Detection of somatic TP53 mutation in surgically resected small-cell lung cancer by targeted exome sequencing: association with longer relapse-free survival
Hiroshi Yokouchi,
Hiroshi Nishihara,
Toshiyuki Harada,
Shigeo Yamazaki,
Hajime Kikuchi,
Satoshi Oizumi,
Hidetaka Uramoto,
Fumihiro Tanaka,
Masao Harada,
Kenji Akie,
Fumiko Sugaya,
Yuka Fujita,
Kei Takamura,
Tetsuya Kojima,
Mitsunori Higuchi,
Osamu Honjo,
Yoshinori Minami,
Naomi Watanabe,
Masaharu Nishimura,
Hiroyuki Suzuki,
Hirotoshi Dosaka-Akita,
Hiroshi Isobe
Affiliations
Hiroshi Yokouchi
Department of Pulmonary Medicine, Fukushima Medical University, Fukushima 960-1295, Japan; Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo 003-0804, Japan; Corresponding author.
Hiroshi Nishihara
Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan
Toshiyuki Harada
Center for Respiratory Diseases, JCHO Hokkaido Hospital, Sapporo 062-8618, Japan
Shigeo Yamazaki
Department of Thoracic Surgery, Keiyukai Sapporo Hospital, Sapporo 003-0027, Japan
Hajime Kikuchi
First Department of Medicine, Hokkaido University School of Medicine, Sapporo 060-8638, Japan; First Department of Medicine, Obihiro Kosei Hospital, Obihiro 080-0016, Japan
Satoshi Oizumi
Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo 003-0804, Japan
Hidetaka Uramoto
Second Department of Surgery, University of Occupational and Environmental Health, Kita-kyushu 807-8555, Japan; Department of Thoracic Surgery, Kanazawa Medical University, Uchinada 920-0293, Japan
Fumihiro Tanaka
Second Department of Surgery, University of Occupational and Environmental Health, Kita-kyushu 807-8555, Japan
Masao Harada
Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo 003-0804, Japan
Kenji Akie
Department of Respiratory Disease, Sapporo City General Hospital, Sapporo 060-8604, Japan
Fumiko Sugaya
Department of Respiratory Medicine, Teine Keijinkai Hospital, Sapporo 006-8555, Japan
Yuka Fujita
Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center, Asahikawa 070-8644, Japan
Kei Takamura
First Department of Medicine, Obihiro Kosei Hospital, Obihiro 080-0016, Japan
Tetsuya Kojima
Department of Medical Oncology, KKR Sapporo Medical Center, Sapporo 062-0931, Japan
Mitsunori Higuchi
Department of Thoracic Surgery, Fukushima Red Cross Hospital, Fukushima 960-8530, Japan; Department of Thoracic Surgery, Aizu Medical Center, Aizuwakamatsu, Fukushima 969-3492, Japan
Osamu Honjo
Department of Respiratory Medicine, Sapporo-Kosei General Hospital, Sapporo 060-0033, Japan; Department of Respiratory Medicine, Sapporo Minami Sanjo Hospital, Sapporo 060-0063, Japan
Yoshinori Minami
Respiratory Center, Asahikawa Medical University, Asahikawa 078-8510, Japan
Naomi Watanabe
Department of Internal Medicine, Sunagawa City Medical Center, Sunagawa 073-0196, Japan
Masaharu Nishimura
First Department of Medicine, Hokkaido University School of Medicine, Sapporo 060-8638, Japan
Hiroyuki Suzuki
Department of Chest Surgery, Fukushima Medical University, Fukushima 960-1295, Japan
Hirotoshi Dosaka-Akita
Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
Hiroshi Isobe
Department of Medical Oncology, KKR Sapporo Medical Center, Sapporo 062-0931, Japan
Objectives: Few reports have explored clinical biomarkers, including those identified by targeted exome sequencing (TES) of surgically resected small-cell lung cancer (SCLC) and correlation with patient survival. Patients and methods: We collected formalin-fixed paraffin-embedded tumor samples from 127 patients with SCLC who had undergone surgery and analysed nonsynonymous somatic gene mutation profiles by TES of 26 cancer-related genes using next-generation sequencing (NGS) and web databases (UMIN Registration No. 000010117). Results: We detected 38 nonsynonymous somatic tumor protein p53 (TP53) mutations in 43 (54.4%) patients. Among these TP53 lesions, we identified clinically relevant mutations including those encoding Y220C, R248W, R249M, M237I, and R273L substitutions in the p53 protein. These mutations have been reported to be associated with certain clinical outcomes or biology in other types of malignancies but not in SCLC. Moreover, nonsynonymous somatic mutations of TP53 were positively associated with relapse-free survival (RFS) (median, 17.33 months [95% confidence interval (CI), 3.86–30.79] in a mutation-positive group vs 10.39 months (6.96–13.82) in a mutation-negative group, p = 0.042). Multivariate analysis revealed that nonsynonymous somatic TP53 mutation was an independent factor of prolongation of RFS (hazard ratio: 0.51, 95% CI: 0.29–0.89, p = 0.019) but not overall survival (OS). Conclusion: These data suggested that TES may play a critical role for promoting reverse-translational studies, including investigations of the biology of TP53 mutations in different stages of SCLC. Accumulation of the data using cancer panels with a broader range of genes, including TP53, is expected to be useful for future clinical applications for patients with SCLC.
