Mutational spectrum of tobacco associated oral squamous carcinoma and its therapeutic significance

Nishant Batta, Manoj Pandey, Nishant Batta, Manoj Pandey

Abstract

Oral squamous cell cancer (OSCC) is a common malignancy attributed to use of chewing smokeless tobacco and smoking. Most of the targeted strategies are based on EGFR expression and mutation; however, none of them has shown significant improvement in survival and response rates. We carried out this study to evaluate mutational profile of tobacco associated oral carcinoma with special emphasis on EGFR and its downstream events.

Patients and methods: A total of 46 histologically proven cases were recruited between January 2017 and January 2019. Apart from detailed clinical and histological studies, the paraffin-embedded tissue was submitted for expression of 50 genes using Next Generation Sequencing using Ion Ampliseq Cancer Hotspot Panel v2.

Results: The mean age of patients was 47.8 ± 10.9 years. Majority had tumors on buccal mucosa (24) and tongue (13). Nineteen of these tumors were larger than 4 cm, and 5 had adjacent site involvement. Thirty one were node positive. TP53 mutations were commonest seen in 19 followed by CDKN2A in 11, HRAS in 8, PIK3CA in 3, SMARCB1 in 2, and KIT, EGFR, BRAF, STK11, ABL1, RB1 in one case each. Concomitant TP53 mutation was identified with other mutations like CDKN2A, HRAS, KIT, PIK3CA, STK11, SMARCB1, ABL1, and RB1 making tobacco-associated OSCC as a heterogeneous mutational tumor with multiple events. A patient with TP53 mutations has poor disease free survival (47.4 vs 63% p = 0.17); however, this was not statistically significant.

Conclusion: The study shows a heterogeneous mutational spectrum with multiple mutational events in OSCC. The low EGFR mutation rates and higher mutations in EGFR downstream pathways including that in TP53 and HRAS suggest that anti EGFR strategies may not succeed in these tumors and newer agents and therapeutic combinations need to be tried.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Kaplan-Meier survival curve showing difference in survival between p53 mutated and wild groups. The 18 months DFS rates were 53.3% and 71.4% for TP53 mutation present and absent respectively (log rank = 1.44; p = 0.229)

References

    1. Dikshit R, Gupta PC, Ramasundarahettige C, Gajalakshmi V, Aleksandrowicz L, Rajendra Badwe R, et al. Cancer mortality in India: a nationally representative survey. The Lancet. 2012;379:1807–1816. doi: 10.1016/S0140-6736(12)60358-4.
    1. Khan, Z. An overview of oral cancer in Indian subcontinent and recommendations to decrease its incidence. Webmed Central Cancer 3, WMC003626 (2012) (accessed August 2013).
    1. Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45:309–316. doi: 10.1016/j.oraloncology.2008.06.002.
    1. World Health Organization. Tobacco free initiative tobacco/research/cancer/en/ (accessed on 26 Oct 2013).
    1. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Betel-quid and areca-nut chewing and some areca-nut-derived nitrosamines. IARC monographs on the evaluation of carcinogenic risks to humans v. 85 Lyon, France, 2003 ( Monographs/vol85/mono85.pdf) accessed 2013.
    1. Boffetta P, Hecht S, Gray N, Gupta P, Strad K. Smokeless tobacco and cancer. Lancet Oncol. 2008;9:667–675. doi: 10.1016/S1470-2045(08)70173-6.
    1. Gupta PC, Ray CS, Sinha DN, Singh PK. Smokeless tobacco: a major public health problem in the SEA region: a review. Ind. J. Pub. Health. 2011;55:199–209. doi: 10.4103/0019-557X.89948.
    1. Chocolatewala NM, Chaturvedi P. Role of human papilloma virus in the oral carcinogenesis: an Indian perspective. J. Can. Res. Ther. 2009;5:71–77. doi: 10.4103/0973-1482.52788.
    1. Vincenzi B, Zoccoli A, Pantano F, Venditti O, Galluzzo S. Cetuximab: from bench to bedside. Curr Cancer Drug Targets. 2010;10(1):80–95. doi: 10.2174/156800910790980241.
    1. Stanton P, et al. Epidermal growth factor receptor expression by human squamous cell carcinomas of the head and neck, cell lines and xenografts. Br J Cancer. 1994;70(3):427–433. doi: 10.1038/bjc.1994.322.
    1. Bonner JA, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567–578. doi: 10.1056/NEJMoa053422.
    1. Vermorken JB, et al. Platinum-based chemotherapy plus cetuximab in head and neck Cancer. N Engl J Med. 2008;359(11):1116–1127. doi: 10.1056/NEJMoa0802656.
    1. Licitra L, et al. Predictive value of epidermal growth factor receptor expression for first-line chemotherapy plus cetuximab in patients with head and neck and colorectal cancer: analysis of data from the EXTREME and CRYSTAL studies. Eur J Cancer. 2013;49(6):1161–1168. doi: 10.1016/j.ejca.2012.11.018.
    1. Vermorken JB, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J ClinOncol. 2007;25(16):2171–2177. doi: 10.1200/JCO.2006.06.7447.
    1. Vermorken JB, et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol. 2013;14(8):697–710. doi: 10.1016/S1470-2045(13)70181-5.
    1. Eriksen JG, et al. OC-009: update of the randomised phase III trial DAHANCA 19: primary C-RT or RT and zalutumumab for squamous cell carcinomas of head and neck. RadiotherOncol. 2015;114:10.
    1. Cowley GP, Smith JA, Gusterson BA. Increased EGF receptors on human squamous carcinoma cell lines. Br J Cancer. 1986;53(2):223–229. doi: 10.1038/bjc.1986.39.
    1. Abdul Razak AR, et al. A phase II trial of dacomitinib, an oral pan-human EGF receptor (HER) inhibitor, as first-line treatment in recurrent and/or metastatic squamous-cell carcinoma of the head and neck. Ann Oncol. 2012;24(3):761–769. doi: 10.1093/annonc/mds503.
    1. Kim HS, et al. Phase II clinical and exploratory biomarker study of dacomitinib in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck. Clin Cancer Res. 2015;21(3):544–552. doi: 10.1158/1078-0432.CCR-14-1756.
    1. Ferris RL, et al. Nivolumabvs investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. OralOncol. 2018;81:45–51.
    1. Ferris RL, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856–1867. doi: 10.1056/NEJMoa1602252.
    1. Hsu C, et al. Safety and antitumor activity of pembrolizumab in patients with programmed death-ligand 1–positive nasopharyngeal carcinoma: results of the KEYNOTE-028. StudyJClinOncol. 2017;35:4050–4056.
    1. Sina M, et al. P53 gene codon 72 polymorphism in patients with oral squamous cell carcinoma in the population of northern Iran. Med Oral Patol Oral Cir Bucal. 2014;19(6):e550–e555. doi: 10.4317/medoral.19794.
    1. Vlad, et al. High-risk TP53 mutations are associated with extra nodal extension in oral cavity squamous cell carcinoma. Clin Cancer Res. 2018;24(7):1727–1733. doi: 10.1158/1078-0432.CCR-17-0721.
    1. Pickering CR, et al. Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers. Cancer Discov. 2013;3(7):770–781. doi: 10.1158/-12-0537.
    1. Song et al. Common and complex Notch1 mutations in Chinese oral squamous cell carcinoma. Clin Cancer Res. 2014;1;20(3):701-710.
    1. Boyle JO, et al. The incidence of p53 mutations increases with progression of head and neck cancer. Cancer Res. 1993;53(19):4477–4480.
    1. Lazarus P, et al. Relationship between p53 mutation incidence in oral cavity squamous cell carcinomas and patient tobacco use. Carcinogenesis. 1996;17(4):733–739. doi: 10.1093/carcin/17.4.733.
    1. Ostwald C, et al. p53 mutational spectra are different between squamous-cell carcinomas of the lip and the oral cavity. Int J Cancer. Int J Cancer. 2000;88(1):82–86. doi: 10.1002/1097-0215(20001001)88:1<82::AID-IJC13>;2-N.
    1. Fadlullah MZ, et al. Genetically-defined novel oral squamous cell carcinoma cell lines for the development of molecular therapies. Oncotarget. 2016;7(19):27802–27818. doi: 10.18632/oncotarget.8533.
    1. Okada T, Iizuka N, Yamada-Okabe H, Mori N, Tamesa T, Takemoto N, Tangoku A, Hamada K, Nakayama H, Miyamoto T, Uchimura S, Hamamoto Y, Oka M. Gene expression profile linked to p53 status in hepatitis C virus-related hepatocellular carcinoma. FEBS Lett. 2003;555(3):583–590. doi: 10.1016/S0014-5793(03)01345-0.
    1. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807–1812. doi: 10.1126/science.1164382.
    1. Dubot C, Bernard V, Sablin MP, Vacher S, Chemlali W, Schnitzler A, et al. Comprehensive genomic profiling of head and neck squamous cell carcinoma reveals FGFR1 amplifications and tumour genomic alterations burden as prognostic biomarkers of survival. Eur J Cancer. 2018;91:47–55. doi: 10.1016/j.ejca.2017.12.016.
    1. Loeffler-Ragga J, et al. Low incidence of mutations in EGFR kinase domain in Caucasian patients with head and neck squamous cell carcinoma. European Journal of Cancer. 2006;42(1):109–111. doi: 10.1016/j.ejca.2005.08.034.
    1. Bos JL. The ras gene family and human carcinogenesis. Mutation Research. 1988;195:255–271. doi: 10.1016/0165-1110(88)90004-8.
    1. Michmerhuizen NL, Birkeland AC, Bradford CR, Brenner JC. Genetic determinants in head and neck squamous cell carcinoma and their influence on global personalized medicine. Genes Cancer. 2016;7(5-6):182–200.
    1. Sathyan KM, Nalinakumari KR, Kannan S. H-Ras mutation modulates the expression of major cell cycle regulatory proteins and disease prognosis in oral carcinoma. Modern Pathology. 2007;20:1141–1148. doi: 10.1038/modpathol.3800948.
    1. Milasin, et al. High incidence of H-ras oncogene mutations in squamous cell carcinoma of lip vermilion. J Oral Pathol Med. 1994;23:298–301. doi: 10.1111/j.1600-0714.1994.tb00065.x.
    1. Das N, Majumder J. UB Dasgupta. Ras gene mutations in oral cancer in eastern India Oral Oncology. 2000;36:76–80.
    1. Weber A, et al. Mutations of the BRAF gene in squamous cell carcinoma of the head and neck. Oncogene. 2003;22:4757–4759. doi: 10.1038/sj.onc.1206705.
    1. Karl C, Bruckman, et al. Mutational analyses of the BRAF, KRAS, and PIK3CA genes in oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral RadiolEndod. 2010;110:632–637. doi: 10.1016/j.tripleo.2010.05.002.
    1. Lim, et al. Differential mechanisms of CDKN2A (p16) alteration in oral tongue squamous cell carcinomas and correlation with patient outcome. Int. J. Cancer. 2014;135:887–895. doi: 10.1002/ijc.28727.
    1. Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554. doi: 10.1126/science.1096502.
    1. Kozaki, et al. PIK3CA mutation is an oncogenic aberration at advanced stages of oral squamous cell carcinoma. Cancer Sci. 2006;97:1351–1358. doi: 10.1111/j.1349-7006.2006.00343.x.
    1. Chen S, Liu H, Liao C, Huang P, Huang Y, Hsu A, et al. Ultra-deep targeted sequencing of advanced oral squamous cell carcinoma identifies a mutation-based prognostic gene signature. Oncotarget. 2015;6(20):1866–1880.
    1. Feldman R, Gatalica Z, Knezetic J, Reddy S, Nathan C, Javadi N, Teknos T. Molecular profiling of head and neck squamous cell carcinoma. Head & Neck. 2016:E1625–38.
    1. Lui VWY, Hedberg ML, Li H, et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discovery. 2013;3:761–769. doi: 10.1158/-13-0103.
    1. Inokuchi K, Yamaguchi H, Tarusawa M, et al. Abnormality of c-kit oncoprotein in certain patients with chronic myelogenousleukemia—potential clinical significance. Leukemia. 2002;16:170–177. doi: 10.1038/sj.leu.2402341.
    1. Tan, et al. Tongue carcinoma infrequently harbor common actionable genetic alterations. BMC Cancer. 2014;14:679. doi: 10.1186/1471-2407-14-679.
    1. Chung CH, Guthrie VB, Masica DL, Tokheim C, Kang H, Richmon J, Agrawal N, Fakhry C, Quon H, Subramaniam RM, Zuo Z, Seiwert T, Chalmers ZR, Frampton GM, Ali SM, Yelensky R, Stephens PJ, Miller VA, Karchin R, Bishop JA.Genomic alterations in head and neck squamous cell carcinoma determined by cancer gene-targeted sequencing. Ann Oncol. 2015;26(6):1216-1223. doi: 10.1093/annonc/mdv109. Epub 2015 Feb 23.
    1. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, Kryukov GV, Lawrence MS, Sougnez C, McKenna A, Shefler E, Ramos AH, Stojanov P, Carter SL, Voet D, Cortés ML, Auclair D, Berger MF, Saksena G, Guiducci C, Onofrio RC, Parkin M, Romkes M, Weissfeld JL, Seethala RR, Wang L, Rangel-Escareño C, Fernandez-Lopez JC, Hidalgo-Miranda A, Melendez-Zajgla J, Winckler W, Ardlie K, Gabriel SB, Meyerson M, Lander ES, Getz G, Golub TR, Garraway LA, Grandis JR. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333(6046):1157–1160. doi: 10.1126/science.1208130.
    1. Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ, Fakhry C, Xie TX, Zhang J, Wang J, Zhang N, El-Naggar AK, Jasser SA, Weinstein JN, Treviño L, Drummond JA, Muzny DM, Wu Y, Wood LD, Hruban RH, Westra WH, Koch WM, Califano JA, Gibbs RA, Sidransky D, Vogelstein B, Velculescu VE, Papadopoulos N, Wheeler DA, Kinzler KW, Myers JN. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science. 2011;333(6046):1154-1157. doi: 10.1126/science.1206923. Epub 2011 Jul 28.

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