Cancer Epidemiology 38 (2014) 550–555
Contents lists available at ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Significant association between hypolipoproteinemia(a) and lifetime risk of cancer: An autopsy study from a community-based Geriatric Hospital Makiko Naka Mieno a,1, Motoji Sawabe b,d,1,*, Noriko Tanaka e,1, Ken-ichi Nakahara c, Akihiko Hamamatsu b, Kouji Chida b, Urara Sakurai b, Tomio Arai b, Kazumasa Harada c, Seijiro Mori c, Takashi Inamatsu c, Toshio Ozawa c, Naoko Honma f, Junko Aida f, Kaiyo Takubo f, Satoru Matsushita c a
Department of Medical Informatics, Center for Information, Jichi Medical University, Shimotsuke 329-0498, Tochigi, Japan Departments of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan Departments of Internal Medicine, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan d Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan e Department of Biostatistics, Clinical Research Center, National Center for Global Health and Medicine, Tokyo 162-8655, Japan f Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 8 February 2014 Received in revised form 22 July 2014 Accepted 30 July 2014 Available online 19 August 2014
Background: Our recent study showed that a low lipoproteinemia(a) [Lp(a)] level was a risk factor for cancer and all-cause deaths. The purpose of this study was to verify the role of the Lp(a) level on cancer among consecutive autopsy cases. Methods: The subjects consisted of 1354 cases (775 men and 579 women). The average age at death was 79.9 years. Hypolipoproteinemia(a) was defined as an Lp(a) level of below 80 mg/L. Overall, 62.3% of the subjects had suffered from at least one to a maximum of five malignancies throughout their lives. The most frequent type of malignancy was gastric cancer, followed by leukemia, lung cancer, and colon cancer. Results: The cancer-bearing status decreased linearly according to the Lp(a) level in both men and women (P = 0.01 and P < 0.001, respectively). The median Lp(a) level was significantly lower among the cases with hepato-biliary–pancreatic cancers or hematopoietic malignancy, but was higher among cases with lung cancer, especially lung adenocarcinoma. Hypolipoproteinemia(a) was a significant risk factor for any origins of cancer, with an odds ratio of 1.94 (95% CI, 1.45–2.60; P < 0.001). It was also a risk factor for hepato-biliary cancers and leukemia, but it was a protective factor for lung cancer. Conclusions: Our findings suggested hypolipoproteinemia(a) would be a significant risk factor for cancer except lung cancer. This study complements our previous study showing that hypolipoproteinemia(a) would increase the lifetime risk of cancer other than lung cancer. ß 2014 Elsevier Ltd. All rights reserved.
Keywords: Lipoprotein(a) Malignant neoplasms Autopsy Anti-neoplastic effect Lung cancer
1. Introduction Large-scale prospective cohort studies and their meta-analyses have shown that hyper-lipoproteinemia(a) [Lp(a)] is a risk factor for cardiovascular diseases [1]. Our previous study also suggested
* Corresponding author at: Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan. Tel.: +81 3 5803 5370; fax: +81 3 5803 5375. E-mail addresses: [email protected], [email protected] (M. Sawabe). 1 These authors have contributed equally to this work. http://dx.doi.org/10.1016/j.canep.2014.07.013 1877-7821/ß 2014 Elsevier Ltd. All rights reserved.
that hyper-lipoproteinemia(a) directly promotes coronary atherosclerosis and myocardial infarction [2]. Although the association between Lp(a) and cardiovascular diseases is widely observed, the physiological function and metabolism of apolipoprotein(a) [apo(a)] and its association with other diseases remain unknown. The apo(a) gene (LPA) and the plasminogen gene share a number of characteristic repeat domains which is called Kringle. Angiostatin, a degraded product of plasminogen, exerts an anti-neoplastic effect by inhibiting angiogenesis [3]. As LPA also has Kringle structures, apo(a) may also possess an anti-neoplastic effect. Several in vitro and in vivo studies have supported an antineoplastic effect of apo(a) [4–8], but clinical studies have reported
M.N. Mieno et al. / Cancer Epidemiology 38 (2014) 550–555
contradictory results, with the serum Lp(a) level being elevated in cancer-bearing patients or not being significantly different from that of the control group [9–17]. These clinical studies, however, have several limitations. The number of cancer cases was generally small, and some studies lacked data regarding the histological type or clinical stage of the cancer or the presence or absence of metastasis to the liver, which produces Lp(a). Lp(a) is an acute phase reactant [18,19]. Some types of cancer or advanced cancers are often complicated by inflammation, such as obstructive pneumonia in lung cancer. These previous clinical studies did not pay attention to these complications. To assess these issues, we analyzed the association between the Lp(a) level and mortality using data from the Jichi Medical School (JMS) cohort study and reported that a low Lp(a) concentration (
Contents lists available at ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Significant association between hypolipoproteinemia(a) and lifetime risk of cancer: An autopsy study from a community-based Geriatric Hospital Makiko Naka Mieno a,1, Motoji Sawabe b,d,1,*, Noriko Tanaka e,1, Ken-ichi Nakahara c, Akihiko Hamamatsu b, Kouji Chida b, Urara Sakurai b, Tomio Arai b, Kazumasa Harada c, Seijiro Mori c, Takashi Inamatsu c, Toshio Ozawa c, Naoko Honma f, Junko Aida f, Kaiyo Takubo f, Satoru Matsushita c a
Department of Medical Informatics, Center for Information, Jichi Medical University, Shimotsuke 329-0498, Tochigi, Japan Departments of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan Departments of Internal Medicine, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan d Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan e Department of Biostatistics, Clinical Research Center, National Center for Global Health and Medicine, Tokyo 162-8655, Japan f Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 8 February 2014 Received in revised form 22 July 2014 Accepted 30 July 2014 Available online 19 August 2014
Background: Our recent study showed that a low lipoproteinemia(a) [Lp(a)] level was a risk factor for cancer and all-cause deaths. The purpose of this study was to verify the role of the Lp(a) level on cancer among consecutive autopsy cases. Methods: The subjects consisted of 1354 cases (775 men and 579 women). The average age at death was 79.9 years. Hypolipoproteinemia(a) was defined as an Lp(a) level of below 80 mg/L. Overall, 62.3% of the subjects had suffered from at least one to a maximum of five malignancies throughout their lives. The most frequent type of malignancy was gastric cancer, followed by leukemia, lung cancer, and colon cancer. Results: The cancer-bearing status decreased linearly according to the Lp(a) level in both men and women (P = 0.01 and P < 0.001, respectively). The median Lp(a) level was significantly lower among the cases with hepato-biliary–pancreatic cancers or hematopoietic malignancy, but was higher among cases with lung cancer, especially lung adenocarcinoma. Hypolipoproteinemia(a) was a significant risk factor for any origins of cancer, with an odds ratio of 1.94 (95% CI, 1.45–2.60; P < 0.001). It was also a risk factor for hepato-biliary cancers and leukemia, but it was a protective factor for lung cancer. Conclusions: Our findings suggested hypolipoproteinemia(a) would be a significant risk factor for cancer except lung cancer. This study complements our previous study showing that hypolipoproteinemia(a) would increase the lifetime risk of cancer other than lung cancer. ß 2014 Elsevier Ltd. All rights reserved.
Keywords: Lipoprotein(a) Malignant neoplasms Autopsy Anti-neoplastic effect Lung cancer
1. Introduction Large-scale prospective cohort studies and their meta-analyses have shown that hyper-lipoproteinemia(a) [Lp(a)] is a risk factor for cardiovascular diseases [1]. Our previous study also suggested
* Corresponding author at: Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan. Tel.: +81 3 5803 5370; fax: +81 3 5803 5375. E-mail addresses: [email protected], [email protected] (M. Sawabe). 1 These authors have contributed equally to this work. http://dx.doi.org/10.1016/j.canep.2014.07.013 1877-7821/ß 2014 Elsevier Ltd. All rights reserved.
that hyper-lipoproteinemia(a) directly promotes coronary atherosclerosis and myocardial infarction [2]. Although the association between Lp(a) and cardiovascular diseases is widely observed, the physiological function and metabolism of apolipoprotein(a) [apo(a)] and its association with other diseases remain unknown. The apo(a) gene (LPA) and the plasminogen gene share a number of characteristic repeat domains which is called Kringle. Angiostatin, a degraded product of plasminogen, exerts an anti-neoplastic effect by inhibiting angiogenesis [3]. As LPA also has Kringle structures, apo(a) may also possess an anti-neoplastic effect. Several in vitro and in vivo studies have supported an antineoplastic effect of apo(a) [4–8], but clinical studies have reported
M.N. Mieno et al. / Cancer Epidemiology 38 (2014) 550–555
contradictory results, with the serum Lp(a) level being elevated in cancer-bearing patients or not being significantly different from that of the control group [9–17]. These clinical studies, however, have several limitations. The number of cancer cases was generally small, and some studies lacked data regarding the histological type or clinical stage of the cancer or the presence or absence of metastasis to the liver, which produces Lp(a). Lp(a) is an acute phase reactant [18,19]. Some types of cancer or advanced cancers are often complicated by inflammation, such as obstructive pneumonia in lung cancer. These previous clinical studies did not pay attention to these complications. To assess these issues, we analyzed the association between the Lp(a) level and mortality using data from the Jichi Medical School (JMS) cohort study and reported that a low Lp(a) concentration (
