PMID- 29500766 OWN - NLM STAT- MEDLINE DCOM- 20190212 LR - 20190215 IS - 1534-4681 (Electronic) IS - 1068-9265 (Linking) VI - 25 IP - 6 DP - 2018 Jun TI - Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung. PG - 1564-1571 LID - 10.1245/s10434-018-6401-1 [doi] AB - 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. FAU - Okamoto, Tatsuro AU - Okamoto T AD - Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. tatsuro@surg2.med.kyushu-u.ac.jp. AD - 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. FAU - Takada, Kazuki AU - Takada K AD - Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Sato, Seijiro AU - Sato S AD - Division of Thoracic and Cardiovascular Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. FAU - Toyokawa, Gouji AU - Toyokawa G AD - Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Tagawa, Tetsuzo AU - Tagawa T AD - Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Shoji, Fumihiro AU - Shoji F AD - Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Nakanishi, Ryota AU - Nakanishi R AD - Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Oki, Eiji AU - Oki E AD - Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Koike, Terumoto AU - Koike T AD - Division of Thoracic and Cardiovascular Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. FAU - Nagahashi, Masayuki AU - Nagahashi M AD - Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. FAU - Ichikawa, Hiroshi AU - Ichikawa H AD - Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. FAU - Shimada, Yoshifumi AU - Shimada Y AD - Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. FAU - Watanabe, Satoshi AU - Watanabe S AD - Department of Respiratory Medicine and Infectious Disease, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. FAU - Kikuchi, Toshiaki AU - Kikuchi T AD - Department of Respiratory Medicine and Infectious Disease, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. FAU - Akazawa, Kouhei AU - Akazawa K AD - Department of Medical Informatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. FAU - Lyle, Stephen AU - Lyle S AD - University of Massachusetts Medical School, Worcester, MA, USA. FAU - Takabe, Kazuaki AU - Takabe K AD - Breast Surgery, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA. AD - Department of Surgery, University at Buffalo Jacobs School of Medicine and Biosciences, The State University of New York, Buffalo, NY, USA. FAU - Okuda, Shujiro AU - Okuda S AD - Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. FAU - Sugio, Kenji AU - Sugio K AD - Department of Thoracic and Breast Surgery, Faculty of Medicine, Oita University, Oita, Japan. FAU - Wakai, Toshifumi AU - Wakai T AD - Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. FAU - Tsuchida, Masanori AU - Tsuchida M AD - Division of Thoracic and Cardiovascular Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. FAU - Maehara, Yoshihiko AU - Maehara Y AD - Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. LA - eng GR - Grant-in-Aid from the Japan Society for the Promot/Tatsuro Okamoto/ PT - Journal Article DEP - 20180302 PL - United States TA - Ann Surg Oncol JT - Annals of surgical oncology JID - 9420840 RN - 0 (B7-H1 Antigen) RN - 0 (CD274 protein, human) RN - 0 (CDKN2B protein, human) RN - 0 (Cyclin-Dependent Kinase Inhibitor p15) RN - 0 (SOX2 protein, human) RN - 0 (SOXB1 Transcription Factors) RN - 0 (Tumor Suppressor Protein p53) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - EC 2.7.10.2 (TNK2 protein, human) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (PTEN protein, human) SB - IM MH - Aged MH - Aged, 80 and over MH - B7-H1 Antigen/metabolism MH - Carcinoma, Squamous Cell/*genetics/metabolism/pathology MH - Cyclin-Dependent Kinase Inhibitor p15/genetics MH - DNA Mutational Analysis MH - Female MH - Humans MH - Lung/*pathology MH - Lung Neoplasms/*genetics/metabolism/pathology MH - Male MH - Middle Aged MH - *Mutation MH - Neoplasm Grading MH - PTEN Phosphohydrolase/genetics MH - Protein-Tyrosine Kinases/genetics MH - SOXB1 Transcription Factors/genetics MH - Tumor Suppressor Protein p53/genetics EDAT- 2018/03/04 06:00 MHDA- 2019/02/13 06:00 CRDT- 2018/03/04 06:00 PHST- 2017/12/10 00:00 [received] PHST- 2018/03/04 06:00 [pubmed] PHST- 2019/02/13 06:00 [medline] PHST- 2018/03/04 06:00 [entrez] AID - 10.1245/s10434-018-6401-1 [pii] AID - 10.1245/s10434-018-6401-1 [doi] PST - ppublish SO - Ann Surg Oncol. 2018 Jun;25(6):1564-1571. doi: 10.1245/s10434-018-6401-1. Epub 2018 Mar 2.