Tatsuro Okamoto1,2, Kazuki Takada3, Seijiro Sato4, Gouji Toyokawa3, Tetsuzo Tagawa3, Fumihiro Shoji3, Ryota Nakanishi3, Eiji Oki3, Terumoto Koike4, Masayuki Nagahashi5, Hiroshi Ichikawa5, Yoshifumi Shimada5, Satoshi Watanabe6, Toshiaki Kikuchi6, Kouhei Akazawa7, Stephen Lyle8, Kazuaki Takabe9,10, Shujiro Okuda11, Kenji Sugio12, Toshifumi Wakai5, Masanori Tsuchida4, Yoshihiko Maehara3. 1. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. tatsuro@surg2.med.kyushu-u.ac.jp. 2. Department of Respiratory Medicine and Infectious Disease, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. tatsuro@surg2.med.kyushu-u.ac.jp. 3. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 4. Division of Thoracic and Cardiovascular Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. 5. Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. 6. Department of Respiratory Medicine and Infectious Disease, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. 7. Department of Medical Informatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. 8. University of Massachusetts Medical School, Worcester, MA, USA. 9. Breast Surgery, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA. 10. Department of Surgery, University at Buffalo Jacobs School of Medicine and Biosciences, The State University of New York, Buffalo, NY, USA. 11. Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. 12. Department of Thoracic and Breast Surgery, Faculty of Medicine, Oita University, Oita, Japan.
Abstract
BACKGROUND: Lung squamous cell carcinoma (LSCC) is a major histological subtype of lung cancer. In this study, we investigated genomic alterations in LSCC and evaluated the clinical implications of mutation burden (MB) in LSCC. METHODS: Genomic alterations were determined in Japanese patients with LSCC (N = 67) using next-generation sequencing of 415 known cancer genes. MB was defined as the number of non-synonymous mutations per 1 Mbp. Programmed death-ligand 1 (PD-L1) protein expression in cancer cells was evaluated by immunohistochemical analysis. RESULTS: TP53 gene mutations were the most common alteration (n = 51/67, 76.1%), followed by gene alterations in cyclin-dependent kinase inhibitor 2B (CDKN2B; 35.8%), CDKN2A (31.3%), phosphatase and tensin homolog (30.0%), and sex-determining region Y-box 2 (SOX2, 28.3%). Histological differentiation was significantly poorer in tumors with high MB (greater than or equal to the median MB) compared with that in tumors with low MB (less than the median MB; p = 0.0446). The high MB group had more tumors located in the upper or middle lobe than tumors located in the lower lobe (p = 0.0019). Moreover, cancers in the upper or middle lobes had significantly higher MB than cancers in the lower lobes (p = 0.0005), and tended to show higher PD-L1 protein expression (p = 0.0573). SOX2 and tyrosine kinase non-receptor 2 amplifications were associated with high MB (p = 0.0065 and p = 0.0010, respectively). CONCLUSIONS: The MB level differed according to the tumor location in LSCC, suggesting that the location of cancer development may influence the genomic background of the tumor.
BACKGROUND: Lung squamous cell carcinoma (LSCC) is a major histological subtype of lung cancer. In this study, we investigated genomic alterations in LSCC and evaluated the clinical implications of mutation burden (MB) in LSCC. METHODS: Genomic alterations were determined in Japanese patients with LSCC (N = 67) using next-generation sequencing of 415 known cancer genes. MB was defined as the number of non-synonymous mutations per 1 Mbp. Programmed death-ligand 1 (PD-L1) protein expression in cancer cells was evaluated by immunohistochemical analysis. RESULTS:TP53 gene mutations were the most common alteration (n = 51/67, 76.1%), followed by gene alterations in cyclin-dependent kinase inhibitor 2B (CDKN2B; 35.8%), CDKN2A (31.3%), phosphatase and tensin homolog (30.0%), and sex-determining region Y-box 2 (SOX2, 28.3%). Histological differentiation was significantly poorer in tumors with high MB (greater than or equal to the median MB) compared with that in tumors with low MB (less than the median MB; p = 0.0446). The high MB group had more tumors located in the upper or middle lobe than tumors located in the lower lobe (p = 0.0019). Moreover, cancers in the upper or middle lobes had significantly higher MB than cancers in the lower lobes (p = 0.0005), and tended to show higher PD-L1 protein expression (p = 0.0573). SOX2 and tyrosine kinase non-receptor 2 amplifications were associated with high MB (p = 0.0065 and p = 0.0010, respectively). CONCLUSIONS: The MB level differed according to the tumor location in LSCC, suggesting that the location of cancer development may influence the genomic background of the tumor.