Skip to main content

Advertisement

SpringerLink
Log in

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

  • Thoracic Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Chen Z, Fillmore CM, Hammerman PS, Kim CF, Wong KK. Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer. 2014;14:535–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Tsao AS, Scagliotti GV, Bunn PA Jr, et al. Scientific Advances in Lung Cancer 2015. J Thorac Oncol. 2016;11:613–638

    Article  PubMed  Google Scholar 

  3. Gandara DR, Hammerman PS, Sos ML, Lara PN Jr, Hirsch FR. Squamous cell lung cancer: from tumor genomics to cancer therapeutics. Clin Cancer Res. 2015;21:2236–2243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489:519–525

    Article  PubMed Central  Google Scholar 

  5. Kim Y, Hammerman PS, Kim J, et al. Integrative and comparative genomic analysis of lung squamous cell carcinomas in East Asian patients. J Clin Oncol. 2014;32:121–128

    Article  CAS  PubMed  Google Scholar 

  6. Heist RS, Mino-Kenudson M, Sequist LV, et al. FGFR1 amplification in squamous cell carcinoma of the lung. J Thorac Oncol. 2012;7:1775-1780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science. 2013;339:1546–1558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Champiat S, Ferte C, Lebel-Binay S, Eggermont A, Soria JC. Exomics and immunogenics: bridging mutational load and immune checkpoints efficacy. Oncoimmunology. 2014;3:e27817

    Article  PubMed  PubMed Central  Google Scholar 

  10. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–2454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. International Union Against Cancer. The TNM Classification of Malignant Tumors, 7th Edition. 2009.

  13. Galateau-Salle F, Churg A, Roggli V, Travis WD. The 2015 World Health Organization Classification of tumors of the pleura: advances since the 2004 classification. J Thorac Oncol. 2016;11:142–154

    Article  PubMed  Google Scholar 

  14. Nagahashi M, Wakai T, Shimada Y, et al. Genomic landscape of colorectal cancer in Japan: clinical implications of comprehensive genomic sequencing for precision medicine. Genome Med. 2016;8:136

    Article  PubMed  PubMed Central  Google Scholar 

  15. Takada K, Okamoto T, Toyokawa G, et al. The expression of PD-L1 protein as a prognostic factor in lung squamous cell carcinoma. Lung Cancer. 2017;104:7–15

    Article  PubMed  Google Scholar 

  16. Hecht SS. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst. 1999;91:1194–1210

    Article  CAS  PubMed  Google Scholar 

  17. Byers TF, Vena JE, Rzepka TF. Predilection of lung cancer for the upper lobes: an epidemiologic inquiry. J Natl Cancer Inst. 1984;72:1271–1275

    CAS  PubMed  Google Scholar 

  18. Gurney JW, Schroeder BA. Upper lobe lung disease: physiologic correlates. Review. Radiology. 1988;167:359–366

    Article  CAS  PubMed  Google Scholar 

  19. Bishawi M, Moore W, Bilfinger T. Severity of emphysema predicts location of lung cancer and 5-y survival of patients with stage I non-small cell lung cancer. J Surg Res. 2013;184:1–5

    Article  PubMed  Google Scholar 

  20. Kinsey CM, Estepar RS, Zhao Y, et al. Invasive adenocarcinoma of the lung is associated with the upper lung regions. Lung Cancer. 2014;84:145–150

    Article  PubMed  PubMed Central  Google Scholar 

  21. Bae K, Jeon KN, Lee SJ, Kim HC, Ha JY, Park SE, et al. Severity of pulmonary emphysema and lung cancer: analysis using quantitative lobar emphysema scoring. Medicine (Baltimore). 2016;95:e5494

    Article  PubMed  PubMed Central  Google Scholar 

  22. Petrelli F, Tomasello G, Borgonovo K, et al. Prognostic survival associated with left-sided vs right-sided colon cancer: a systematic review and meta-analysis. JAMA Oncol. 2017;3:211–219

    Article  Google Scholar 

  23. Fields AP, Justilien V, Murray NR. The chromosome 3q26 OncCassette: a multigenic driver of human cancer. Adv Biol Regul. 2016;60:47–63

    Article  CAS  PubMed  Google Scholar 

  24. Wang J, Qian J, Hoeksema MD, et al. Integrative genomics analysis identifies candidate drivers at 3q26-29 amplicon in squamous cell carcinoma of the lung. Clin Cancer Res. 2013;19:5580–5590

    Article  CAS  PubMed  Google Scholar 

  25. Brunelli M, Bria E, Nottegar A, et al. True 3q chromosomal amplification in squamous cell lung carcinoma by FISH and aCGH molecular analysis: impact on targeted drugs. PLoS ONE. 2012;7:e49689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lin Q, Wang J, Childress C, Yang W. The activation mechanism of ACK1 (activated Cdc42-associated tyrosine kinase 1). Biochem J. 2012;445:255–264

    Article  CAS  PubMed  Google Scholar 

  27. Mahajan K, Mahajan NP. ACK1/TNK2 tyrosine kinase: molecular signaling and evolving role in cancers. Oncogene. 2015;34:4162–4167

    Article  CAS  PubMed  Google Scholar 

Download references

Disclosure

Author declares that they have no conflict of interest.

Funding

This project was supported by funding from Denka Co. Ltd. Tatsuro Okamoto is supported by Grant-in-Aid from the Japan Society for the Promotion of Science (#15K10263).

Author information

Authors and Affiliations

  1. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Tatsuro Okamoto MD, PhD, Kazuki Takada MD, PhD, Gouji Toyokawa MD, PhD, Tetsuzo Tagawa MD, PhD, Fumihiro Shoji MD, PhD, Ryota Nakanishi MD, PhD, Eiji Oki MD, PhD & Yoshihiko Maehara MD, PhD

  2. Division of Thoracic and Cardiovascular Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Seijiro Sato MD, PhD, Terumoto Koike MD, PhD & Masanori Tsuchida MD, PhD

  3. Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Masayuki Nagahashi MD, PhD, Hiroshi Ichikawa MD, PhD, Yoshifumi Shimada MD, PhD & Toshifumi Wakai MD, PhD

  4. Department of Respiratory Medicine and Infectious Disease, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Tatsuro Okamoto MD, PhD, Satoshi Watanabe MD, PhD & Toshiaki Kikuchi MD, PhD

  5. Department of Medical Informatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Kouhei Akazawa PhD

  6. Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Shujiro Okuda PhD

  7. Department of Thoracic and Breast Surgery, Faculty of Medicine, Oita University, Oita, Japan

    Kenji Sugio MD, PhD

  8. University of Massachusetts Medical School, Worcester, MA, USA

    Stephen Lyle MD, PhD

  9. Breast Surgery, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA

    Kazuaki Takabe MD, PhD

  10. Department of Surgery, University at Buffalo Jacobs School of Medicine and Biosciences, The State University of New York, Buffalo, NY, USA

    Kazuaki Takabe MD, PhD

Authors
  1. Tatsuro Okamoto MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazuki Takada MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seijiro Sato MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gouji Toyokawa MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tetsuzo Tagawa MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fumihiro Shoji MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ryota Nakanishi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eiji Oki MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Terumoto Koike MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Masayuki Nagahashi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hiroshi Ichikawa MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yoshifumi Shimada MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Satoshi Watanabe MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Toshiaki Kikuchi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Kouhei Akazawa PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Stephen Lyle MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Kazuaki Takabe MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Shujiro Okuda PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Kenji Sugio MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Toshifumi Wakai MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Masanori Tsuchida MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Yoshihiko Maehara MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tatsuro Okamoto MD, PhD.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 21 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Okamoto, T., Takada, K., Sato, S. et al. Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung. Ann Surg Oncol 25, 1564–1571 (2018). https://doi.org/10.1245/s10434-018-6401-1

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-018-6401-1

Keywords

Search

Navigation