Impact of copy number variant and single nucleotide polymorphism of the programmed death‑ligand 1 gene, programmed death‑ligand 1 protein expression and therapy regimens on overall survival in a large group of Caucasian patients with non‑small cell lung carcinoma

Grenda,Anna; Krawczyk,Paweł; Kucharczyk,Tomasz; Błach,Justyna; Reszka,Katarzyna; Chmielewska,Izabela; Buczkowski,Jarosław; Kieszko,Robert; Siwiec,Jan; Kubiatowski,Tomasz; Bożyk,Aleksandra; Krukowska,Kinga; Jarosz,Bożena; Paśnik,Iwona; Pankowski,Juliusz; Świniuch,Daria; Stencel,Katarzyna; Gil,Michał; Lew,Kinga; Ramlau,Rodryg; Szczęsna,Aleksandra; Fidler,Sebastian; Sieracki,Andrzej; Każarnowicz,Andrzej; Serwatowski,Piotr; Grodzki,Tomasz; Milanowski,Janusz

doi:10.3892/ol.2021.12710

Impact of copy number variant and single nucleotide polymorphism of the programmed death‑ligand 1 gene, programmed death‑ligand 1 protein expression and therapy regimens on overall survival in a large group of Caucasian patients with non‑small cell lung carcinoma

Authors:
- Anna Grenda
- Paweł Krawczyk
- Tomasz Kucharczyk
- Justyna Błach
- Katarzyna Reszka
- Izabela Chmielewska
- Jarosław Buczkowski
- Robert Kieszko
- Jan Siwiec
- Tomasz Kubiatowski
- Aleksandra Bożyk
- Kinga Krukowska
- Bożena Jarosz
- Iwona Paśnik
- Juliusz Pankowski
- Daria Świniuch
- Katarzyna Stencel
- Michał Gil
- Kinga Lew
- Rodryg Ramlau
- Aleksandra Szczęsna
- Sebastian Fidler
- Andrzej Sieracki
- Andrzej Każarnowicz
- Piotr Serwatowski
- Tomasz Grodzki
- Janusz Milanowski
View Affiliations

Affiliations: Chair and Department of Pneumology, Oncology and Allergology, Medical University of Lublin, 20‑090 Lublin, Poland, Institute of Genetics and Immunology Genim LCC, 20‑609 Lublin, Poland, Department of Clinical Oncology, Saint Jan of Dukla Oncology Centre of the Lublin Region, 20‑090 Lublin, Poland, Chair and Department of Neurosurgery and Paediatric Neurosurgery, Medical University of Lublin, 20‑090 Lublin, Poland, Chair and Department of Clinical Pathomorphology, Medical University of Lublin, 20‑090 Lublin, Poland, Department of Pathology, Specialist Hospital for Lung Diseases ‘Rebirth’ Klara Jelska, 34‑500 Zakopane, Poland, Chair and Department of Clinical Oncology, Poznań University of Medical Sciences, 60‑569 Poznań, Poland, Department of Lung Diseases with Oncology Subdivision, Mazovian Center for the Treatment of Lung Diseases and Tuberculosis, 60‑569 Otwock, Poland, Department of Oncology, Provincial Hospital Center of The Jeleniogórska Valley, 58‑506 Jelenia Góra, Poland, Department of Clinical Oncology, Independent Public Provincial Hospital Pope John Paul II in Zamość, 22‑404 Zamość, Poland, Department of Oncology, Chemotherapy Subdivision, Independent Public Group of Tuberculosis and Pulmonary Diseases in Olsztyn, 10‑357 Olsztyn, Poland, Department of Clinical Oncology and Chemotherapy, Pomeranian Medical University, 70‑891 Szczecin, Poland, Chair and Department of Thoracic Surgery, Pomeranian Medical University, 70‑891 Szczecin, Poland
Published online on: April 7, 2021 https://doi.org/10.3892/ol.2021.12710
Article Number: 449
Copyright: © Grenda et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Anti‑programmed death‑1 or anti‑programmed death‑ligand 1 (PD‑L1) blockade may be ineffective in some patients with non‑small cell lung cancer (NSCLC) with high percentage of tumor cells with PD‑L1 expression. In addition, immunotherapy may provide great benefits in patients without PD‑L1 expression. The present study assessed PD‑L1 protein expression by immunohistochemistry, copy number variation (CNV) of PD‑L1 and two single nucleotide polymorphisms (SNPs), rs822335 and rs822336, in the promoter of PD‑L1 by quantitative PCR in 673 patients with NSCLC. Overall survival time of patients with NSCLC depending on the assessed predictive factors (PD‑L1 CNV or SNP) and the treatment methods (immunotherapy in first/second line of treatment or chemotherapy) was analyzed. The present study revealed significantly higher PD‑L1 copies number in patients with ≥10% and ≥50% of tumor cells with PD‑L1 expression compared to patients with lower percentage of PD‑L1‑positive tumor cells (P=0.02 and P=0.0002, respectively). There was a significant positive correlation (R=0.2; P=0.01) between number of PD‑L1 copies and percentage of tumor cells with PD‑L1 protein expression. Percentage of tumor cells with PD‑L1 expression was lower in patients with TT genotype of the rs822335 polymorphism compared to those with CC genotype (P=0.03). The present study observed significantly higher risk of death in patients treated with chemotherapy compared to those treated with immunotherapy (P<0.0001; hazard ratio=2.4768; 95% confidence interval, 2.0120‑3.0490). The present study demonstrated a close relationship between PD‑L1 copies number, genotype of rs822335 PD‑L1 polymorphism and PD‑L1 protein expression on tumor cells. However, the impact of CNV and SNPs of PD‑L1 on overall survival of patients with NSCLC requires further investigation.

View Figures

View References

1	European Respiratory Society, . European Lung White Book. www.erswhitebook.org/files/public/Chapters/19_lung_cancer.pdfJanuary 22–2021
2	Lung Cancer Europe, . Report on Lung Cancer: Challenges in lung cancer in Europe. https://www.lungcancereurope.eu/wp-content/uploads/2017/10/LuCE-Report-final.pdfJanuary 22–2021
3	Navada S, Lai P, Schwartz AG and Kalemkerian GP: Temporal trends in small cell lung cancer: Analysis of the national Surveillance Epidemiology and End-Results (SEER) database. J Clin Oncol. 24 (Suppl 18):70822006. View Article : Google Scholar
4	Bagley SJ, Bauml JM and Langer CJ: PD-1/PD-L1 immune checkpoint blockade in non-small cell lung cancer. Clin Adv Hematol Oncol. 13:676–683. 2015.PubMed/NCBI
5	Iwai Y, Hamanishi J, Chamoto K and Honjo T: Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci. 24:262017. View Article : Google Scholar : PubMed/NCBI
6	Brahmer JR, Govindan R, Anders RA, Antonia SJ, Sagorsky S, Davies MJ, Dubinett SM, Ferris A, Gandhi L, Garon EB, et al: The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC). J Immunother Cancer. 6:752018. View Article : Google Scholar : PubMed/NCBI
7	Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al KEYNOTE-024 Investigators, : KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 375:1823–1833. 2016. View Article : Google Scholar : PubMed/NCBI
8	García A, Recondo G, Greco M, de la Vega M, Perazzo F, Recondo G, Avagnina A and Denninghoff V: Correlation between PD-L1 expression (clones 28-8 and SP263) and histopathology in lung adenocarcinoma. Heliyon. 6:e041172020. View Article : Google Scholar : PubMed/NCBI
9	Hirsch FR, McElhinny A, Stanforth D, Ranger-Moore J, Jansson M, Kulangara K, Richardson W, Towne P, Hanks D, Vennapusa B, et al: PD-L1 immunohistochemistry assays for lung cancer: Results from phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project. J Thorac Oncol. 12:208–222. 2017. View Article : Google Scholar : PubMed/NCBI
10	Wojas-Krawczyk K, Kalinka E, Grenda A, Krawczyk P and Milanowski J: Beyond PD-L1-markers for lung cancer immunotherapy. Int J Mol Sci. 20:E19152019. View Article : Google Scholar
11	Vokes EE, Ready N, Felip E, Horn L, Burgio MA, Antonia SJ, Arén Frontera O, Gettinger S, Holgado E, Spigel D, et al: Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases. Ann Oncol. 29:959–965. 2018. View Article : Google Scholar : PubMed/NCBI
12	Herbst RS, Baas P, Perez-Gracia JL, Felip E, Kim DW, Han JY, Molina JR, Kim JH, Dubos Arvis C, Ahn MJ, et al: Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival: An updated analysis of KEYNOTE-010 trial. Ann Oncol. 30:281–289. 2019. View Article : Google Scholar : PubMed/NCBI
13	Bordoni R, Ciardiello F, von Pawel J, Cortinovis D, Karagiannis T, Ballinger M, Sandler A, Yu W, He P, Matheny C, et al: Patient-reported outcomes in OAK: A phase III study of atezolizumab versus docetaxel in advanced non-small-cell lung cancer. Clin Lung Cancer. 19:441–449.e4. 2018. View Article : Google Scholar : PubMed/NCBI
14	Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, de Wit M, et al PACIFIC Investigators, : overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 379:2342–2350. 2018. View Article : Google Scholar : PubMed/NCBI
15	Lee SY, Jung DK, Choi JE, Jin CC, Hong MJ, Do SK, Kang HG, Lee WK, Seok Y, Lee EB, et al: PD-L1 polymorphism can predict clinical outcomes of non-small cell lung cancer patients treated with first-line paclitaxel-cisplatin chemotherapy. Sci Rep. 6:259522016. View Article : Google Scholar : PubMed/NCBI
16	Ma Y, Liu X, Zhu J, Li W, Guo L, Han X, Song B, Cheng S and Jie L: Polymorphisms of co-inhibitory molecules (CTLA-4/PD-1/PD-L1) and the risk of non-small cell lung cancer in a Chinese population. Int J Clin Exp Med. 8:16585–16591. 2015.PubMed/NCBI
17	Lee SY, Jung DK, Choi JE, Jin CC, Hong MJ, Do SK, Kang HG, Lee WK, Seok Y, Lee EB, et al: Functional polymorphisms in PD-L1 gene are associated with the prognosis of patients with early stage non-small cell lung cancer. Gene. 599:28–35. 2017. View Article : Google Scholar : PubMed/NCBI
18	Du W, Zhu J, Chen Y, Zeng Y, Shen D, Zhang N, Ning W, Liu Z and Huang JA: Variant SNPs at the microRNA complementary site in the B7 H1 3 untranslated region increase the risk of non small cell lung cancer. Mol Med Rep. 16:2682–2690. 2017. View Article : Google Scholar : PubMed/NCBI
19	Yeo MK, Choi SY, Seong IO, Suh KS, Kim JM and Kim KH: Association of PD-L1 expression and PD-L1 gene polymorphism with poor prognosis in lung adenocarcinoma and squamous cell carcinoma. Hum Pathol. 68:103–111. 2017. View Article : Google Scholar : PubMed/NCBI
20	Chen YB, Mu CY, Chen C and Huang JA: Association between single nucleotide polymorphism of PD-L1 gene and non-small cell lung cancer susceptibility in a Chinese population. Asia Pac J Clin Oncol. 10:e1–6. 2014. View Article : Google Scholar
21	Cheng S, Zheng J, Zhu J, Xie C, Zhang X, Han X, Song B, Ma Y and Liu J: PD-L1 gene polymorphism and high level of plasma soluble PD-L1 protein may be associated with non-small cell lung cancer. Int J Biol Markers. 30:e364–e368. 2015. View Article : Google Scholar
22	Nomizo T, Ozasa H, Tsuji T, Funazo T, Yasuda Y, Yoshida H, Yagi Y, Sakamori Y, Nagai H, Hirai T, et al: Clinical impact of single nucleotide polymorphism in PD-L1 on response to nivolumab for advanced non-small-cell lung cancer patients. Sci Rep. 7:451242017. View Article : Google Scholar : PubMed/NCBI
23	Vohra M, Sharma AR, Prabhu B N and Rai PS: SNPs in sites for DNA methylation, transcription factor binding, and miRNA targets leading to allele-specific gene expression and Contributing to complex disease risk: A systematic review. Public Health Genomics. 23:155–170. 2020. View Article : Google Scholar : PubMed/NCBI
24	Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, et al KEYNOTE-042 Investigators, : Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial. Lancet. 393:1819–1830. 2019. View Article : Google Scholar : PubMed/NCBI
25	Pacheco JM, Gao D and Camidge DR: Extended follow-up on KEYNOTE-024 suggests significant survival benefit for pembrolizumab in patients with PD-L1 ≥50%, but unanswered questions remain. Ann Transl Med. 7 (Suppl 3):S1272019. View Article : Google Scholar : PubMed/NCBI
26	Yoshimura K, Inoue Y, Karayama M, Tsuchiya K, Mori K, Suzuki Y, Iwashita Y, Kahyo T, Kawase A, Tanahashi M, et al: Heterogeneity analysis of PD-L1 expression and copy number status in EBUS-TBNA biopsy specimens of non-small cell lung cancer: Comparative assessment of primary and metastatic sites. Lung Cancer. 134:202–209. 2019. View Article : Google Scholar : PubMed/NCBI
27	Inoue Y, Yoshimura K, Mori K, Kurabe N, Kahyo T, Mori H, Kawase A, Tanahashi M, Ogawa H, Inui N, et al: Clinical significance of PD-L1 and PD-L2 copy number gains in non-small-cell lung cancer. Oncotarget. 7:32113–32128. 2016. View Article : Google Scholar : PubMed/NCBI
28	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
29	Krawczyk P, Grenda A, Wojas-Krawczyk K, Nicoś M, Kucharczyk T, Jarosz B, Reszka K, Pankowski J, Krukowska K, Bożyk A, et al: PD-L1 gene copy number and promoter polymorphisms regulate PD-L1 expression in tumor cells of non-small cell lung cancer patients. Cancer Genet. 237:10–18. 2019. View Article : Google Scholar : PubMed/NCBI
30	Ikeda S, Okamoto T, Okano S, Umemoto Y, Tagawa T, Morodomi Y, Kohno M, Shimamatsu S, Kitahara H, Suzuki Y, et al: PD-L1 is upregulated by simultaneous amplification of the PD-L1 and JAK2 genes in non-small cell lung cancer. J Thorac Oncol. 11:62–71. 2016. View Article : Google Scholar : PubMed/NCBI
31	NCBI Resource Coordinators, . Database resources of the National Center for Biotechnology Information. Nucleic Acids Res. 42:D7–D17. 2014. View Article : Google Scholar
32	George J, Saito M, Tsuta K, Iwakawa R, Shiraishi K, Scheel AH, Uchida S, Watanabe SI, Nishikawa R, Noguchi M, et al: Genomic amplification of CD274 (PD-L1) in small-cell lung cancer. Clin Cancer Res. 23:1220–1226. 2017. View Article : Google Scholar : PubMed/NCBI