Professors involved

Kevin Urayama, Division of Epidemiology, kevura@luke.ac.jp
Osamu Takahashi, Division of Epidemiology
Satomi Sato, Division of Health and Behavioral Science

Introduction

Hematological malignancies are collectively the most common types of cancers diagnosed in
children. Unfortunately, progress in understanding their causes has been slow, delaying efforts for prevention. But there is good news: significant improvements in survival rates have been achieved over the past couple decades, with nearly 80-90% of affected people now able to go on living a full life. However, due to the effects of the disease and intensive treatment, this population is still uniquely vulnerable to various short-term and long-term adverse health effects including neurocognitive deficits, emotional problems, metabolic, reproductive, and hormonal abnormalities, and late effects involving the heart, lungs, and digestive system. As the lives of these children are just beginning, careful long-term clinical follow-up is essential, and the identification of risk factors and markers for early detection and prevention will optimize opportunities for appropriate care.

Collaborators

Atsushi Manabe, Department of Pediatrics, Hokkaido University
Daisuke Hasegawa, Department of Pediatrics, St. Luke’s International University
Masatoshi Takagi, Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University
Motohiro Kato, Children’s Cancer Center, National Center for Child Health and Development
Kimikazu Matsumoto, Children’s Cancer Center, National Center for Child Health and Development
Katsuyoshi Koh, Department of Pediatric Hematology/Oncology, Saitama Children’s Medical Center
Yasushi Ishida, Pediatric Medical Center, Ehime Prefectural Central Hospital
Shuki Mizutani, Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University
Toshihiro Tanaka, Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University
Fumihiko Matsuda, Center for Genomic Medicine, Kyoto University
Takahisa Kawaguchi, Center for Genomic Medicine, Kyoto University
Keitaro Matsuo, Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute
Yoichi Tanaka, School of Pharmacy, Kitasato University
Hiroaki Goto, Division of Hematology/Oncology & Regenerative Medicine, Kanagawa Children’s Medical Center
Dai Keino, Division of Hematology/Oncology & Regenerative Medicine, Kanagawa Children’s Medical Center
Takeshi Inukai, Department of Pediatrics, University of Yamanashi

Project details

Within an existing well-established network of major clinical centers within the Kanto and surrounding regions treating childhood cancers, we have assembled a series of ongoing studies aimed at addressing three major themes in the epidemiology of childhood hematological cancers regarding the role of: 1) inherited genetics in the risk of childhood leukemia development, 2) pregnancy-related and early postnatal factors in the risk of childhood hematological malignancies, and 3) factors influencing the development of adverse late effects in survivors of childhood cancers.
Inherited genetic susceptibility is being examined within a series of over 1,000 patients and 5,000 controls in a genome-wide association study (GWAS) with the goal of identifying genetic variants associated with childhood leukemia development and clinical outcomes. In parallel, within a separate series of patients (cases) and population-based matched controls, a questionnaire-based data collection effort and DNA sample collection is being pursued to examine emerging hypotheses on the causes of childhood hematologic cancers pertaining to the pregnancy and early postnatal period and its interaction with genetic factors (gene-environment interactions).
Finally, in a prospective cohort study of childhood cancer survivors, annual follow-up is being conducted, at which time detailed information is collected on various lifestyle-related risk factors and health status related to both clinical late affects as well as quality of life issues.

Grant funding

JSPS Grant-in-Aid for Scientific Research on Innovative Areas, (Co-Investigator), 2015-2019
JSPS Grant-in-Aid for Scientific Research C (Co-Investigator), 2017-2019
JSPS Grant-in-Aid for Scientific Research B (Principal Investigator), 2018-2021
MSD Life Science Foundation (Principal Investigator), 2018-2020
National Center for Child Health and Development Grant Program (Principal Investigator), 2018-2020
Leukemia Research Foundation Japan (Principal Investigator), 2019-2020

Publications

Hangai M, Urayama KY, Tanaka J, Kato K, Nishiwaki S, Koh K, Noguchi M, Kato K, Yoshida N, Sato M, Goto H, Yuza Y, Hashii Y, Atsuta Y, Mizuta S, Kato M. Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in Adolescents and Young Adults. Biology of Blood and Marrow Transplantation, 2019, 25(8):1597-1602.

Urayama K, Takagi M, Kawaguchi T, Matsuo K, Tanaka Y, Ayukara Y, Arakawa Y, Hasegawa D, Yuza Y, Kaneko T, Noguchi T, Taneyama Y, Ota S, Inukai T, Yanagimachi M, Keino D, Koike K, Toyama D, Nakazawa Y, Kurosawa H, Nakamura K, Moriwaki K, Goto H, Sekinaka Y, Morita D, Kato M, Takita J, Tanaka T, Inazawa H, Koh K, Ishida Y, Ohara A, Mizutani S, Matsuda F, Manabe A. Regional evaluation of childhood acute lymphoblastic leukemia genetic susceptibility loci among Japanese. Scientific Reports, 2018, 8:789. doi:10.1038/s41598-017-19127-7.

Maeda K, Hasegawa D, Urayama KY, Tsujimoto S, Azami Y, Ozawa M, Manabe A. Risk factors for psychological and psychosomatic symptoms among children with malignancies. Journal of Paediatrics and Child Health, 2017;54(4):411-415.

Huang M, Inukai T, Kagami K, Abe M, Shinohara T, Watanabe A, Somazu S, Oshiro H, Goi K, Goto H, Minegishi M, Iwamoto S, Urayama KY, Sugita K. Splicing variant profiles and single nucleotide polymorphisms of the glucocorticoid receptor gene in relation to glucocorticoid-sensitivity of B-cell precursor acute lymphoblastic leukaemia. Hematological Oncology, 2017, 36(1):245-251.

Daida A, Yoshihara H, Inai I, Hasegawa D, Ishida Y, Urayama KY, Manabe A. Risk factors for hospital-acquired clostridium difficile infection among pediatric patient with cancer. Journal of Pediatric Hematology and Oncology, 2017, 39(3):e167-e172.

Urayama KY. Maternal pregnancy and postnatal factors affecting immune development and risk of childhood acute lymphoblastic leukemia. Japanese Journal of Pediatric Hematology Oncology, 2016, 53(5).

Takagi M and Urayama K. Inherited genetic variants associated with childhood acute lymphoblastic leukemia risk. Japanese Journal of Clinical Hematology, 2016, 57(7):891-9.

Tsujimoto SI, Yanagimachi M, Tanoshima R, Urayama KY, Tanaka F, Aida N, Goto H, Ito S. Influence of ADORA2A gene polymorphism on leukoencephalopathy risk in MTX-treated pediatric patients affected by hematological malignancies. Pediatric Blood Cancer, 2016, 63(11):1983-9.

Tanaka Y, Kato M, Hasegawa D, Urayama KY, Nakadate H, Kondoh K, Nakamura K, Koh K, Komiyama T, Manabe A. Susceptibility to 6-mercaptopurine toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukemia. British Journal of Haematology, 2015, 1(1):109-15.

Rudant J, Lightfood T, Urayama KY, Petridou E, Dockerty JD, Magnani C, Milne E, Spector LG, Ashton L,　Dessypris N, Kang AY, Miller M, Rondelli R, Simpson J, Stiakaki E, Orsi L, Roman E, Metayer C, Infante-Rivard C, Clavel J. Childhood acute lymphoblastic leukemia and indicators of early immune stimulation: a Childhood Leukemia International Consortium (CLIC) Study. American Journal of Epidemiology, 2015, 181(8):549-62.

Hwang AE, Urayama KY, McKean-Cowdin R, Cozen W. Epidemiology and Etiology of Acute Lymphoblastic Leukemia. In V. Pullarkat, Contemporary Management of Acute Lymphoblastic Leukemia (1st ed., pp. 10-48). New Delhi, India: Jaypee Brothers Medical Publishers, 2014.

Urayama KY and Manabe A. Genomic evaluations of childhood acute lymphoblastic leukemia susceptibility across race/ethnicities. Japanese Journal of Clinical Hematology, 2014, 55(10):2242-8.

Ishida Y, Maeda M, Urayama KY, Kyotani C, Aoki Y, Kato Y, Goto S, Sakaguchi S, Sugita K, Tokuyama M, Nakadate N, Ishii E, Tsuchida M, and Ohara A. Secondary cancers among children with acute lymphoblastic leukemia treated by the Tokyo Children’s Cancer Study Group protocols: a retrospective study. British Journal of Haematology, 2014, 164:101-112.

Urayama KY, Thompson P, Taylor M, Trachtenberg E, Chokkalingam AP. Genetic variation in the extended major histocompatibility complex and susceptibility to childhood acute lymphoblastic leukemia: a review of the evidence. Frontiers in Oncology, 2013, 3:300.

Urayama KY, Chokkalingam AP, Manabe A, Mizutani S. Current evidence for an inherited genetic basis of childhood acute lymphoblastic leukemia. International Journal of Hematology, 2013;97(1):3-19.

Urayama KY, Chokkalingam AP, Metayer C, Hansen H, May S, Ramsay P, Wiemels JL, Wiencke JK, Trachtenberg E, Thompson P, Ishida Y, Brennan P, Jolly KW, Termuhlen AM, Taylor GM, Barcellos LF, and Buffler PA. SNP association mapping across the extended major histocompatibility complex and risk of B-cell precursor acute lymphoblastic leukemia in children. PLoS One, 2013;8(8):e72557.

Urayama KY, Chokkalingam AP, Metayer C, Ma X, Selvin S, Barcellos LF, Wiemels JL, Wiencke JK, Taylor GM, Brennan P, Dahl DV, Trachtenberg E, and Buffler PA. HLA-DP genetic variation, proxies for early life immune modulation and childhood acute lymphoblastic leukemia risk. Blood, 2012;120(15):3039-47.