Deletion of cyclin dependent kinase inhibitor 2a gene as a marker of oropharyngeal carcinomas non-associated with human papillomavirus and its prognostic value

I.S. Shponka; Bondarenko O.O. Bondarenko ч; O.V. Kovtunenko; V.V. Rakhmanov

doi:10.26641/2307-0404.2024.2.307479

Автор(и)

I.S. Shponka Dnipro State Medical University, Volodymyra Vernadskoho str., 9, Dnipro, 49044, Україна https://orcid.org/0000-0002-7561-6489
Bondarenko O.O. Bondarenko ч Dnipro State Medical University, Volodymyra Vernadskoho str., 9, Dnipro, 49044, Україна https://orcid.org/0000-0002-9739-9219
O.V. Kovtunenko Dnipro State Medical University, Volodymyra Vernadskoho str., 9, Dnipro, 49044, Україна https://orcid.org/0000-0002-0562-7684
V.V. Rakhmanov Dnipro State Medical University, Volodymyra Vernadskoho str., 9, Dnipro, 49044, Україна https://orcid.org/0000-0003-3200-6039

DOI:

https://doi.org/10.26641/2307-0404.2024.2.307479

Ключові слова:

squamous cell carcinoma, oropharynx, p16, human papillomavirus, cyclin dependent kinase inhibitor 2a gene, hybridization in situ

Анотація

Patients with human papilloma virus associated oropharyngeal squamous cell carcinoma generally have better treatment outcomes and prognosis compared to those with non-papillomavirus-associated oropharyngeal squamous cell carcinoma. However, prognostic evaluation for non-papillomavirus-associated oropharyngeal squamous cell carcinoma remains a problem that could be solved through the molecular mechanisms of squamous cell carcinoma for the purpose of further development of target therapies. Detection of cyclin dependent kinase inhibitor 2a gene deletion in oropharyngeal squamous cell carcinomas can have clinical significance as it may serve as a prognostic marker and potentially guide treatment decisions. To investigate and analyze cyclin dependent kinase inhibitor 2a gene alterations in oropharyngeal squamous cell carcinoma comparing with clinical data (age of the patient, TNM stage), their histological features and occurrence of papillomavirus infection markers (p16 expression). Formalin-fixed and paraffin-embedded samples after transoral radical surgery of oropharyngeal tumors from 26 male patients with average age 57.35±10.33 years were studied. Histological, immunohistochemical analyses and fluorescent in-situ hybridization were performed to assess histological features, p16 expression, and cyclin dependent kinase inhibitor 2a gene gene abnormalities respectively. Homozygous deletion of cyclin dependent kinase inhibitor 2a gene was statistically analyzed and compared with p16 expression, age, and occurrence of nodal metastases in investigated patients. Our study demonstrated that the patients with non-papillomavirus-oropharyngeal squamous cell carcinoma with cyclin dependent kinase inhibitor 2a gene homozygous deletion had the highest risk of the nodal metastases development. Our findings suggest that not only detection of the loss of p16 expression, but also the evaluation of homozygous cyclin dependent kinase inhibitor 2a gene deletion might be predictive of worse outcome specifically in oropharyngeal squamous cell carcinomas.

Посилання

Berdugo J, Rooper LM, Chiosea SI. RB1, p16, and Human Papillomavirus in Oropharyngeal Squamous Cell Carcinoma. Head Neck Pathol. 2021;15(4):1109-18. doi: https://doi.org/10.1007/s12105-021-01317-5

Preissner SH, Nahles S, Preissner S, Heiland M, Koerdt S. Influence of sex on survival rates of HPV-po-sitive oropharyngeal cancers. Front Oncol. 2022;12:917890. doi: https://doi.org/10.3389/fonc.2022.917890

Mylly M, Nissi L, Huusko T, et al. Epidemiological Study of p16 Incidence in Head and Neck Squamous Cell Carcinoma 2005-2015 in a Representative Northern European Population. Cancers (Basel). 2022;14(22):5717. doi: https://doi.org/10.3390/cancers14225717

Lewis JS, Chernock RD, Ma XJ, Flanagan JJ, Luo Y, Gao G, et al. Partial p16 staining in oropharyngeal squamous cell carcinoma: extent and pattern correlate with human papillomavirus RNA status. Mod Pathol. 2012;25(9):1212-20. doi: https://doi.org/10.1038/modpathol.2012.79

Vazquez-Guillen JM, Palacios-Saucedo GC, Ala-nis-Valdez AY, et al. p16INK4a and pRb expression in laryngeal squamous cell carcinoma with and without infection by EBV or different genotypes of HPV: a retro-spective study. Infect Agents Cancer. 2023 Jul 11;18(1):43. doi: https://doi.org/10.1186/s13027-023-00514-x

Sivarajah S, Kostiuk M, Lindsay C, et al. EGFR as a biomarker of smoking status and survival in oropha-ryngeal squamous cell carcinoma. J of Otolaryngol - Head Neck Surg. 2019;48:1. doi: https://doi.org/10.1186/s40463-018-0323-6

Gadhikar MA, Zhang J, Shen L, et al. CDKN2A/p16 Deletion in Head and Neck Cancer Cells Is Associated with CDK2 Activation, Replication Stress, and Vulnerability to CHK1 Inhibition. Cancer Res. 2018;78(3):781-97. doi: https://doi.org/10.1158/0008-5472.CAN-17-2802

Aesif SW, Aubry MC, Yi ES, et al. Loss of p16INK4A Expression and Homozygous CDKN2A Dele-tion Are Associated with Worse Outcome and Younger Age in Thymic Carcinomas. J Thorac Oncol. 2017;12(5):860-71. doi: https://doi.org/10.1016/j.jtho.2017.01.028

Chen WS, Bindra RS, Mo A, et al. CDKN2A Copy Number Loss Is an Independent Prognostic Factor in HPV-Negative Head and Neck Squamous Cell Carcinoma. Front Oncol. 2018;8:95. doi: https://doi.org/10.3389/fonc.2018.00095

Buckley L, Jackett L, Clark J, Gupta R. HPV-related Oropharyngeal Carcinoma: A Review of Clinical and Pathologic Features With Emphasis on Updates in Clinical and Pathologic Staging. Adv Anat Pathol. 2018;25(3):180-8. doi: https://doi.org/10.1097/PAP.0000000000000179

Bancroft JD, Layton C. The hematoxylins and eosin. In: Suvarna SK, Layton C, Bancroft JD, editors. Bancroft's Theory and Practice of Histological Techniques. 8th ed. Elsevier; 2019. p. 126-138. doi: https://doi.org/10.1016/B978-0-7020-6864-5.00010-4

de Ferreira C, Dufloth R, de Carvalho AC, et al. Correlation of p16 immunohistochemistry with clinical and epidemiological features in oropharyngeal squamous-cell carcinoma. PLoS One. 2021;16(6):e0253418. doi: https://doi.org/10.1371/journal.pone.0253418

Pessôa IA, Amorim CK, Ferreira WAS, et al. Detection and Correlation of Single and Concomitant TP53, PTEN, and CDKN2A Alterations in Gliomas. Int J Mol Sci. 2019;20(11):2658. doi: https://doi.org/10.3390/ijms20112658

Grzechowiak I, Graś J, Szymańska D, et al. The Oncogenic Roles of PTTG1 and PTTG2 Genes and Pseudogene PTTG3P in Head and Neck Squamous Cell Carcinomas. Diagnostics (Basel). 2020;10(8):606. doi: https://doi.org/10.3390/diagnostics10080606

Moeckelmann N, Ebrahimi A, Tou YK, et al. Prognostic implications of the 8th edition American Joint Committee on Cancer (AJCC) staging system in oral cavity squamous cell carcinoma. Oral Oncol. 2018;85:82-6. doi: https://doi.org/10.1016/j.oraloncology.2018.08.013