Hepatitis B and C Virus Infection and Risk of Pancreatic Cancer: A Population-Based Cohort Study (JPHC Study Cohort II)

A recent meta-analysis including studies conducted in China, South Korea, Taiwan, and the United States found chronic hepatitis B and C virus infection increased the risk of pancreatic cancer (1). Another Taiwanese study found null results (2). The status of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection is different between Japan and other countries. The aim of this study was to, for the first time in Japan, assess the association between chronic infection of hepatitis virus and pancreatic cancer risk in the Japan Public Health Center (JPHC)–based prospective study.

Details of the study design (3), questionnaire, blood checkup and laboratory analysis, and follow-up information have been detailed in a previous article (4). The study protocol was approved by the Institutional Review Board of the National Cancer Center, Japan (approval number: 13-021, 16-59). We restricted subjects to those who responded to the questionnaire and provided their blood (n = 20,887). We further excluded those with unavailable data on HCV and HBV infection status from the blood samples (n = 68) and those with a history of cancer (n = 459). Finally, a total of 20,360 individuals were included in this analysis. Details of cancer incidence identification have also been described elsewhere (4). A total of 116 incident pancreatic cancer cases (C25) were identified.

Plasma samples were screened for hepatitis B surface antigen (HBsAg) by reverse passive hemagglutination (R-PHA). Antibodies against hepatitis B core antigen (anti-HBc) were analyzed by R-PHA with a commercial kit common in Japan. For anti-HCV antibody (anti-HCV), a third-generation immunoassay was applied (4).

Person-years of follow-up from the date of baseline survey were calculated until the date of diagnosis of pancreatic cancer, date of death, move from the public health center area, or December 31st 2010, whichever occurred first. Statistical analyses were performed using Stata version 13 (StataCorp). Multivariate-adjusted HRs and corresponding 95% confidence intervals (CI) of pancreatic cancer were calculated for HBsAg, anti-HBc, and anti-HCV by Cox proportional hazards model. In model 1, we adjusted for sex, year of age at baseline (40–44, 45–49, 50–54, 55–59, 60–64, and 65–69), and study area (six areas treated as strata). In model 2, we additionally adjusted for body mass index (<25.0 kg/m², 25.0–26.9 kg/m², and ≥27.0 kg/m²), diabetes (yes or no), and smoking status (never, former, and current). In model 3, we replaced follow-up time with age as the time scale due to the strong association with pancreatic cancer risk.

Among 20,360 participants, 116 pancreatic cancer cases were identified after a mean follow-up of 16 years (324,394 person years). Basic study characteristics have been reported by Abe and colleagues (4). Hepatitis B and C were not statistically significantly associated with the risk of developing pancreatic cancer. Compared with individuals without a positive infection marker, the multivariate-adjusted HRs were 1.22 (95% CI, 0.81–1.84) for anti-HBc and 0.69 (95% CI, 0.28–1.69) for anti-HCV (Table 1). There were 0 pancreatic cancer cases among participants with a positive HBsAg marker.

We did not observe a significant association between anti-HBc, a marker for past HBV exposure, and anti-HCV antibodies and the risk of pancreatic cancer in this large Japanese population-based cohort study. This study did not find cases among HBsAg-positive, hepatitis B–positive, HBV carrier, and subjects. In contrast to our study, a previous meta-analysis, predominantly case–control studies, in other Asian countries found HBsAg and anti-HCV antibodies increased the risk of pancreatic cancer (1). Additional studies in Korea and Sweden also suggested anti-HCV antibodies could be associated with an increased risk (5, 6), while a recent study in Taiwan found null results for all antibody variations (2).

Established risk factors of pancreatic cancer such as tobacco smoking, chronic pancreatitis, obesity, and diabetes account for <50% of cases (7). Some mechanisms have been proposed by Michaud (8). Inflammation is critical in the development of pancreatic carcinogenesis, but the causes other than pancreatitis are unclear. Michaud postulates that infections may influence tumor progression rather than initiation. Anti-HBc–positive status, the serobiologic marker of past exposure to HBV, had an increased risk of developing pancreatic cancer.

Strengths and limitations to the study have been described by Abe and colleagues (4). Briefly, strengths include the large sample, high response rate, and low loss to follow-up and relatively long years of follow-up. Limitations include the mainly nonmetropolitan population, relatively limited number of pancreatic cancer cases, the voluntary nature of the blood samples, the lack of potential exposures related to HBV and HCV in the survey, and not combining anti-HBc and HBsAg in HBV infection due to the concept of seroconversion.

Further research, especially for HBsAg, is needed to confirm our results. Particularly, regional pooled analysis of cohort studies may be useful due to the relatively small number of cases per positive infection marker.

No potential conflicts of interest were disclosed.

Conception and design: M. Inoue, M. Iwasaki, M. Mizokami, S. Tsugane

Development of methodology: M. Inoue, M. Mizokami

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): M. Inoue, N. Sawada, M. Iwasaki, T. Shimazu, T. Yamaji, M. Mizokami, S. Tsugane

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): S.K. Abe, M. Inoue, M. Iwasaki, T. Yamaji, Y. Tanaka, S. Tsugane

Writing, review, and/or revision of the manuscript: S.K. Abe, M. Inoue, M. Iwasaki, T. Shimazu, T. Yamaji, S. Sasazuki, E. Saito, M. Mizokami, S. Tsugane

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): M. Inoue, N. Sawada, M. Mizokami, S. Tsugane

Study supervision: M. Inoue, M. Mizokami, S. Tsugane

The authors thank the Ibaraki, Niigata, Osaka, Kochi, Nagasaki, and Okinawa Cancer Registries for providing their incidence data. The authors acknowledge the members of the JPHC-based prospective study (principal investigator, S. Tsugane) group: S. Tsugane, N. Sawada, M. Iwasaki, S. Sasazuki, T. Yamaji, T. Shimazu, and T. Hanaoka, National Cancer Center, Tokyo; J. Ogata, S. Baba, T. Mannami, A. Okayama, and Y. Kokubo, National Cerebral and Cardiovascular Center, Osaka; K. Miyakawa, F. Saito, A. Koizumi, Y. Sano, I. Hashimoto, T. Ikuta, Y. Tanaba, H. Sato, Y. Roppongi, T. Takashima, and H. Suzuki, Iwate Prefectural Ninohe Public Health Center, Iwate; Y. Miyajima, N. Suzuki, S. Nagasawa, Y. Furusugi, N. Nagai, Y. Ito, S. Komatsu, and T. Minamizono, Akita Prefectural Yokote Public Health Center, Akita; H. Sanada, Y. Hatayama, F. Kobayashi, H. Uchino, Y. Shirai, T. Kondo, R. Sasaki, Y. Watanabe, Y. Miyagawa, Y. Kobayashi, M. Machida, K. Kobayashi, and M. Tsukada, Nagano Prefectural Saku Public Health Center, Nagano; Y. Kishimoto, E. Takara, T. Fukuyama, M. Kinjo, M. Irei, and H. Sakiyama, Okinawa Prefectural Chubu Public Health Center, Okinawa; K. Imoto, H. Yazawa, T. Seo, A. Seiko, F. Ito, F. Shoji, and R. Saito, Katsushika Public Health Center, Tokyo; A. Murata, K. Minato, K. Motegi, T. Fujieda, and S. Yamato, Ibaraki Prefectural Mito Public Health Center, Ibaraki; K. Matsui, T. Abe, M. Katagiri, M. Suzuki, K. and Matsui, Niigata Prefectural Kashiwazaki and Nagaoka Public Health Center, Niigata; M. Doi, A. Terao, Y. Ishikawa, and T. Tagami, Kochi Prefectural Chuo-higashi Public Health Center, Kochi; H. Sueta, H. Doi, M. Urata, N. Okamoto, F. Ide, H. Goto, and R Fujita, Nagasaki Prefectural Kamigoto Public Health Center, Nagasaki; H. Sakiyama, N. Onga, H. Takaesu, M. Uehara, T. Nakasone, and M. Yamakawa, Okinawa Prefectural Miyako Public Health Center, Okinawa; F. Horii, I. Asano, H. Yamaguchi, K. Aoki, S. Maruyama, M. Ichii, and M. Takano, Osaka Prefectural Suita Public Health Center, Osaka; Y. Tsubono, Tohoku University, Miyagi; K. Suzuki, Research Institute for Brain and Blood Vessels Akita, Akita; Y. Honda, K. Yamagishi, S. Sakurai, and N. Tsuchiya, University of Tsukuba, Ibaraki; M. Kabuto, National Institute for Environmental Studies, Ibaraki; M. Yamaguchi, Y. Matsumura, S. Sasaki, and S. Watanabe, National Institute of Health and Nutrition, Tokyo; M. Akabane, Tokyo University of Agriculture, Tokyo; T. Kadowaki and M. Inoue, The University of Tokyo, Tokyo; M. Noda and T. Mizoue, National Center for Global Health and Medicine, Tokyo; Y. Kawaguchi, Tokyo Medical and Dental University, Tokyo; Y. Takashima and Y. Yoshida, Kyorin University, Tokyo; K. Nakamura and R. Takachi, Niigata University, Niigata; J. Ishihara, Sagami Women's University, Kanagawa; S. Matsushima and S. Natsukawa, Saku General Hospital, Nagano; H. Shimizu, Sakihae Institute, Gifu; H. Sugimura, Hamamatsu University School of Medicine, Shizuoka; S. Tominaga, Aichi Cancer Center, Aichi; N. Hamajima, Nagoya University, Aichi; H. Iso and T. Sobue, Osaka University, Osaka; M. Iida, W. Ajiki, and A. Ioka, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka; S. Sato, Chiba Prefectural Institute of Public Health, Chiba; E. Maruyama, Kobe University, Hyogo; M. Konishi, K. Okada, and I. Saito, Ehime University, Ehime; N. Yasuda, Kochi University, Kochi; S. Kono, Kyushu University, Fukuoka; S. Akiba, Kagoshima University, Kagoshima; T. Isobe, Keio University; Y. Sato, Tokyo Gakugei University.

This work was supported by National Cancer Center Research and Development Fund [23-A-31(toku), 26-A-2; since 2011; to S.K. Abe, M. Inoue, N. Sawada, M. Iwasaki, T. Shimazu, T. Yamaji, E. Saito, S. Sasazuki, and S. Tsugane]; a Grant-in-Aid for Cancer Research (from 1989 to 2010; to M. Inoue and S. Tsugane); and Research on Hepatitis (H18-Kannen-Ippan-003) from the Ministry of Health, Labour, and Welfare of Japan (to M. Inoue).

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