Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung

Tatsuro Okamoto, Kazuki Takada, Seijiro Sato, Gouji Toyokawa, Tetsuzo Tagawa, Fumihiro Shoji, Ryota Nakanishi, Eiji Oki, Terumoto Koike, Masayuki Nagahashi, Hiroshi Ichikawa, Yoshifumi Shimada, Satoshi Watanabe, Toshiaki Kikuchi, Kouhei Akazawa, Stephen Lyle, Kazuaki Takabe, Shujiro Okuda, Kenji Sugio, Toshifumi WakaiMasanori Tsuchida, Yoshihiko Maehara

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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.

Original languageEnglish
Pages (from-to)1564-1571
Number of pages8
JournalAnnals of Surgical Oncology
Volume25
Issue number6
DOIs
Publication statusPublished - Jun 1 2018

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Squamous Cell Carcinoma
Lung
Mutation
Neoplasms
Cyclin-Dependent Kinase Inhibitor p15
Ligands
Neoplasm Genes
p53 Genes
Receptor Protein-Tyrosine Kinases
Phosphoric Monoester Hydrolases
Lung Neoplasms
Proteins

All Science Journal Classification (ASJC) codes

  • Surgery
  • Oncology

Cite this

Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung. / Okamoto, Tatsuro; Takada, Kazuki; Sato, Seijiro; Toyokawa, Gouji; Tagawa, Tetsuzo; Shoji, Fumihiro; Nakanishi, Ryota; Oki, Eiji; Koike, Terumoto; Nagahashi, Masayuki; Ichikawa, Hiroshi; Shimada, Yoshifumi; Watanabe, Satoshi; Kikuchi, Toshiaki; Akazawa, Kouhei; Lyle, Stephen; Takabe, Kazuaki; Okuda, Shujiro; Sugio, Kenji; Wakai, Toshifumi; Tsuchida, Masanori; Maehara, Yoshihiko.

In: Annals of Surgical Oncology, Vol. 25, No. 6, 01.06.2018, p. 1564-1571.

Research output: Contribution to journalArticle

Okamoto, T, Takada, K, Sato, S, Toyokawa, G, Tagawa, T, Shoji, F, Nakanishi, R, Oki, E, Koike, T, Nagahashi, M, Ichikawa, H, Shimada, Y, Watanabe, S, Kikuchi, T, Akazawa, K, Lyle, S, Takabe, K, Okuda, S, Sugio, K, Wakai, T, Tsuchida, M & Maehara, Y 2018, 'Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung', Annals of Surgical Oncology, vol. 25, no. 6, pp. 1564-1571. https://doi.org/10.1245/s10434-018-6401-1
Okamoto, Tatsuro ; Takada, Kazuki ; Sato, Seijiro ; Toyokawa, Gouji ; Tagawa, Tetsuzo ; Shoji, Fumihiro ; Nakanishi, Ryota ; Oki, Eiji ; Koike, Terumoto ; Nagahashi, Masayuki ; Ichikawa, Hiroshi ; Shimada, Yoshifumi ; Watanabe, Satoshi ; Kikuchi, Toshiaki ; Akazawa, Kouhei ; Lyle, Stephen ; Takabe, Kazuaki ; Okuda, Shujiro ; Sugio, Kenji ; Wakai, Toshifumi ; Tsuchida, Masanori ; Maehara, Yoshihiko. / Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung. In: Annals of Surgical Oncology. 2018 ; Vol. 25, No. 6. pp. 1564-1571.
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title = "Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung",
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.",
author = "Tatsuro Okamoto and Kazuki Takada and Seijiro Sato and Gouji Toyokawa and Tetsuzo Tagawa and Fumihiro Shoji and Ryota Nakanishi and Eiji Oki and Terumoto Koike and Masayuki Nagahashi and Hiroshi Ichikawa and Yoshifumi Shimada and Satoshi Watanabe and Toshiaki Kikuchi and Kouhei Akazawa and Stephen Lyle and Kazuaki Takabe and Shujiro Okuda and Kenji Sugio and Toshifumi Wakai and Masanori Tsuchida and Yoshihiko Maehara",
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TY - JOUR

T1 - Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung

AU - Okamoto, Tatsuro

AU - Takada, Kazuki

AU - Sato, Seijiro

AU - Toyokawa, Gouji

AU - Tagawa, Tetsuzo

AU - Shoji, Fumihiro

AU - Nakanishi, Ryota

AU - Oki, Eiji

AU - Koike, Terumoto

AU - Nagahashi, Masayuki

AU - Ichikawa, Hiroshi

AU - Shimada, Yoshifumi

AU - Watanabe, Satoshi

AU - Kikuchi, Toshiaki

AU - Akazawa, Kouhei

AU - Lyle, Stephen

AU - Takabe, Kazuaki

AU - Okuda, Shujiro

AU - Sugio, Kenji

AU - Wakai, Toshifumi

AU - Tsuchida, Masanori

AU - Maehara, Yoshihiko

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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.

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.

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