Prevalence of pathogenic variants in cancer-predisposing genes in second cancer after childhood solid cancers.
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Yoshida Masanori, Nakabayashi Kazuhiko, Yang Wentao, Sato-Otsubo Aiko, Tsujimoto Shin-Ichi, Ogata-Kawata Hiroko, Kawai Tomoko, Ishiwata Keisuke, Sakamoto Mika, Okamura Kohji, Yoshida Kaoru, Shirai Ryota, Osumi Tomoo, Kiyotani Chikako, Shioda Yoko, Terashima Keita, Ishimaru Sae, Yuza Yuki, Takagi Masatoshi, Arakawa Yuki, Imamura Toshihiko, Hasegawa Daisuke, Inoue Akiko, Yoshioka Takako, Ito Shuichi, Tomizawa Daisuke, Koh Katsuyoshi, Matsumoto Kimikazu, Kiyokawa Nobutaka, Ogawa Seishi, Manabe Atsushi, Niwa Akira, Hata Kenichiro, Yang Jun J, Kato Motohiro
Аннотация
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.