (oncogenes) of 

downstream genes, has been linked to CRC carcinogenesis 

[10-14] . The key pathways in CRC carcinogenesis, including 

loss of cell cycle regulation control (p 16INK4α ), silencing 

of DNA mismatch repair genes (MLH1, MGMT), loss 

of function of apoptosis genes (DAPK), and abolishment 

of carcinogen metabolism (GSTP1), involve changes in 

promoter methylation [15] . Accumulating evidence suggests 

that epigenetic, including DNA methylation, abnormalities 

are a driving force of carcinogenesis [16] . Notably, a 

recent study induced cancer in Apc Min/+ mice through 

over expressing the de novo DNA methyltransferases Dnmt3a1 

and Dnmt3b1 and thereby established a direct causal 

connection between DNA hypermethylation and the development 

of colon tumors [17] . However, evidence for the 

role that these mechanisms play in human populations 

remains incomplete. Case control studies are unable to 

differentiate methylation changes associated with tumor 

susceptibility from those changes that derive solely from 

tumor progression. For this reason, prospective studies 

are needed to examine whether certain DNA methylation 

changes precede cancer development. 

Notable DNA methylation pattern changes have been 

observed in CRC tissue [18-22] , which could classify CRC 

molecular subtypes. For example, the CpG island methylator 

phenotype (panels of four to eight CpG islands) [23-26] 

has distinct pathogenic features that could have prognostic 

implications and suggest avenues for prevention 

or therapy. However to date, prospective data on DNA 

methylation and risk of incident CRC have not been reported, 

and data from non-target tissue, including leukocytes, 

are sparse. Study in mice have shown that changes 

of methylation in leukocyte DNA were parallel those 

observed in other somatic tissues [27] . Emerging data suggest 

that leukocyte DNA methylation might be linked to 

susceptibility of bladder cancer [28] , lung cancer [29] , cervical 

intraepithelial neoplasia [30] . The study of DNA methylation 

status in peripheral leukocytes in relation to CRC 

risk has mainly been conducted among hereditary nonpolyposis 

CRC patients to compare methylation status 

between tissues [31-35] . Limited epidemiological studies have 

only examined small sets of genes [36,37] in case-control 

settings. To date, no report has examined the association 

between DNA methylation and CRC risk in a prospective 

study setting. 

We conducted a nested case-control study within the 

α-tocopherol, β-carotene (ATBC) cancer prevention study 

to explore the relationship between CRC risk and genespecific 

DNA methylation from pre-diagnostic leukocytes. 

MATERIALS AND METHODS 

ATBC study 

The ATBC cancer prevention study was a double-blinded, 

placebo-controlled, 2 × 2 factorial design trial, which assessed 

the effect of ATBC, or both, on the incidence of 

cancer in male smokers [38-40] . The prospective cohort comprised 

of 29 133 Finish men, aged 50-69 years at study 

entry (1985-1988), who smoked at least 5 cigarettes per 

day. Participants were randomly assigned to groups receiving 

ATBC, both supplements, or placebo for 5-8 years until 

April 30, 1993 or death. Incident cases were identified 

through the Finnish Cancer Registry. Medical records for 

each cancer case were reviewed centrally by study physicians 

or oncologists for diagnosis confirmation. Questionnaire 

based general risk factor, education, family history, 

medical history, detailed smoking, and dietary information, 

as well as anthropometry, were collected at baseline. 

Whole blood biospecimens were collected from subjects 

close to the end of the intervention (before 1993). 

This trial was approved by the institutional review 

boards of the National Institute for Health and Welfare 

of Finland and the National Cancer Institute of USA. All 

participants provided written informed consent. 

Study subjects 

We conducted a nested case-control study within the 



ATBC study. All participants were male smokers. All the 

incident cases with colon and rectal adenocarcinomas 

(International Classification of Diseases 9, codes 153 

and 154) identified through the latest follow-up (April 

2006) that had a pre-diagnostic blood sample were included 

in this study. Controls were cancer-free subjects 

identified through April 2006, who provided a blood 

sample, were frequency matched to the cases by age at 

study entry (± 5 years), date of blood draw (± 90 d), and 

smoking intensity (± 10 cigarettes/d). Leukocyte DNA 

was extracted from pre-diagnostic buffy coat sample of 

all study subjects. 

DNA methylation assay 

For the current study, 1 μg DNA from each study subject 

was treated with the bisulfate conversion kit from Zymo Research 

(D5008) (http://www.zymoresearch.com ) to convert 

unemthylated cytosines to uracil and leave methylated ones 

intact. Bisulfite converted DNA was then genotyped using 

a commercially available chip, the Illumina GoldenGate 

Methylation Cancer Panel 1 (Appendix 3) (http://www. 

illumina.com/pages.ilmn?ID=193), to differentiate the 

methylated and unmethylated cytosine. The chip covers 

1505 CpG sites, which are located in the promoter regions 

of 807 genes reflecting a broad spectrum of carcinogenic 

processes including tumor suppressor genes, oncogenes, 

genes involved in DNA repair, cell cycle control, 

differentiation, apoptosis, X-linked, and imprinted genes. 

All of the 454 samples (224 cases and 230 controls) were 

tested in five 96 well-plate chips/ batches. Matched case 

and control samples were placed within the same batch 

in random order. Duplicates from each of 2 QC subjects 

in each of 5 batches were randomly and blindly dispersed 

among study samples in order to assess variability of the 

assay. 

Statistical analysis 

Raw data for methylated (M) alleles and unmethylated (U) 

alleles of each CpG site were exported from GenomeStudio 

Data Analysis Software (Illumina). Ten samples were 

excluded because 5% or more of the markers exceeded 

the threshold for non-specific cross-hybridization (P 

value of detection > 0.1). Then quantile normalization 

[41] was conducted on both M and U, and β values 

for each CpG site were generated for statistical analysis. 

The β value was expressed as percentage of methylated 

cytosines as follows: β = min (M, 0)/[min (U, 0) + min 

(M, 0) + 100], and was used as the proxy of methylation 

level at each CpG site. Principal component analysis was 

conducted based on overall β values of each individual to 

detect outlier individuals: the first two (principal) components, 

which explained most of the variance between individuals, 

were selected. Four samples which were outside 

the range of ± 5 SD of each principal component were 

excluded. A total of 440 subjects were eligible for the final 

analysis. 

Methylation levels for each CpG site were classified 

into tertiles according to the distribution among controls. 


Table 1 Characteristics of cases and controls n (%) 

Logistic regression was used to estimate the association 

between the risk for CRC and each CpG site. Adjustment 

for date of blood draw and smoking intensity did 

not modify the results substantially so we only included 

age as covariate among the matching factors. Batch differences 

of QC samples were non-negligible and adjustment 

for batch variable modified the results significantly. 

Therefore, we reported the results from logistic regression 

adjusted for age and batch factor. 

Taking advantage of the prospective design of the 

current study, we explored the effect of latency, which 

was defined as the difference in days between the date 

of blood draw to reported date of cancer diagnosis (for 

CRC cases). The range of latency (ranging 0-13.4 years) 

allowed us to classify cases into three categories: short 

(0-4.8 years), medium (4.9-8.9 years), and long latency 

groups (9.0-13.4 years). Proportional odds regression was 

used to estimate the association between DNA methylation 

and CRC risk by coding cases according to latency. 

In addition, another set of logistic regression analyses 

(partial logistic regression) were conducted with cases 

restricted to those having short and medium latencies. If 

we assume methylation of some CpG sites changes over 

time in relation to tumor progression, this model should 

enhance the detection of these markers by excluding subjects 

with long latency. 

To evaluate the potential false positive findings due to 

multiple testing, we adjusted the P values using a Bonferroni 

correction for the total number of all the CpG sites 

tested in the current analysis (1505 sites). All the analyses 

were conducted with SAS9.1 or R software and all the 

tests are two sided. 

RESULTS 

Controls 

(n = 219) 

Cases 

(n = 221) 

Age of randomization (mean) (yr) 58 (54-62) 58 (54-61) 0.7 

ATBC 0.33 

Placebo 62 (28) 48 (22) 

Β-carotene 56 (26) 60 (27) 

VitE 49 (22) 62 (28) 

Both 52 (24) 51 (23) 

Family history of CRC 6 (3) 6 (3) 0.98 

Smoking age (mean) (yr) 20 (17-22) 19 (17-20) 0.18 

Smoking years (mean) (yr) 36 (30-42) 37 (31-42) 0.26 

BMI (kg/m 2 ) 0.03 

< 25 80 (36) 75 (34) 

25-29.9 113 (52) 99 (45) 

≥ 30 26 (12) 47 (21) 

1 P from T-test for continuous variables or χ 2 test for categorical variables. 

CRC: Colorectal cancer; ATBC: α-tocopherol, β-carotene; BMI: Body mass 

index. 

A total of 221 CRC cases and 219 frequency matched 

controls with successful DNA methylation measurements 

were included in the current analysis. Cases and controls 


August 15, 2012|Volume 4|Issue 8| 

P 1

A 

Frequency 


Table 2 Methylation of CpG sites associated with colorectal cancer development (P value < 0.01 before multiple testing correction) 1 

Marker name 2nd tertile vs 1st tertile 3rd tertile vs 1st tertile P 2 

500 

300 

100 

0 

OR L95 U95 OR L95 U95 

DSP 1.09876 0.95772 1.26057 1.26539 1.11734 1.43306 0.000599826 

MLH3 1.04349 0.90638 1.20134 1.26606 1.0994 1.45798 0.000731318 

FLT4 1.25952 1.10631 1.43394 1.14513 0.98989 1.32473 0.00096231 

INSR 1.16236 1.01962 1.32509 1.24011 1.09317 1.40681 0.001490452 

GLA 1.37049 1.15665 1.62388 1.44612 1.19452 1.75072 0.001636963 

PTCH2 1.18022 1.03475 1.34615 1.26374 1.11417 1.43339 0.001637435 

GSTM2 1.24321 1.09656 1.40947 1.17084 1.02674 1.33516 0.001994473 

HCK 1.18573 1.04409 1.34659 1.19691 1.03199 1.38819 0.002287131 

PLAGL1 0.91619 0.80363 1.04451 0.87645 0.75745 1.01414 0.002326078 

PARP1 1.07016 0.95 1.20553 0.86663 0.75535 0.9943 0.003005978 

COL18A1 1.23987 1.08901 1.41162 1.20014 1.05351 1.36719 0.003163099 

KCNK4 1.19498 1.05273 1.35645 1.15065 1.00785 1.31368 0.003250103 

GJB2 1.16605 1.02831 1.32224 1.02785 0.89877 1.17547 0.003317356 

SEMA3F 1.16703 1.01753 1.33848 1.16456 1.01456 1.33673 0.00380004 

HBII 0.89709 0.79121 1.01713 0.86969 0.7624 0.99207 0.004064919 

SEMA3C 1.08773 0.96383 1.22756 0.87597 0.76919 0.99757 0.004352617 

MME_ 1.18426 1.04194 1.34601 1.17187 1.02959 1.3338 0.005258668 

WNT1_ 1.18575 1.02807 1.36761 1.07102 0.91035 1.26004 0.005648004 

SGCE 1.0712 0.93671 1.22501 1.22832 1.08144 1.39516 0.00629186 

PDE1B_ 1.24257 1.09182 1.41413 1.21384 1.04623 1.40831 0.008629968 

HIC1 1.16348 1.01124 1.33864 1.22483 1.06765 1.40515 0.008997589 

PODXL 1.16034 1.02143 1.31815 1.12456 0.98675 1.2816 0.009182736 

IL18BP 1.17737 1.0254 1.35188 1.07299 0.91441 1.25908 0.009206805 

DKC1 1.05822 0.92046 1.2166 1.22886 1.05463 1.43187 0.009315729 

B3GALT5 0.95137 0.83621 1.08239 1.20365 1.05804 1.3693 0.009772808 

SNRPN 0.85441 0.7514 0.97155 0.98115 0.86779 1.1093 0.00995797 

1 The markers detected here could be markers indicating susceptibility; 2 P from logistic regression model (all cases were included). 

Histogram of controls (mean) 

0.0 0.2 0.4 0.6 0.8 1.0 

Controls (mean) 

Figure 1 Histogram for data distribution. A: Means of β for all CpG sites in controls; B: SD of β for all CpG sites in controls. 

were similar with regard to age, supplement treatment, 

family history of CRC, smoking starting age, and smoking 

duration (years) (Table 1). Cases had relatively higher 

body mass index than controls. The median age of cancer 

diagnosis of cases was 69.5 years old, which is over 

10 years after study entry (median = 58 years old). The 

histograms (Figure 1) show the data distribution of β 

values for all CpG sites in controls, suggesting most CpG 

sites in controls were unmethylated. 

In analysis comparing all cases to all controls using 

logistic regression model, the CpG sites with differential 

methylation are candidate sites potentially related to susceptibility. 

Of the 1505 CpG sites analyzed, 25 sites were 

B 

Frequency 

600 

400 

200 

0 

Histogram of controls (SD) 

0.0 0.1 0.2 0.3 0.4 

Controls (SD) 

associated with CRC risk at P < 0.01 level and are shown 

in Table 2. None of these 25 sites exceeded a Bonferroni 

threshold for significance (threshold is 3.3 × 10 -5 for 1500 

tests). However, the most statistically significant CpG site 

associated with risk was DSP_P440_R (P = 6.0 × 10 -4 ) 

with the second tertile displaying a 1.01-fold risk (95% 

CI: 0.96-1.26) and the third tertile displaying a 1.26-fold 

risk (95% CI: 1.12-1.43) comparing with the lowest tertile 

of methylation. 

To capture markers whose status changed over time 

(potentially reflecting tumor progression), we incorporated 

the time variable, latency, in analysis using proportional 

odds regression by coding the cases as three 



Table 3 Methylation of CpG sites related to colorectal cancer development with different latencies (P value < 0.01 before multiple 

testing correction) 1 


OR L95 U95 OR L95 U95 

DSP 1.52027 0.91054 2.53831 2.62423 1.65105 4.17103 0.000104474 

PTCH2 1.86565 1.14946 3.02807 2.55851 1.60114 4.08832 0.000327688 

GLA 3.22896 1.66054 6.27879 3.62345 1.70627 7.69478 0.000529374 

FLT4 2.49882 1.55051 4.02713 1.7312 1.02958 2.91095 0.000651567 

B3GALT5 0.91735 0.5746 1.46454 2.11128 1.31709 3.38434 0.000726807 

INSR 1.88977 1.16281 3.07122 2.44371 1.52713 3.91043 0.0007899 

GSTM2 2.29464 1.44903 3.63373 1.92103 1.18011 3.12712 0.001165928 

FASTK 1.66117 1.02457 2.69331 2.26999 1.43313 3.59553 0.001992703 

MLH3 1.12063 0.67503 1.86036 2.15187 1.31098 3.53213 0.002175877 

HOXC6 1.2189 0.75795 1.96015 2.06861 1.32056 3.24043 0.002826542 

MGMT 2.42747 1.34114 4.39373 2.71599 1.45027 5.08638 0.00448402 

SYBL1 1.35661 0.89446 2.05754 0.63927 0.39971 1.02239 0.004618893 

PDE1B 2.12203 1.33959 3.36151 1.74663 1.01704 2.9996 0.004839975 

SEMA3C 1.34045 0.87915 2.04378 0.62126 0.38566 1.0008 0.004858838 

AFF3 2.11473 1.30773 3.41973 1.88147 1.16588 3.03628 0.005422481 

HCK 2.0406 1.27766 3.25911 2.0338 1.19416 3.46382 0.005503 

PXN 1.92122 1.24421 2.9666 1.12493 0.66824 1.89374 0.005766585 

PARP1 1.19708 0.79209 1.80913 0.55056 0.33191 0.91323 0.006004429 

TK1 1.83172 1.07512 3.12075 2.24792 1.34064 3.76922 0.006184503 

SGCE 1.21217 0.74619 1.96916 1.9685 1.25257 3.09363 0.006354949 

MME 2.00858 1.25423 3.21663 1.94042 1.20308 3.12967 0.00664085 

RARA 1.51526 0.94405 2.43209 2.07639 1.31635 3.27525 0.006899358 

COL18A1 2.08647 1.28893 3.37752 1.90316 1.17926 3.07144 0.007110996 

SEMA3F 1.98588 1.21715 3.24014 2.03976 1.22672 3.39166 0.007292652 

ITGB4 2.08685 1.2669 3.43748 2.02919 1.20223 3.42495 0.007595246 

PTPRH 0.47922 0.30082 0.76343 0.71909 0.44823 1.15361 0.007598903 

SMO 1.52188 0.95276 2.43094 2.08604 1.3032 3.33915 0.008280298 

DKC1 1.25326 0.76383 2.05632 2.20393 1.27785 3.80116 0.008427231 

TRPM5 2.22962 1.33245 3.73087 1.80604 1.01389 3.21707 0.008971559 

EVI1 1.62829 1.01415 2.61431 2.08373 1.29638 3.34927 0.009481166 

EPHA3 1.93252 1.21576 3.07185 1.85827 1.15814 2.98165 0.009792546 

1 Latency: according to the time difference between blood draw and cancer diagnosis, cases were classified to three categories-short, medium, and long 

latency; 2 P from proportional odds regression model (all cases were included). 

categories according to latency. Of the 1505 CpG sites 

analyzed, 31 sites were associated with CRC risk at P 

< 0.01 level (Table 3). Though none of these 31 sites 

remained statistically significant after Bonferroni correction, 

the most statistically significant CpG site associated 

with CRC risk achieved a P value of 1.0 × 10 -4 . The CpG 

site is located in DSP gene, and the risk estimate was 1.52 

(95% CI: 0.91-2.53) and 2.62 (95% CI: 1.65-4.17) for the 

second and third tertile comparing with the lowest tertile 

respectively. 

To further explore the time-related DNA methylation 

change, we conducted partial logistic regression analysis 

by excluding the one third of the cases with the longest 

latency, and only comparing cases with short and medium 

latency to controls. In this analysis, 26 sites were associated 

with CRC risk at P < 0.01 level (Table 4). None 

of them remain statistically significant after Bonferroni 

correction. GLA_E98_R was the top hit with over 30% 

elevated risk (P = 1.3 × 10 -4 ) for subjects with highest 

methylation level compared to those at the lower level. 

As stated in methods, changes in methylation of 

CpG sites over time, can suggest a relationship to tumor 

progression; models incorporating time/latency informa- 


tion (the proportional odds model and the partial logistic 

regression model) are designed to detect such a pattern. 

The regular logistic regression model comparing all cases 

to all controls should select all risk-associated markers. 

These include both susceptibility-related markers (which 

differ between cases and controls and do not change over 

time), as well as progression-related, (which change over 

time with tumor progression). To differentiate the CpG 

sites whose methylation levels are susceptibility related 

from those that are potentially tumor progression- related, 

we compared the top CpG sites selected from the 

three models (full logistic regression, proportional odds, 

and partial logistic regression). We found that methylation 

levels of some CpG sites, like those in the DSP 

gene, were consistently associated with CRC risk across 

three models, suggesting these associations were unaltered 

by time prior to diagnosis, or tumor progression; 

the available evidence therefore suggests that they are 

related to cancer predisposition. On the other hand, the 

methylation levels of some other sites, such as B3GALT5 

and GLA genes, were associated with CRC risk at lower 

p values in analysis from models incorporating latency 

information than from standard model (the all logistic re- 




Table 4 Methylation of CpG sites associated with colorectal cancer with short to mediate latency (P value < 0.01 before multiple 

testing correction) 1 


gression model); the time/latency pattern observed suggests 

that the markers are tumor progression- related. 

DISCUSSION 

OR L95 U95 OR L95 U95 

GLA 1.31618 1.12303 1.54256 1.31082 1.09072 1.57534 0.000126734 

DSP 1.12406 0.9868 1.2804 1.25115 1.11146 1.4084 0.000305565 

B3GALT5 1.00109 0.88664 1.1303 1.18931 1.05066 1.34625 0.001334159 

MLH3 1.01719 0.89178 1.16025 1.2404 1.08916 1.41263 0.001421327 

PTCH2 1.18044 1.04387 1.33487 1.24209 1.1026 1.39922 0.002140961 

FLT4 1.26038 1.1159 1.42356 1.15518 1.01153 1.31924 0.002164413 

SGCE 1.05149 0.92678 1.19299 1.19126 1.05786 1.34148 0.002535873 

HOXC6 1.02303 0.90426 1.15741 1.16253 1.03342 1.30777 0.002602644 

PDE1B 1.19845 1.06385 1.35009 1.10584 0.96046 1.27323 0.002706305 

COL18A1 1.2126 1.07142 1.37239 1.19961 1.06058 1.35687 0.002968143 

TRPM5 1.16951 1.02324 1.3367 1.10173 0.94879 1.27933 0.003084609 

EVI1 1.06179 0.93967 1.19979 0.94512 0.8274 1.07959 0.003902443 

GSTM2 1.24009 1.10312 1.39407 1.13952 1.0059 1.29089 0.003956314 

FASTK 1.12763 0.99513 1.27778 1.17539 1.04318 1.32436 0.004798386 

PARP1 1.08475 0.97053 1.2124 0.87907 0.77119 1.00203 0.005028903 

PTGS2 1.03008 0.91145 1.16415 1.15319 1.02574 1.29648 0.00571389 

WRN 0.97839 0.8614 1.11128 1.09867 0.96629 1.24918 0.005779497 

EPO 1.14731 1.01334 1.299 1.13034 0.9854 1.2966 0.006090622 

GPC3 1.19056 1.03981 1.36316 1.09698 0.94341 1.27556 0.006093671 

TK1 1.13458 0.98846 1.30232 1.20862 1.05753 1.3813 0.006272625 

EVI1 1.14882 1.01559 1.29953 1.17851 1.04142 1.33364 0.006474115 

EPHB2 1.15596 1.02875 1.2989 1.05233 0.92701 1.19459 0.006504075 

SEMA3C 1.10197 0.98427 1.23375 0.89579 0.7921 1.01304 0.00677389 

HLA_DPA1 1.14664 1.00965 1.30223 1.09326 0.95971 1.24538 0.006960326 

SYBL1 1.06835 0.9547 1.19553 0.90635 0.80226 1.02394 0.007029222 

INSR 1.19021 1.05214 1.34639 1.25474 1.11332 1.41412 0.008045993 

1 The logistic regression analysis only includes cases with short and medium latency; 2 P from proportional odds regression model (all 

cases were included). 

In our study, more than 1500 CpG sites from 807 genes 

were evaluated among 440 study subjects, which is the 

first prospective study for CRC risk focusing on genespecific 

DNA methylation to date. By comparing all the 

cases with all the controls, we found that the methylation 

levels of some CpG sites were associated with CRC risk. 

The methylation of these genes might be related to CRC 

susceptibility. By incorporating latency information in 

the analysis, we found some associations between DNA 

methylation and CRC risk were latency-related, suggesting 

the methylation in these genes altered with tumor 

progression. However, these results are cross-sectional, 

and further studies with repeated blood draws from the 

same subjects are needed to refine the temporal pattern 

prior to cancer diagnosis among same individuals. 

Following the report from Feinberg and colleagues 

that colon cancer cells had different DNA methylation 

patterns in some genes compared to their normal counterparts 

[42] , many studies have been conducted using colon 

cancer as a cancer model for methylation regulation 

in the past three decades. Methylation in several genes 

had been reported to be involved in the pathogenesis 

of colorectal precursor lesions and adenomas, as well as 

adenocarcinomas [43] . However, epidemiological studies to 

date have only tested limited sets of CpG sites in small 

numbers of subjects [36,44,45] . The reported associations require 

confirmation and methylation levels of other genes 

remained to be described. Although further replication is 

needed, our study is among the most comprehensive and 

large studies. 

Epigenetic regulation of gene expression is specific 

for each cell type, within different tissues, according to 

stages of development or differentiation [11,46] . Most studies 

of DNA methylation in CRC have been conducted 

by comparing tumor tissue DNA with adjacent normal 

tissue DNA from cancer patients [47] . Circulating DNA 

from serum also has been studied [48-50] , although this 

might reflect methylation status in DNA released from 

tumor tissue, and could be influenced by tumor volume, 

vascularity, stage, grade, metastasis, et al. Methylation 

patterns from other DNA sources have only had fragmentary 

study [36,51] . Selected epigenetic markers could be 

heritable from one generation to the next [52] , or affected 

by aging or environmental exposures throughout life [53] . 

It is reasonable to hypothesize that DNA methylation 

status in some genes is associated with cancer susceptibility. 

Therefore, methylation patterns of germline tissue, 

including that derived from blood leukocyte DNA might 

be related to cancer risk. Changes of methylation in leu- 



kocyte DNA have been shown to parallel other somatic 

tissues in mice [27] , and have been linked to susceptibility 

of certain cancers [28] . Certainly, we could not rule out the 

possibility that different tissues have different response 

to environmental exposure and that methylation status 

in leukocytes may not fully reflect the changes in the target 

tissue [27] . In the current study, we found methylation 

levels of some genes, like DSP, were consistently associated 

with CRC risk across all three models, suggesting a 

relationship to cancer risk that is invariant over time, that 

is unaffected by tumor progression. We recognize that 

the procedure that favor tumor initiation and progression 

may have both similar (as we observed) and independent 

elements and specifically targeted populations will be 

required to explore the later hypothesis in future studies. 

Though further confirmation is required, our results 

provide some evidence that DNA methylation of some 

genes could be related to cancer susceptibility. 

Aberrantly increased DNA methylation in the promoter 

region of hMLH1 gene in germline DNA has 

been reported among nonpolyposis CRC patients [32-35] . 

Hypermethylation in the MSH2 gene of germline DNA 

was also observed among early onset CRC patients [31] . 

Interestingly, the inverse relationship between leukocyte 

DNA genomic methylation and colorectal adenoma 

progression was found stronger for nonadvanced rather 

than advanced adenoma in a case-control study, which 

suggests that leukocyte DNA genomic methylation may 

be more important as an etiologic factor in early adenomas 

[54] . All these data suggest that the methylation levels 

of some genes either increase or decrease over time with 

tumor progression. Though further studies are required 

to replicate and confirm, our results suggest that methylation 

levels of some genes, i.e., GLA, B3GALT5, et al, 

could be markers of tumor progression, and methylation 

levels of some genes, i.e., DSP et al, were more likely 

markers of susceptibility. Also, some genes whose methylation 

levels were positively associated with CRC risk, i.e., 

DSP, MLH3, et al, suggest they might be tumor suppressing-like 

genes, and those showed negative association, i.e., 

PLAL1, et al, might be oncogenic-like genes. 

Our study has several advantages. First, it is nested 

within the ATBC cohort, which offers a substantial, 

representative, well characterized, and relatively homogeneous 

population of male smokers. Second, data on 

cancer diagnoses and key covariates were systematically 

collected. Third, this is the first prospective populationbased 

study to explore the role of gene-specific DNA 

methylation in colorectal carcinogenesis with a large number 

of CpG sites. DNA obtained from blood samples at 

baseline allows us to assess methylation status prior to 

cancer diagnosis, and explore the latency effect on the 

associations. Although to our knowledge the sample size 

is among the largest reported to date, variations of DNA 

methylation in leukocytes are less prominent than those 

observed in colorectal tissue/tumor comparisons; thus 

we had limited power to detect markers with moderate 

and small effect sizes. Another limitation is that this study 


is restricted to male Finnish smokers. The advantage of 

homogeneity implies the limitation that the results are not 

entirely generalizable to other populations. Furthermore, 

we only have one blood draw from each subject, which 

limits our power to precisely explore the direct effect of 

latency on the association between DNA methylation and 

cancer risk. 

In summary, the results from this prospective study 

suggest that the methylation level of some genes were associated 

with cancer susceptibility and some were related 

with tumor progression. Further studies are warranted to 

confirm and refine our results. 


The authors thank Tim Sheehy and Dominick Parisi for 

sample preparation, and Kirk Snyder, Information Management 

Services, Silver Spring, MD, for data management. 

Finally, we acknowledge the study participants for 

donating their time and making this study possible. 

COMMENTS 

Background 

Recent data suggest a link between leukocyte DNA methylation and cancer 

risk. However, data on DNA methylation from a prospective study, which may 

provide evidence for causality, are sparse. 

Research frontiers 

Results may provide new insights into the etiology of colorectal cancer (CRC) 

and suggest new cancer prevention strategies. 

Innovations and breakthroughs 

Data on DNA methylation from a prospective study, which could provide causality 

evidence, are missing. This is among the first prospective studies to examine 

gene-specific methylation status in germ-line DNA prior to CRC diagnosis. 

Applications 

Results may provide new insights into the etiology of CRC and suggest new 

cancer prevention strategies. The approach we propose, methylation profiling of 

PBMC DNA from prospectively obtained samples and its relation to CRC risk, 

should be relevant to other cancers. 

Terminology 

Methylation: Methylation is the covalent addition of a methyl group to cytosine 

residue, which is an epigenetic event that affects cell function by altering gene 

expression. Prospective study: Prospective study follows over time a group of 

similar individuals who differ with respect to certain factors under study, to determine 

how these factors affect rates of a certain disease. 

Peer review 

The comparison was made between ca. 200 pairs, thus small case-control 

study with comprehensive methylation pattern. There were no sites where 

methylation differences survived Bonferroni threshold of significance. Timedependent 

DNA methylation was suspected, but no cases gave DNA at different 

times. However, the design is ambitious and the results are potentially 

important. 

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Christiani DC. Correlation of global and gene-specific DNA 

methylation in maternal-infant pairs. PLoS One 2010; 5: 

e13730 

53 Christensen BC, Houseman EA, Marsit CJ, Zheng S, 

Wrensch MR, Wiemels JL, Nelson HH, Karagas MR, Padbury 

JF, Bueno R, Sugarbaker DJ, Yeh RF, Wiencke JK, 

Kelsey KT. Aging and environmental exposures alter tissuespecific 

DNA methylation dependent upon CpG island context. 

PLoS Genet 2009; 5: e1000602 

54 Lim U, Flood A, Choi SW, Albanes D, Cross AJ, Schatzkin 

A, Sinha R, Katki HA, Cash B, Schoenfeld P, Stolzenberg- 

Solomon R. Genomic methylation of leukocyte DNA in relation 

to colorectal adenoma among asymptomatic women. 

Gastroenterology 2008; 134: 47-55 

S- Editor Wang JL L- Editor A E- Editor Zheng XM 






World J Gastrointest Oncol 2012 August 15; 4(8): I 




Acknowledgments to reviewers of World Journal of 

Gastrointestinal Oncology 

We acknowledge our sincere thanks to our reviewers. Many 

reviewers have contributed their expertise and time to the 

peer review, a critical process to ensure the quality of our 

World Series Journals. Both the editors of the journals and 

authors of the manuscripts submitted to the journals are 

grateful to the following reviewers for reviewing the articles 

(either published or rejected) over the past period of time. 

Vedat Goral, Professor, Department of Gastroenterology, Dicle 

University, School of Medicine, Diyarbakir 21280, Turkey 

John Griniatsos, MD, Assistant Professor, Department of Surgery, 

University of Athens, Medical School, 1st LAIKO Hospital, 17 Agiou 

Thoma str, GR 115-27, Athens, Greece 

Jian-Kun Hu, MD, PhD, Associate Professor, Department of 

Gastrointestinal Surgery, West China Hospital, Sichuan University, 

Chengdu 610041, Sichuan Province, China 

Peter JK Kuppen, PhD, Associate Professor, Department of Surgery, 

Leiden University Medical Center, 2300 RC Leiden, Netherlands 

Yu-Min Li, PhD, Professor, Second Hospital of Lanzhou University, 

Lanzhou 730030, Gansu Province, China 

Antonio Macrì, Associate Professor, Department of Human Pathology, 

General Surgery Unit, University of Messina, Via Consolare Valeria, 

98125 Messina, Italy 

Simon Ng, Professor, Division of Colorectal Surgery, Department of 

Surgery, University of Hong Kong; Department of Surgery, Prince of 

Wales Hospital, Shatin, Room 64045, 4/F, Clinical Sciences Building, 

Hong Kong, China 

Vittorio Ricci, MD, PhD, Associate Professor, Director, Laboratory 

of Cellular and Molecular Gastroenterology, Department of Physiology, 

Human Physiology Section, University of Pavia Medical School, Via 

Forlanini 6, 27100 Pavia, Italy 

Paul M Schneider, MD, Professor, Department of Surgery, University 

Hospital Zurich, Raemistrasse 100, Zurich 8008, Switzerland 

Masao Seto, MD, PhD, Division of Molecular Medicine, Aichi Cancer 

Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi 

464-8681, Japan 

Jaw Yuan Wang, Professor, MD, PhD, Department of Surgery, 

Kaohsiung Medical University and Hospital, 100, Tzyou 1st Road, 

Kaohsiung 807, Taiwan, China 

Imtiaz Ahmed Wani, MD, Amira Kadal, Srinagar, Kashmir 190009, 

India 

Yo-ichi Yamashita, MD, PhD, Department of Surgery, Hiroshima 

Red Cross Hospital and Atomic Bomb Survivors Hospital, Senda-machi 

1-9-6, Naka-ku, Hiroshima 730-8619, Japan 

WJGO|www.wjgnet.com I August 15, 2012|Volume 4|Issue 8|




Events Calendar 2012 

January 14-17, 2012 

10th Oncology Controversies and 

Advances Update 

Steamboat Springs, 

CO, United States 

January 19-21, 2012 

EASL Monothematic Conference: 

IMLI - Immune Mediated Liver 

Injury 

Birmingham, United Kingdom 

January 19-21, 2012 

American Society of Clinical 

Oncology 2012 Gastrointestinal 

Cancers Symposium 

San Francisco, CA, United States 

January 19-21, 2012 

2012 Gastrointestinal Cancers 

Symposium 


January 20-21, 2012 

American Gastroenterological 

Association Clinical Congress of 

Gastroenterology and Hepatology 

Miami Beach, FL, United States 

February 2-4, 2012 

2012 Genitourinary Cancers 

Symposium 


February 6-8, 2012 

Pediatric Cancer Translational 

Genomics 

Phoenix, AZ, United States 

February 8–10, 2012 

The 84th Annual Meeting of Japanese 

Gastric Cancer Association 

Osaka, Japan 

February 10-11, 2012 

Cancer Survivorship for Clinicians 

Seattle, WA, United States 

February 14-17, 2012 

ASCO Multidisciplinary Cancer 

Management Course 

Eldoret, Kenya 

February 20-24, 2012 

Word Conference on Colorectal 

Cancer 

FL, United States 

February 22-23, 2012 

National Cancer Institute Annual 

Biospecimen Research Network 

Symposium: “Advancing Cancer 

Research Through Biospecimen 

Science” 

Bethesda, MD, United States 

February 22-25, 2012 

30th German Cancer Congress 

Berlin, Germany 

February 24, 2012 

ASCO-German Cancer Society 

Joint Symposium, German Cancer 

Congress 


February 24-27, 2012 

Canadian Digestive Diseases Week 

2012 

Montreal, Canada 

March 7-8, 2012 

First International Gulf Joint 

Conference: Management of colon, 

breast, and lung cancer (Joint 

Symposium) 

Dammam, Saudi Arabia 

March 9-10, 2012 

ESMO Conference on Sarcoma and 

GIST 

Milan, Italy 

March 10-11, 2012 

Colorectal Polyps and Cancers: A 

Multidisciplinary Approach 

Scottsdale, AZ, United States 


March 17-21, 2012 

Methods in Cancer Research 

Workshop (Advanced Cancer 

Course) 

Al Asha, Saudi Arabia 

March 22-24, 2012 

The 1st St.Gallen EORTC 

Gastrointestinal Cancer Conference 

St.Gallen, Switzerland 

April 13-15, 2012 

Asian Oncology Summit 2012 

Singapore, Singapore 

April 15-17, 2012 

European Multidisciplinary 

Colorectal Cancer Congress 2012 

Prague, Czech 

April 18-20, 2012 

The International Liver Congress 

2012 

Barcelona, Spain 

April 19-21, 2012 

Internal Medicine 2012 

New Orleans, LA, United States 

April 20–21, 2012 

OOTR 8th Annual Conference - 

Organisation for Oncology and 

Translational Research 

Kyoto, Japan 

April 28, 2012 

Issues in Pediatric Oncology 

Kiev, Ukraine 

May 19-22, 2012 

Digestive Disease Week 2012 

San Diego, CA, United States 

June 18-21, 2012 

Pancreatic Cancer: Progress and 

Challenges 

Lake Tahoe, NV, United States 

June 27-30, 2012 

ESMO 14th World Congress on 

World J Gastrointest Oncol 2012 August 15; 4(8): I 



MEETINGS 

Gastrointestinal Cancer 2012 

International Convention Center Of 

Barcelona, 

Barcelona, Italy 

July 1–5, 2012 

10th World Congress of the 

International Hepato-Pancreato- 

Biliary Association 

Paris, France 

July 5-7, 2012 

International Research Conference 

on Liver Cancer 

Heidelberg, Germany 

July 6-8, 2012 

The 3rd Asia – Pacific Primary Liver 

Cancer Expert Meeting “A Bridge to 

a Consensus on HCC Management” 

Shanghai, China 

September 1-4, 2012 

OESO 11th World Conference 

Como, Italy 


ILCA 2012 - Sixth Annual Conference 

of the International Liver Cancer 

Association 



Research Symposium, Inflammation 

and Cancer 

Houston, TX, United States 

October 15 - 17 2012 

13th World Congress of the 

International Society for Diseases of 

the Esophagus 

Venice, Italy 

December 5-8, 2012 

22nd World Congress of the 

International Association of 

Surgeons, Gastroenterologists and 

Oncologists 

Bangkok, Thailand 





GENERAL INFORMATION 

World Journal of Gastrointestinal Oncology (World J Gastrointest Oncol, 

WJGO, ISSN 1948-5204, DOI: 10.4251), is a monthly, open-access 

(OA), peer-reviewed journal supported by an editorial board of 404 

experts in gastrointestinal oncology from 41 countries. 

The biggest advantage of the OA model is that it provides free, 

full-text articles in PDF and other formats for experts and the public 

without registration, which eliminates the obstacle that traditional 

journals possess and usually delays the speed of the propagation and 

communication of scientific research results. The open access model 

has been proven to be a true approach that may achieve the ultimate 

goal of the journals, i.e. the maximization of the value to the readers, 

authors and society. 

Maximization of personal benefits 

The role of academic journals is to exhibit the scientific levels of 

a country, a university, a center, a department, and even a scientist, 

and build an important bridge for communication between scientists 

and the public. As we all know, the significance of the publication 

of scientific articles lies not only in disseminating and communicating 

innovative scientific achievements and academic views, as well 

as promoting the application of scientific achievements, but also in 

formally recognizing the "priority" and "copyright" of innovative 

achievements published, as well as evaluating research performance 

and academic levels. So, to realize these desired attributes of WJGO 

and create a well-recognized journal, the following four types of personal 

benefits should be maximized. The maximization of personal 

benefits refers to the pursuit of the maximum personal benefits in a 

well-considered optimal manner without violation of the laws, ethical 

rules and the benefits of others. (1) Maximization of the benefits of 

editorial board members: The primary task of editorial board members 

is to give a peer review of an unpublished scientific article via online 

office system to evaluate its innovativeness, scientific and practical 

values and determine whether it should be published or not. During 

peer review, editorial board members can also obtain cutting-edge 

information in that field at first hand. As leaders in their field, they 

have priority to be invited to write articles and publish commentary 

articles. We will put peer reviewers’ names and affiliations along with 

the article they reviewed in the journal to acknowledge their contribution; 

(2) Maximization of the benefits of authors: Since WJGO is an 

OA journal, readers around the world can immediately download and 

read, free of charge, high-quality, peer-reviewed articles from WJGO 

official website, thereby realizing the goals and significance of the 

communication between authors and peers as well as public reading; 

(3) Maximization of the benefits of readers: Readers can read or use, 

free of charge, high-quality peer-reviewed articles without any limits, 

and cite the arguments, viewpoints, concepts, theories, methods, 

results, conclusion or facts and data of pertinent literature so as to 

validate the innovativeness, scientific and practical values of their own 

research achievements, thus ensuring that their articles have novel 

arguments or viewpoints, solid evidence and correct conclusion; and 

(4) Maximization of the benefits of employees: It is an iron law that a 

first-class journal is unable to exist without first-class editors, and only 

first-class editors can create a first-class academic journal. We insist 

on strengthening our team cultivation and construction so that every 

employee, in an open, fair and transparent environment, could contribute 

their wisdom to edit and publish high-quality articles, thereby 

realizing the maximization of the personal benefits of editorial board 

members, authors and readers, and yielding the greatest social and 

economic benefits. 

Aims and scope 

The major task of WJGO is to report rapidly the most recent advances 

in basic and clinical research on gastrointestinal oncology. The 

topics of WJGO cover the carcinogenesis, tumorigenesis, metastasis, 

diagnosis, prevention, prognosis, clinical manifestations, nutritional 

support, molecular mechanisms, and therapy of benign and malignant 

tumors of the digestive tract. This cover epidemiology, etiology, immunology, 

molecular oncology, cytology, pathology, genetics, genomics, 

proteomics, pharmacology, pharmacokinetics, nutrition, diagnosis 

and therapeutics. This journal will also provide extensive and timely 

review articles on oncology. 

Columns 

The columns in the issues of WJGO will include: (1) Editorial: To 

introduce and comment on major advances and developments in the 

field; (2) Frontier: To review representative achievements, comment 

on the state of current research, and propose directions for future 

research; (3) Topic Highlight: This column consists of three formats, 

including (A) 10 invited review articles on a hot topic, (B) a commentary 

on common issues of this hot topic, and (C) a commentary on 

the 10 individual articles; (4) Observation: To update the development 

of old and new questions, highlight unsolved problems, and provide 

strategies on how to solve the questions; (5) Guidelines for Basic 

Research: To provide guidelines for basic research; (6) Guidelines for 

Clinical Practice: To provide guidelines for clinical diagnosis and treatment; 

(7) Review: To review systemically progress and unresolved 

problems in the field, comment on the state of current research, and 

make suggestions for future work; (8) Original Articles: To report innovative 

and original findings in gastrointestinal oncology; (9) Brief 

Articles: To briefly report the novel and innovative findings in cardiology; 

(10) Case Report: To report a rare or typical case; (11) Letters to 

the Editor: To discuss and make reply to the contributions published 

in WJGO, or to introduce and comment on a controversial issue of 

general interest; (12) Book Reviews: To introduce and comment on 

quality monographs of gastrointestinal oncology; and (13) Guidelines: 

To introduce consensuses and guidelines reached by international and 

national academic authorities worldwide on the research in gastrointestinal 

oncology. 

Name of journal 


ISSN 


World J Gastrointest Oncol 2012 August 15; 4(8): I-V 



INSTRUCTIONS TO AUTHORS 

Editorial-in-Chief 

Wasaburo Koizumi, MD, PhD, Professor, Chairman, Department 

of Gastroenterology, Gastrointestinal Oncology, School of Medicine, 

Kitasato University, 2-1-1 Asamizodai Minamiku Sagamihara Kanagawa 

252-0380, Japan 

Hsin-Chen Lee, PhD, Professor, Institute of Pharmacology, School 

of Medicine, National Yang-Ming University, Taipei, 112, Taiwan, 

China 

Dimitrios H Roukos, MD, PhD, Professor, Personalized Cancer 



Instructions to authors 

Genomic Medicine, Human Cancer Biobank Center, Ioannina University, 

Metabatiko Ktirio Panepistimiou Ioanninon, Office 229, Ioannina, 

TK 45110, Greece 

Editorial Office 


Editorial Department: Room 903, Building D, 

Ocean International Center, 

No. 62 Dongsihuan Zhonglu, 

Chaoyang District, Beijing 100025, China 



Telephone: +86-10-85381891 

Fax: +86-10-85381893 

Indexing/abstracting 

PubMed Central, PubMed, Digital Object Identifier, and Directory 

of Open Access Journals. 

Published by 

Baishideng Publishing Group Co., Limited 

SPECIAL STATEMENT 

All articles published in this journal represent the viewpoints of the 

authors except where indicated otherwise. 

Biostatistical editing 

Statisital review is performed after peer review. We invite an expert 

in Biomedical Statistics to evaluate the statistical method used in the 

paper, including t-test (group or paired comparisons), chi-squared 

test, Ridit, probit, logit, regression (linear, curvilinear, or stepwise), 

correlation, analysis of variance, analysis of covariance, etc. The reviewing 

points include: (1) Statistical methods should be described 

when they are used to verify the results; (2) Whether the statistical 

techniques are suitable or correct; (3) Only homogeneous data can be 

averaged. Standard deviations are preferred to standard errors. Give 

the number of observations and subjects (n). Losses in observations, 

such as drop-outs from the study should be reported; (4) Values such 

as ED50, LD50, IC50 should have their 95% confidence limits calculated 

and compared by weighted probit analysis (Bliss and Finney); 

and (5) The word ‘significantly’ should be replaced by its synonyms (if 

it indicates extent) or the P value (if it indicates statistical significance). 

Conflict-of-interest statement 

In the interests of transparency and to help reviewers assess any potential 

bias, WJGO requires authors of all papers to declare any competing 

commercial, personal, political, intellectual, or religious interests 

in relation to the submitted work. Referees are also asked to indicate 

any potential conflict they might have reviewing a particular 

paper. Before submitting, authors are suggested to read “Uniform 

Requirements for Manuscripts Submitted to Biomedical Journals: 

Ethical Considerations in the Conduct and Reporting of Research: 

Conflicts of Interest” from International Committee of Medical 

Journal Editors (ICMJE), which is available at: http://www.icmje. 

org/ethical_4conflicts.html. 

Sample wording: [Name of individual] has received fees for serving 

as a speaker, a consultant and an advisory board member for [names 

of organizations], and has received research funding from [names of 

organization]. [Name of individual] is an employee of [name of organization]. 

[Name of individual] owns stocks and shares in [name of 

organization]. [Name of individual] owns patent [patent identification 

and brief description]. 

Statement of informed consent 

Manuscripts should contain a statement to the effect that all human 

studies have been reviewed by the appropriate ethics committee or it 

should be stated clearly in the text that all persons gave their informed 

consent prior to their inclusion in the study. Details that might disclose 

the identity of the subjects under study should be omitted. Au- 

thors should also draw attention to the Code of Ethics of the World 

Medical Association (Declaration of Helsinki, 1964, as revised in 

2004). 

Statement of human and animal rights 

When reporting the results from experiments, authors should follow 

the highest standards and the trial should conform to Good Clinical 

Practice (for example, US Food and Drug Administration Good Clinical 

Practice in FDA-Regulated Clinical Trials; UK Medicines Research 

Council Guidelines for Good Clinical Practice in Clinical Trials) and/ 

or the World Medical Association Declaration of Helsinki. Generally, 

we suggest authors follow the lead investigator’s national standard. If 

doubt exists whether the research was conducted in accordance with 

the above standards, the authors must explain the rationale for their 

approach and demonstrate that the institutional review body explicitly 

approved the doubtful aspects of the study. 

Before submitting, authors should make their study approved by 

the relevant research ethics committee or institutional review board. 

If human participants were involved, manuscripts must be accompanied 

by a statement that the experiments were undertaken with the 

understanding and appropriate informed consent of each. Any personal 

item or information will not be published without explicit consents 

from the involved patients. If experimental animals were used, 

the materials and methods (experimental procedures) section must 

clearly indicate that appropriate measures were taken to minimize 

pain or discomfort, and details of animal care should be provided. 

SUBMISSION OF MANUSCRIPTS 

Manuscripts should be typed in 1.5 line spacing and 12 pt. Book 

Antiqua with ample margins. Number all pages consecutively, and 

start each of the following sections on a new page: Title Page, Abstract, 

Introduction, Materials and Methods, Results, Discussion, 

Acknowledgements, References, Tables, Figures, and Figure Legends. 

Neither the editors nor the publisher are responsible for the 

opinions expressed by contributors. Manuscripts formally accepted 

for publication become the permanent property of Baishideng 

Publishing Group Co., Limited, and may not be reproduced by any 

means, in whole or in part, without the written permission of both 

the authors and the publisher. We reserve the right to copy-edit and 

put onto our website accepted manuscripts. Authors should follow 

the relevant guidelines for the care and use of laboratory animals of 

their institution or national animal welfare committee. For the sake of 

transparency in regard to the performance and reporting of clinical 

trials, we endorse the policy of the ICMJE to refuse to publish papers 

on clinical trial results if the trial was not recorded in a publiclyaccessible 

registry at its outset. The only register now available, to our 

knowledge, is http://www.clinicaltrials.gov sponsored by the United 

States National Library of Medicine and we encourage all potential 

contributors to register with it. However, in the case that other registers 

become available you will be duly notified. A letter of recommendation 

from each author’s organization should be provided with 

the contributed article to ensure the privacy and secrecy of research is 

protected. 

Authors should retain one copy of the text, tables, photographs 

and illustrations because rejected manuscripts will not be returned to 

the author(s) and the editors will not be responsible for loss or damage 

to photographs and illustrations sustained during mailing. 

Online submissions 

Manuscripts should be submitted through the Online Submission 

System at: http://www.wjgnet.com/esps/. Authors are 

highly recommended to consult the ONLINE INSTRUC- 

TIONS TO AUTHORS (http://www.wjgnet.com/1948-5204/ 

g_info_20100312180518.htm) before attempting to submit online. For 

assistance, authors encountering problems with the Online Submission 

System may send an email describing the problem to wjgo@ 

wjgnet.com, or by telephone: +86-10-85381891. If you submit your 

manuscript online, do not make a postal contribution. Repeated online 

submission for the same manuscript is strictly prohibited. 

WJGO|www.wjgnet.com II August 15, 2012|Volume 4|Issue 8|

MANUSCRIPT PREPARATION 

All contributions should be written in English. All articles must be 

submitted using word-processing software. All submissions must be 

typed in 1.5 line spacing and 12 pt. Book Antiqua with ample margins. 

Style should conform to our house format. Required information for 

each of the manuscript sections is as follows: 

Title page 

Title: Title should be less than 12 words. 

Running title: A short running title of less than 6 words should be 

provided. 

Authorship: Authorship credit should be in accordance with the 

standard proposed by International Committee of Medical Journal 

Editors, based on (1) substantial contributions to conception and 

design, acquisition of data, or analysis and interpretation of data; (2) 

drafting the article or revising it critically for important intellectual 

content; and (3) final approval of the version to be published. Authors 

should meet conditions 1, 2, and 3. 

Institution: Author names should be given first, then the complete 

name of institution, city, province and postcode. For example, Xu- 

Chen Zhang, Li-Xin Mei, Department of Pathology, Chengde Medical 

College, Chengde 067000, Hebei Province, China. One author may 

be represented from two institutions, for example, George Sgourakis, 

Department of General, Visceral, and Transplantation Surgery, Essen 

45122, Germany; George Sgourakis, 2nd Surgical Department, 

Korgialenio-Benakio Red Cross Hospital, Athens 15451, Greece 

Author contributions: The format of this section should be: Author 

contributions: Wang CL and Liang L contributed equally to this work; 

Wang CL, Liang L, Fu JF, Zou CC, Hong F and Wu XM designed 

the research; Wang CL, Zou CC, Hong F and Wu XM performed the 

research; Xue JZ and Lu JR contributed new reagents/analytic tools; 

Wang CL, Liang L and Fu JF analyzed the data; and Wang CL, Liang 

L and Fu JF wrote the paper. 

Supportive foundations: The complete name and number of supportive 

foundations should be provided, e.g. Supported by National 

Natural Science Foundation of China, No. 30224801 

Correspondence to: Only one corresponding address should be 

provided. Author names should be given first, then author title, affiliation, 

the complete name of institution, city, postcode, province, 

country, and email. All the letters in the email should be in lower case. 

A space interval should be inserted between country name and email 

address. For example, Montgomery Bissell, MD, Professor of Medicine, 

Chief, Liver Center, Gastroenterology Division, University of 

California, Box 0538, San Francisco, CA 94143, United States. montgomery.bissell@ucsf.edu 

Telephone and fax: Telephone and fax should consist of +, country 

number, district number and telephone or fax number, e.g. Telephone: 

+86-10-85381891 Fax: +86-10-85381893 

Peer reviewers: All articles received are subject to peer review. Normally, 

three experts are invited for each article. Decision for acceptance 

is made only when at least two experts recommend an article 

for publication. Reviewers for accepted manuscripts are acknowledged 

in each manuscript, and reviewers of articles which were not 

accepted will be acknowledged at the end of each issue. To ensure 

the quality of the articles published in WJGO, reviewers of accepted 

manuscripts will be announced by publishing the name, title/position 

and institution of the reviewer in the footnote accompanying 

the printed article. For example, reviewers: Professor Jing-Yuan Fang, 

Shanghai Institute of Digestive Disease, Shanghai, Affiliated Renji 

Hospital, Medical Faculty, Shanghai Jiaotong University, Shanghai, 

China; Professor Xin-Wei Han, Department of Radiology, The First 

Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan Prov- 


ince, China; and Professor Anren Kuang, Department of Nuclear 

Medicine, Huaxi Hospital, Sichuan University, Chengdu, Sichuan 

Province, China. 

Abstract 

There are unstructured abstracts (no more than 256 words) and 

structured abstracts (no more than 480). The specific requirements 

for structured abstracts are as follows: 

An informative, structured abstracts of no more than 480 words 

should accompany each manuscript. Abstracts for original contributions 

should be structured into the following sections. AIM (no more 

than 20 words): Only the purpose should be included. Please write 

the aim as the form of “To investigate/study/…; MATERIALS 

AND METHODS (no more than 140 words); RESULTS (no more 

than 294 words): You should present P values where appropriate and 

must provide relevant data to illustrate how they were obtained, e.g. 

6.92 ± 3.86 vs 3.61 ± 1.67, P < 0.001; CONCLUSION (no more than 

26 words). 

Key words 

Please list 5-10 key words, selected mainly from Index Medicus, which 

reflect the content of the study. 

Text 

For articles of these sections, original articles and brief articles, the 

main text should be structured into the following sections: INTRO- 

DUCTION, MATERIALS AND METHODS, RESULTS and DIS- 

CUSSION, and should include appropriate Figures and Tables. Data 

should be presented in the main text or in Figures and Tables, but not 

in both. The main text format of these sections, editorial, topic highlight, 

case report, letters to the editors, can be found at: http://www. 

wjgnet.com/1948-5204/g_info_list.htm. 

Illustrations 

Figures should be numbered as 1, 2, 3, etc., and mentioned clearly 

in the main text. Provide a brief title for each figure on a separate 

page. Detailed legends should not be provided under the 

figures. This part should be added into the text where the figures 

are applicable. Figures should be either Photoshop or Illustrator 

files (in tiff, eps, jpeg formats) at high-resolution. Examples 

can be found at: http://www.wjgnet.com/1007-9327/13/4520. 

pdf; http://www.wjgnet.com/1007-9327/13/4554.pdf; http:// 

www.wjgnet.com/1007-9327/13/4891.pdf; http://www. 

wjgnet.com/1007-9327/13/4986.pdf; http://www.wjgnet. 

com/1007-9327/13/4498.pdf. Keeping all elements compiled is necessary 

in line-art image. Scale bars should be used rather than magnification 

factors, with the length of the bar defined in the legend rather 

than on the bar itself. File names should identify the figure and panel. 

Avoid layering type directly over shaded or textured areas. Please use 

uniform legends for the same subjects. For example: Figure 1 Pathological 

changes in atrophic gastritis after treatment. A: ...; B: ...; C: ...; D: 

...; E: ...; F: ...; G: …etc. It is our principle to publish high resolutionfigures 

for the printed and E-versions. 

Tables 

Three-line tables should be numbered 1, 2, 3, etc., and mentioned 

clearly in the main text. Provide a brief title for each table. Detailed 

legends should not be included under tables, but rather added into the 

text where applicable. The information should complement, but not 

duplicate the text. Use one horizontal line under the title, a second 

under column heads, and a third below the Table, above any footnotes. 

Vertical and italic lines should be omitted. 

Notes in tables and illustrations 

Data that are not statistically significant should not be noted. a P < 0.05, 

b P < 0.01 should be noted (P > 0.05 should not be noted). If there 

are other series of P values, c P < 0.05 and d P < 0.01 are used. A third 

series of P values can be expressed as e P < 0.05 and f P < 0.01. Other 

notes in tables or under illustrations should be expressed as 1 F, 2 F, 3 F; 

or sometimes as other symbols with a superscript (Arabic numer- 

WJGO|www.wjgnet.com III August 15, 2012|Volume 4|Issue 8|


als) in the upper left corner. In a multi-curve illustration, each curve 

should be labeled with ●, ○, ■, □, ▲, △, etc., in a certain sequence. 

Acknowledgments 

Brief acknowledgments of persons who have made genuine contributions 

to the manuscript and who endorse the data and conclusions 

should be included. Authors are responsible for obtaining written 

permission to use any copyrighted text and/or illustrations. 

REFERENCES 

Coding system 

The author should number the references in Arabic numerals according 

to the citation order in the text. Put reference numbers in square 

brackets in superscript at the end of citation content or after the cited 

author’s name. For citation content which is part of the narration, the 

coding number and square brackets should be typeset normally. For 

example, “Crohn’s disease (CD) is associated with increased intestinal 

permeability [1,2] ”. If references are cited directly in the text, they 

should be put together within the text, for example, “From references 

[19,22-24] , we know that...” 

When the authors write the references, please ensure that the 

order in text is the same as in the references section, and also ensure 

the spelling accuracy of the first author’s name. Do not list the same 

citation twice. 

PMID and DOI 

Pleased provide PubMed citation numbers to the reference list, e.g. 

PMID and DOI, which can be found at http://www.ncbi.nlm.nih. 

gov/sites/entrez?db=pubmed and http://www.crossref.org/Simple- 

TextQuery/, respectively. The numbers will be used in E-version of 

this journal. 

Style for journal references 

Authors: the name of the first author should be typed in bold-faced 

letters. The family name of all authors should be typed with the initial 

letter capitalized, followed by their abbreviated first and middle initials. 

(For example, Lian-Sheng Ma is abbreviated as Ma LS, Bo-Rong 

Pan as Pan BR). The title of the cited article and italicized journal title 

(journal title should be in its abbreviated form as shown in PubMed), 

publication date, volume number (in black), start page, and end page 

[PMID: 11819634 DOI: 10.3748/wjg.13.5396]. 

Style for book references 

Authors: the name of the first author should be typed in bold-faced 

letters. The surname of all authors should be typed with the initial letter 

capitalized, followed by their abbreviated middle and first initials. 

(For example, Lian-Sheng Ma is abbreviated as Ma LS, Bo-Rong Pan 

as Pan BR) Book title. Publication number. Publication place: Publication 

press, Year: start page and end page. 

Format 

Journals 

English journal article (list all authors and include the PMID where applicable) 

1 Jung EM, Clevert DA, Schreyer AG, Schmitt S, Rennert J, 

Kubale R, Feuerbach S, Jung F. Evaluation of quantitative contrast 

harmonic imaging to assess malignancy of liver tumors: 

A prospective controlled two-center study. World J Gastroenterol 

2007; 13: 6356-6364 [PMID: 18081224 DOI: 10.3748/wjg.13. 

6356] 

Chinese journal article (list all authors and include the PMID where applicable) 

2 Lin GZ, Wang XZ, Wang P, Lin J, Yang FD. Immunologic effect 

of Jianpi Yishen decoction in treatment of Pixu-diarrhoea. 

Shijie Huaren Xiaohua Zazhi 1999; 7: 285-287 

In press 

3 Tian D, Araki H, Stahl E, Bergelson J, Kreitman M. Signature 

of balancing selection in Arabidopsis. Proc Natl Acad Sci USA 

2006; In press 

Organization as author 

4 Diabetes Prevention Program Research Group. Hypertension, 

insulin, and proinsulin in participants with impaired glu- 

cose tolerance. Hypertension 2002; 40: 679-686 [PMID: 12411462 

PMCID:2516377 DOI:10.1161/01.HYP.0000035706.28494. 

09] 

Both personal authors and an organization as author 

5 Vallancien G, Emberton M, Harving N, van Moorselaar RJ; 

Alf-One Study Group. Sexual dysfunction in 1, 274 European 

men suffering from lower urinary tract symptoms. J Urol 

2003; 169: 2257-2261 [PMID: 12771764 DOI:10.1097/01.ju. 

0000067940.76090.73] 

No author given 

6 21st century heart solution may have a sting in the tail. BMJ 

2002; 325: 184 [PMID: 12142303 DOI:10.1136/bmj.325. 

7357.184] 

Volume with supplement 

7 Geraud G, Spierings EL, Keywood C. Tolerability and safety 

of frovatriptan with short- and long-term use for treatment 

of migraine and in comparison with sumatriptan. Headache 

2002; 42 Suppl 2: S93-99 [PMID: 12028325 DOI:10.1046/ 

j.1526-4610.42.s2.7.x] 

Issue with no volume 

8 Banit DM, Kaufer H, Hartford JM. Intraoperative frozen section 

analysis in revision total joint arthroplasty. Clin Orthop Relat 

Res 2002; (401): 230-238 [PMID: 12151900 DOI:10.1097/0000 

3086-200208000-00026] 

No volume or issue 

9 Outreach: Bringing HIV-positive individuals into care. HRSA 

Careaction 2002; 1-6 [PMID: 12154804] 

Books 

Personal author(s) 

10 Sherlock S, Dooley J. Diseases of the liver and billiary system. 

9th ed. Oxford: Blackwell Sci Pub, 1993: 258-296 

Chapter in a book (list all authors) 

11 Lam SK. Academic investigator’s perspectives of medical treatment 

for peptic ulcer. In: Swabb EA, Azabo S. Ulcer disease: 

investigation and basis for therapy. New York: Marcel Dekker, 

1991: 431-450 

Author(s) and editor(s) 

12 Breedlove GK, Schorfheide AM. Adolescent pregnancy. 2nd 

ed. Wieczorek RR, editor. White Plains (NY): March of Dimes 

Education Services, 2001: 20-34 

Conference proceedings 

13 Harnden P, Joffe JK, Jones WG, editors. Germ cell tumours 

V. Proceedings of the 5th Germ cell tumours Conference; 2001 

Sep 13-15; Leeds, UK. New York: Springer, 2002: 30-56 

Conference paper 

14 Christensen S, Oppacher F. An analysis of Koza's computational 

effort statistic for genetic programming. In: Foster JA, 

Lutton E, Miller J, Ryan C, Tettamanzi AG, editors. Genetic 

programming. EuroGP 2002: Proceedings of the 5th European 

Conference on Genetic Programming; 2002 Apr 3-5; Kinsdale, 

Ireland. Berlin: Springer, 2002: 182-191 

Electronic journal (list all authors) 

15 Morse SS. Factors in the emergence of infectious diseases. 

Emerg Infect Dis serial online, 1995-01-03, cited 1996-06-05; 

1(1): 24 screens. Available from: URL: http://www.cdc.gov/ 

ncidod/eid/index.htm 

Patent (list all authors) 

16 Pagedas AC, inventor; Ancel Surgical R&D Inc., assignee. Flexible 

endoscopic grasping and cutting device and positioning tool 

assembly. United States patent US 20020103498. 2002 Aug 1 

Statistical data 

Write as mean ± SD or mean ± SE. 

Statistical expression 

Express t test as t (in italics), F test as F (in italics), chi square test as χ 2 

(in Greek), related coefficient as r (in italics), degree of freedom as υ (in 

Greek), sample number as n (in italics), and probability as P (in italics). 

WJGO|www.wjgnet.com IV August 15, 2012|Volume 4|Issue 8|

Units 

Use SI units. For example: body mass, m (B) = 78 kg; blood pressure, 

p (B) = 16.2/12.3 kPa; incubation time, t (incubation) = 96 h, blood 

glucose concentration, c (glucose) 6.4 ± 2.1 mmol/L; blood CEA 

mass concentration, p (CEA) = 8.6 24.5 mg/L; CO 2 volume fraction, 

50 mL/L CO 2, not 5% CO 2; likewise for 40 g/L formaldehyde, not 

10% formalin; and mass fraction, 8 ng/g, etc. Arabic numerals such as 

23, 243, 641 should be read 23 243 641. 

The format for how to accurately write common units and 

quantums can be found at: http://www.wjgnet.com/1948-5204/ 

g_info_20100312183048.htm. 

Abbreviations 

Standard abbreviations should be defined in the abstract and on first 

mention in the text. In general, terms should not be abbreviated unless 

they are used repeatedly and the abbreviation is helpful to the 

reader. Permissible abbreviations are listed in Units, Symbols and Abbreviations: 

A Guide for Biological and Medical Editors and Authors 

(Ed. Baron DN, 1988) published by The Royal Society of Medicine, 

London. Certain commonly used abbreviations, such as DNA, RNA, 

HIV, LD50, PCR, HBV, ECG, WBC, RBC, CT, ESR, CSF, IgG, 

ELISA, PBS, ATP, EDTA, mAb, can be used directly without further 

explanation. 

Italics 

Quantities: t time or temperature, c concentration, A area, l length, m 

mass, V volume. 

Genotypes: gyrA, arg 1, c myc, c fos, etc. 

Restriction enzymes: EcoRI, HindI, BamHI, Kbo I, Kpn I, etc. 

Biology: H. pylori, E coli, etc. 

Examples for paper writing 

Editorial: http://www.wjgnet.com/1948-5204/ 

g_info_20100312180823.htm 

Frontier: http://www.wjgnet.com/1948-5204/ 

g_info_20100312181003.htm 

Topic highlight: http://www.wjgnet.com/1948-5204/ 

g_info_20100312181119.htm 

Observation: http://www.wjgnet.com/1948-5204/ 

g_info_20100312181227.htm 

Guidelines for basic research: http://www.wjgnet.com/1948-5204/ 

g_info_20100312181408.htm 

Guidelines for clinical practice: http://www.wjgnet. 

com/1948-5204/g_info_20100312181552.htm 

Review: http://www.wjgnet.com/1948-5204/ 

g_info_20100312181719.htm 

Original articles: http://www.wjgnet.com/1948-5204/ 

g_info_20100312181919.htm 

Brief articles: http://www.wjgnet.com/1948-5204/ 

g_info_20100312182057.htm 

Case report: http://www.wjgnet.com/1948-5204/ 

g_info_20100312182207.htm 

Letters to the editor: http://www.wjgnet.com/1948-5204/ 

g_info_20100312182320.htm 

Book reviews: http://www.wjgnet.com/1948-5204/ 

g_info_20100312182437.htm 

Guidelines: http://www.wjgnet.com/1948-5204/ 

g_info_20100312182544.htm 


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Science news releases 

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at EurekAlert/AAAS (http://www.eurekalert.org). The title for news 

items should be less than 90 characters; the summary should be less 

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Publication fee 

WJGO is an international, peer-reviewed, OA online journal. Articles 

published by this journal are distributed under the terms of the 

Creative Commons Attribution Non-commercial License, which 

permits use, distribution, and reproduction in any medium, provided 

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