Uticaj patogenih TP53 mutacija na preživljavanje i odgovor na hemioterapiju bolesnika sa HPV-negativnim oralnim karcinomima
Sažetak
Uvod/Cilj. Oralni planocelularni karcinom (OPCK) je najčešći tip karcinoma glave i vrata, koji se odlikuje visokom stopom recidiva i lošim preživljavanjem bolesnika. Dalje razjašnjenje uloge i regulacije TP53, ključnog tumor supresorskog gena, omogućilo bi napredak u predviđanju toka, prognoze i hemioterapijskog odgovora obolelih od OPCK. Zbog toga smo istražili povezanost mutacija gena TP53 sa preživljavanjem i odgovorom na hemioterapiju cisplatinom bolesnika sa HPV-negativnim OPCK. Metode. Potencijalni klinički značaj mutacija TP53 analiziran je kod 82 bolesnika sa HPV-negativnim OPCK. Svi bolesnici su bili podvrgnuti radioterapiji, a 25 bolesnika primilo je hemioterapiju cisplatinom. Negativni HPV status utvrđen je tip-specifičnom metodom polymerase chain reaction (PCR), za visoko rizične HPV 16, 18, 31 i 33. Ciljno sekvenciranje TP53 egzona 4–8 rađeno je Sanger kapilarnim sekvenciranjem. Rezultati. Od 82 HPV-negativnih OPCK bolesnika, njih 49 (59,79%) imalo je TP53 mutaciju, a 26 (31,7%) bolesnika je imalo patogene TP53 mutacije. Bolesnici sa patogenim mutacijama TP53 imali su značajno smanjeno celokupno preživljavanje (p = 0,009). Status recidiva, ali ne i TP53 mutacije, bio je nezavisni marker lošeg preživljavanja bolesnika u našoj studiji [hazard ratio (HR) = 4,733, 95% confidence interval (95% CI): 2,027–11,053; p = 0,0001]. U podgrupi bolesnika koji su bili podvrgnuti hemioterapiji cisplatinom, patogene TP53 mutacije bile su prediktori slabog odgovora na hemioterapiju (p = 0,026). Zaključak. Naši nalazi ukazuju da bi patogene TP53 mutacije u HPV-negativnim OPCK tumorima mogle biti prognostički marker smanjenog ukupnog preživljavanja bolesnika. Pored toga, patogene TP53 mutacije u HPV-negativnom OPCK mogu biti marker lošeg odgovora tih bolesnika na hemioterapiju.
Reference
1. Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. N Engl J Med 2001; 345(26): 1890‒900.
2. Kumar D, Sharma S, Sagar V, Kumar P, Ambasta RK. Molecular signalling saga in tumour biology. J Tumor 2015; 18(3): 309‒13.
3. Petti S. Lifestyle risk factors for oral cancer. Oral Oncol 2009; 45(4‒5): 340–50.
4. Castellsagué X, Alemany L, Quer M, Halec G, Quirós B, Tous S, et al. HPV Involvement in Head and Neck Cancers: Comprehensive Assessment of Biomarkers in 3680 Patients. J Natl Cancer Inst 2016; 108(6): djv403.
5. Isobe M, Emanuel BS, Givol D, Oren M, Croce CM. Localization of gene for human p53 tumour antigen to band 17p13. Nature 1986; 320(6057): 84‒5.
6. Kastan MB, Kuerbitz SJ. Control of G1 arrest after DNA damage. Environ Health Perspect 1993; 101(Suppl 5): 55‒8.
7. Zilfou JT, Lowe SW. Tumor suppressive functions of p53. Cold Spring Harb Perspect Biol 2009; 1(5): a001883.
8. Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 1969; 71(4): 747‒52.
9. World Health Organization. IARC TP53 Database. Lyon: International Agency for Research on Cancer; 2021. Available from: http://p53.iarc.fr.
10. Liu XY, Pestka S, Shi YF. Recent Advances in Cancer Research and Therapy. Amsterdam, Netherlands: Elsevier; 2012. p. 700.
11. Partridge M, Costea DE, Huang X. The changing face of p53 in head and neck cancer. Int J Oral Maxillofac Surg 2007; 36(12): 1123‒38.
12. Bergamaschi D, Gasco M, Hiller L, Sullivan A, Syed N, Trigiante G, et al. p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. Cancer Cell 2003; 3(4): 387‒402.
13. Vivenza D, Monteverde M, Lattanzio L, Tonissi F, Astesana V, Denaro N, et al. Correlation of TP53 and MDM2 genotypes and clinical outcome in platinum-treated head and neck cancer patients with more than 10 years' follow-up. Int J Biol Markers 2016; 31(2): e183‒92.
14. Braakhuis BJ, Snijders PJ, Keune WJ, Meijer CJ, Ruijter-Schippers HJ, Leemans CR, et al. Genetic patterns in head and neck cancers that contain or lack transcriptionally active human papillomavirus. J Natl Cancer Inst 2004; 96(13): 998‒1006.
15. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, et al. The mutational landscape of head and neck squamous cell carcinoma. Science 2011; 333(6046): 1157–60.
16. Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ, et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 2011; 333(6046): 1154–7.
17. Iyer NG, Dogan S, Palmer F, Rahmati R, Nixon IJ, Lee N, et al. Detailed Analysis of Clinicopathologic Factors Demonstrate Distinct Difference in Outcome and Prognostic Factors Between Surgically Treated HPV-Positive and Negative Oropharyngeal Cancer. Ann Surg Oncol 2015; 22(13): 4411‒21.
18. Pérez-Palma E, Gramm M, Nürnberg P, May P, Lal D. Simple ClinVar: an interactive web server to explore and retrieve gene and disease variants aggregated in ClinVar database. Nucleic Acids Res 2019; 47(W1): p. W99–W105.
19. Westra WH. The morphologic profile of HPV-related head and neck squamous carcinoma: implications for diagnosis, prognosis, and clinical management. Head Neck Pathol 2012; 6 (Suppl 1): S48‒54.
20. Caponio VCA, Troiano G, Adipietro I, Zhurakivska K, Arena C, Mangieri D, et al. Computational analysis of TP53 mutational landscape unveils key prognostic signatures and distinct pathobiological pathways in head and neck squamous cell cancer. Br J Cancer 2020; 123(8): 1302‒14.
21. Keck MK, Zuo Z, Khattri A, Stricker TP, Brown CD, Imanguli M, et al. Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes. Clin Cancer Res 2015; 21(4): 870‒81.
22. Weinberger PM, Yu Z, Haffty BG, Kowalski D, Harigopal M, Brandsma J, et al. Molecular classification identifies a subset of human papillomavirus-associated oropharyngeal cancers with favorable prognosis. J Clin Oncol 2006; 24(5): 736‒47.
23. Verma G, Vishnoi K, Tyagi A, Jadli M, Singh T, Goel A, et al. Characterization of key transcription factors as molecular signatures of HPV-positive and HPV-negative oral cancers. Cancer Med 2017; 6(3): 591–604.
24. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, et al. Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer. N Engl J Med 2010; 363(1): 24‒35.
25. Ragin CC, Taioli E. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis. Int J Cancer 2007; 121(8): 1813‒20.
26. Ritchie JM, Smith EM, Summersgill KF, Hoffman HT, Wang D, Klussmann JP, et al. Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx. Int J Cancer 2003; 104(3): 336‒44.
27. Nichols AC, Faquin WC, Westra WH, Mroz EA, Begum S, Clark JR, et al. HPV-16 infection predicts treatment outcome in oropharyngeal squamous cell carcinoma. Otolaryngol Head Neck Surg 2009; 140(2): 228‒34.
28. Hafkamp HC, Manni JJ, Speel EJ. Role of human papillomavirus in the development of head and neck squamous cell carcinomas. Acta Otolaryngol 2004; 124(4): 520‒6.
29. Lindel K, Beer KT, Laissue J, Greiner RH, Aebersold DM. Human papillomavirus positive squamous cell carcinoma of the oropharynx. Cancer 2001; 92(4): 805‒13.
30. Peltenburg LT. Radiosensitivity of tumor cells. Oncogenes and apoptosis. Q J Nucl Med 2000; 44(4): 355‒64.
31. Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008; 100(4): 261‒9.
32. Temam S, Flahault A, Perie S, Monceaux G, Coulet F, Callard P, et al. p53 Gene Status as a Predictor of Tumor Response to Induction Chemotherapy of Patients With Locoregionally Advanced Squamous Cell Carcinomas of the Head and Neck. J Clin Oncol 2000; 18(2): 385‒94.
33. Cabelguenne A, Blons H, de Waziers I, Carnot F, Houllier AM, Soussi T, et al. p53 alterations predict tumor response to neoadjuvant chemotherapy in head and neck squamous cell carcinoma: a prospective series. J Clin Oncol 2000; 18(7): 1465‒73.
34. Perrone F, Bossi P, Cortelazzi B, Locati L, Quattrone P, Pierotti MA, et al. TP53 mutations and pathologic complete response to neoadjuvant cisplatin and fluorouracil chemotherapy in resected oral cavity squamous cell carcinoma. J Clin Oncol 2010; 28(5): 761‒6.
35. Wittekindt C, Wagner S, Sharma SJ, Würdemann N, Knuth J, Reder H, et al. HPV – A different view on Head and Neck Cancer. Laryngorhinootologie 2018; 97(Suppl 1): S48‒S113.
36. Kim R, Lee B, Byun MR, Lee JK, Choi W. Evaluation of pemetrexed and etoposide as therapeutic regimens for human papillomavirus-positive oral and oropharyngeal cancer. PLOS One 2018; 13(7): e0200509.
37. Wu Y, Posner MR, Schumaker LM, Nikitakis N, Goloubeva O, Tan M, et al. Novel biomarker panel predicts prognosis in HPV-negative oropharyngeal cancer: An analysis of the TAX 324 trial (WU). Cancer 2012; 118(7): 1811–7.
38. Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 2014; 740: 364‒78.
39. Zhou G, Liu Z, Myers JN. TP53 Mutations in Head and Neck Squamous Cell Carcinoma and Their Impact on Disease Progression and Treatment Response. J Cell Biochem 2016; 117(12): 2682–92.
40. Tassone P, Old M, Teknos TN, Pan Q. p53-based therapeutics for head and neck squamous cell carcinoma. Oral Oncol 2013; 49(8): 733‒7.
41. Roh JL, Kang SK, Minn I, Califan JA, Sidransky D, Koch WM. p53-Reactivating small molecules induce apoptosis and enhance chemotherapeutic cytotoxicity in head and neck squamous cell carcinoma. Oral Oncol 2011; 47(1): 8‒15.
42. Roh JL, Ko JH, Moon SJ, Ryu CH, Choi JY, Koch WM. The p53-reactivating small-molecule RITA enhances cisplatin-induced cytotoxicity and apoptosis in head and neck cancer. Cancer Letters 2012; 325(1): 35‒41.