Cancer Medicine (May 2023)
Prevalence of pathogenic variants in cancer‐predisposing genes in second cancer after childhood solid cancers
- Masanori Yoshida,
- Kazuhiko Nakabayashi,
- Wentao Yang,
- Aiko Sato‐Otsubo,
- Shin‐ichi Tsujimoto,
- Hiroko Ogata‐Kawata,
- Tomoko Kawai,
- Keisuke Ishiwata,
- Mika Sakamoto,
- Kohji Okamura,
- Kaoru Yoshida,
- Ryota Shirai,
- Tomoo Osumi,
- Chikako Kiyotani,
- Yoko Shioda,
- Keita Terashima,
- Sae Ishimaru,
- Yuki Yuza,
- Masatoshi Takagi,
- Yuki Arakawa,
- Toshihiko Imamura,
- Daisuke Hasegawa,
- Akiko Inoue,
- Takako Yoshioka,
- Shuichi Ito,
- Daisuke Tomizawa,
- Katsuyoshi Koh,
- Kimikazu Matsumoto,
- Nobutaka Kiyokawa,
- Seishi Ogawa,
- Atsushi Manabe,
- Akira Niwa,
- Kenichiro Hata,
- Jun J. Yang,
- Motohiro Kato
Affiliations
- Masanori Yoshida
- Department of Pediatric Hematology and Oncology Research Research Institute, National Center for Child Health and Development Tokyo Japan
- Kazuhiko Nakabayashi
- Department of Maternal‐Fetal Biology Research Institute, National Center for Child Health and Development Tokyo Japan
- Wentao Yang
- Department of Pharmacy and Pharmaceutical Sciences St. Jude Children's Research Hospital Tennessee Memphis USA
- Aiko Sato‐Otsubo
- Department of Pediatric Hematology and Oncology Research Research Institute, National Center for Child Health and Development Tokyo Japan
- Shin‐ichi Tsujimoto
- Department of Pediatric Hematology and Oncology Research Research Institute, National Center for Child Health and Development Tokyo Japan
- Hiroko Ogata‐Kawata
- Department of Maternal‐Fetal Biology Research Institute, National Center for Child Health and Development Tokyo Japan
- Tomoko Kawai
- Department of Maternal‐Fetal Biology Research Institute, National Center for Child Health and Development Tokyo Japan
- Keisuke Ishiwata
- Department of Maternal‐Fetal Biology Research Institute, National Center for Child Health and Development Tokyo Japan
- Mika Sakamoto
- Medical Genome Center Research Institute, National Center for Child Health and Development Tokyo Japan
- Kohji Okamura
- Department of Systems BioMedicine Research Institute, National Center for Child Health and Development Tokyo Japan
- Kaoru Yoshida
- Department of Pediatric Hematology and Oncology Research Research Institute, National Center for Child Health and Development Tokyo Japan
- Ryota Shirai
- Department of Pediatric Hematology and Oncology Research Research Institute, National Center for Child Health and Development Tokyo Japan
- Tomoo Osumi
- Department of Pediatric Hematology and Oncology Research Research Institute, National Center for Child Health and Development Tokyo Japan
- Chikako Kiyotani
- Children's Cancer Center National Center for Child Health and Development Tokyo Japan
- Yoko Shioda
- Children's Cancer Center National Center for Child Health and Development Tokyo Japan
- Keita Terashima
- Children's Cancer Center National Center for Child Health and Development Tokyo Japan
- Sae Ishimaru
- Department of Hematology/Oncology Tokyo Metropolitan Children's Medical Center Tokyo Japan
- Yuki Yuza
- Department of Hematology/Oncology Tokyo Metropolitan Children's Medical Center Tokyo Japan
- Masatoshi Takagi
- Department of Pediatrics and Developmental Biology Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU) Tokyo Japan
- Yuki Arakawa
- Department of Hematology/Oncology Saitama Children's Medical Center Saitama Japan
- Toshihiko Imamura
- Department of Pediatrics Kyoto Prefectural University of Medicine, Graduate School of Medical Science Kyoto Japan
- Daisuke Hasegawa
- Department of Pediatrics St. Luke's International Hospital Tokyo Japan
- Akiko Inoue
- Department of Pediatrics Osaka Medical and Pharmaceutical University Takatsuki Japan
- Takako Yoshioka
- Department of Pathology National Center for Child Health and Development Tokyo Japan
- Shuichi Ito
- Department of Pediatrics, Graduate School of Medicine Yokohama City University Yokohama Japan
- Daisuke Tomizawa
- Children's Cancer Center National Center for Child Health and Development Tokyo Japan
- Katsuyoshi Koh
- Department of Hematology/Oncology Saitama Children's Medical Center Saitama Japan
- Kimikazu Matsumoto
- Children's Cancer Center National Center for Child Health and Development Tokyo Japan
- Nobutaka Kiyokawa
- Department of Pediatric Hematology and Oncology Research Research Institute, National Center for Child Health and Development Tokyo Japan
- Seishi Ogawa
- Department of Pathology and Tumor Biology Graduate School of Medicine, Kyoto University Kyoto Japan
- Atsushi Manabe
- Department of Pediatrics Hokkaido University Graduate School of Medicine Sapporo Japan
- Akira Niwa
- Department of Clinical Application, Center for iPS Cell Research and Application Kyoto University Kyoto Japan
- Kenichiro Hata
- Department of Maternal‐Fetal Biology Research Institute, National Center for Child Health and Development Tokyo Japan
- Jun J. Yang
- Department of Pharmacy and Pharmaceutical Sciences St. Jude Children's Research Hospital Tennessee Memphis USA
- Motohiro Kato
- Department of Pediatric Hematology and Oncology Research Research Institute, National Center for Child Health and Development Tokyo Japan
- DOI
- https://doi.org/10.1002/cam4.5835
- Journal volume & issue
-
Vol. 12,
no. 10
pp. 11264 – 11273
Abstract
Abstract Background Second malignant neoplasms (SMNs) are one of the most severe late complications after pediatric cancer treatment. However, the effect of genetic variation on SMNs remains unclear. In this study, we revealed germline genetic factors that contribute to the development of SMNs after treatment of pediatric solid tumors. Methods We performed whole‐exome sequencing in 14 pediatric patients with SMNs, including three brain tumors. Results Our analysis revealed that five of 14 (35.7%) patients had pathogenic germline variants in cancer‐predisposing genes (CPGs), which was significantly higher than in the control cohort (p < 0.01). The identified genes with variants were TP53 (n = 2), DICER1 (n = 1), PMS2 (n = 1), and PTCH1 (n = 1). In terms of the type of subsequent cancer, leukemia and multiple episodes of SMN had an exceptionally high rate of CPG pathogenic variants. None of the patients with germline variants had a family history of SMN development. Mutational signature analysis showed that platinum drugs contributed to the development of SMN in three cases, which suggests the role of platinum agents in SMN development. Conclusions We highlight that overlapping effects of genetic background and primary cancer treatment contribute to the development of second cancers after treatment of pediatric solid tumors. A comprehensive analysis of germline and tumor samples may be useful to predict the risk of secondary cancers.
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