Clinical significance of RAS pathway alterations in pediatric acute myeloid leukemia
Taeko Kaburagi,
Genki Yamato,
Norio Shiba,
Kenichi Yoshida,
Yusuke Hara,
Ken Tabuchi,
Yuichi Shiraishi,
Kentaro Ohki,
Manabu Sotomatsu,
Hirokazu Arakawa,
Hidemasa Matsuo,
Akira Shimada,
Tomohiko Taki,
Nobutaka Kiyokawa,
Daisuke Tomizawa,
Keizo Horibe,
Satoru Miyano,
Takashi Taga,
Souichi Adachi,
Seishi Ogawa,
Yasuhide Hayashi
Affiliations
Taeko Kaburagi
Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan; Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma
Genki Yamato
Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan; Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma
Norio Shiba
Department of Pediatrics, Yokohama City University Hospital, Kanagawa
Kenichi Yoshida
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University Kyoto
Yusuke Hara
Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma
Ken Tabuchi
Department of Pediatrics, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo
Yuichi Shiraishi
Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo
Kentaro Ohki
Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo
Manabu Sotomatsu
Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma
Hirokazu Arakawa
Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma
Hidemasa Matsuo
Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo
Akira Shimada
Department of Pediatrics, Okayama University, Okayama
Tomohiko Taki
Department or Medical Technology, Kyorin University Faculty of Health Sciences, Tokyo
Nobutaka Kiyokawa
Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo
Daisuke Tomizawa
Division of Leukemia and Lymphoma, Children’s Cancer Center, National Center for Child Health and Development, Tokyo
Keizo Horibe
Clinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi
Satoru Miyano
Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo
Takashi Taga
Department of Pediatrics, Shiga University of Medical Science, Shiga
Souichi Adachi
Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo
Seishi Ogawa
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University Kyoto
Yasuhide Hayashi
Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan; Institute of Physiology and Medicine, Jobu University, Gunma
RAS pathway alterations have been implicated in the pathogenesis of various hematological malignancies. However, their clinical relevance in pediatric acute myeloid leukemia (AML) is not well characterized. We analyzed the frequency, clinical significance, and prognostic relevance of RAS pathway alterations in 328 pediatric patients with de novo AML. RAS pathway alterations were detected in 80 (24.4%) of 328 patients: NF1 (n=7, 2.1%), PTPN11 (n=15, 4.6%), CBL (n=6, 1.8%), NRAS (n=44, 13.4%), KRAS (n=12, 3.7%). Most of these alterations in the RAS pathway were mutually exclusive also together with other aberrations of signal transduction pathways such as FLT3-ITD (P=0.001) and KIT mutation (P=0.004). NF1 alterations were frequently detected in patients with complex karyotype (P=0.031) and were found to be independent predictors of poor overall survival (OS) in multivariate analysis (P=0.007). At least four of seven patients with NF1 alterations had biallelic inactivation. NRAS mutations were frequently observed in patients with CBFB-MYH11 and were independent predictors of favorable outcomes in multivariate analysis (OS, P=0.023; event-free survival [EFS], P=0.037). Patients with PTPN11 mutations more frequently received stem cell transplantation (P=0.035) and showed poor EFS than patients without PTPN11 mutations (P=0.013). Detailed analysis of RAS pathway alterations may enable a more accurate prognostic stratification of pediatric AML and may provide novel therapeutic molecular targets related to this signal transduction pathway.