Skip to main content

Advertisement

Log in

Clinical and molecular characteristics of Jordanian oropharyngeal cancer patients according to P16 expression: a retrospective study and a report of a novel biomarker

  • Original Paper
  • Published:
Medical Molecular Morphology Aims and scope Submit manuscript

Abstract

The purpose of this study was to assess the clinicopathological features of oropharyngeal cancer patients in Jordan based on their HPV status. Sixty-nine biopsies from two hospitals were included. Tissue microarrays were prepared from formalin-fixed paraffin-embedded (FFPE) specimens and stained with antibodies for CDKN2A/P16, EGFR, PI3K, PTEN, AKT, pS473AKT, PS2mTOR, and TIMAP. The cohort was divided according to P16 expression. Chi-square test and survival analyses were employed to evaluate the variations among the study variables and determine the prognostic factors, respectively. P16 expression was found in 55.1% of patients; however, there was no significant association between P16 expression and the patients’ clinicopathological features. The Kaplan–Meier test revealed that smoking in P16-positive group and younger age (< 58 years) negatively impacted disease-free survival (DFS) (P = 0.04 and P = 0.003, respectively). Multivariate Cox regression test indicated that smoking, age, PI3K, and AKT were negative predictors of DFS (P = 0.021, P = 0.002, P = 0.021, and P = 0.009, respectively), while TIMAP was a positive predictor (P = 0.045). Elevated P16 expression is found in more than half of the patients’ specimens. DFS is negatively affected by younger age and the combined effect of smoking and P16 overexpression. TIMAP is overexpressed in P16-positive oropharyngeal cancer, and it is a favorable predictor of DFS.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Park JO, Nam IC, Kim CS, Park SJ, Lee DH, Kim HB et al (2022) Sex differences in the prevalence of head and neck cancers: a 10-year follow-up study of 10 million healthy people. Cancers (Basel). 14(10):2521

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Gillison ML, Koch WM, Capone RB, Spafford M, Westra WH, Wu L et al (2000) Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 92(9):709–720

    Article  PubMed  CAS  Google Scholar 

  3. Baron AE, Franceschi S, Barra S, Talamini R, La Vecchia C (1993) A comparison of the joint effects of alcohol and smoking on the risk of cancer across sites in the upper aerodigestive tract. Cancer Epidemiol Biomarkers Prev. 2(6):519–523

    PubMed  CAS  Google Scholar 

  4. Chen AM, Zahra T, Daly ME, Farwell DG, Luu Q, Gandour-Edwards R et al (2013) Definitive radiation therapy without chemotherapy for human papillomavirus-positive head and neck cancer. Head Neck 35(11):1652–1656

    Article  PubMed  PubMed Central  Google Scholar 

  5. Smolensky D, Rathore K, Bourn J, Cekanova M (2017) Inhibition of the PI3K/AKT pathway sensitizes oral squamous cell carcinoma cells to anthracycline-based chemotherapy in vitro. J Cell Biochem 118(9):2615–2624

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Laimer K, Spizzo G, Gastl G, Obrist P, Brunhuber T, Fong D et al (2007) High EGFR expression predicts poor prognosis in patients with squamous cell carcinoma of the oral cavity and oropharynx: a TMA-based immunohistochemical analysis. Oral Oncol 43(2):193–198

    Article  PubMed  CAS  Google Scholar 

  7. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18(16):1926–1945

    Article  PubMed  CAS  Google Scholar 

  8. Bussink J, van der Kogel AJ, Kaanders JHAM (2008) Activation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer. Lancet Oncol 9(3):288–296

    Article  PubMed  CAS  Google Scholar 

  9. Xie Ming S, Shen Jia L, Yin C, Ruan P, Yao X (2006) Expression of tumor suppressor gene PTEN, PIP3 and cyclin D1 in oral squamous cell carcinoma and their correlations. Zhonghua Kou Qiang Yi Xue Za Zhi. 41(7):407–410

    Google Scholar 

  10. Shashidhar K, Basti S, Swarnamba UN, Ajur S (2022) Surrogate marker P16 in oral/oropharyngeal carcinoma. Int J Health Sci Qassim. https://doi.org/10.53730/ijhs.v6nS4.12275

    Article  Google Scholar 

  11. Cairns P, Polascik TJ, Eby Y, Tokino K, Califano J, Merlo A et al (1995) Frequency of homozygous deletion at p16/CDKN2 in primary human tumours. Nat Genet 11(2):210–212

    Article  PubMed  CAS  Google Scholar 

  12. Moharil R, Khandekar S, Dive A, Bodhade A (2020) Cyclin D1 in oral premalignant lesions and oral squamous cell carcinoma: an immunohistochemical study. J Oral Maxillofac Pathol. 24(2):397

    Article  PubMed  PubMed Central  Google Scholar 

  13. Obeidat M, Bodoor K, Alqudah M, Masaadeh A, Barukba M, Almomani R (2021) TIMAP upregulation correlates negatively with survival in HER2- negative subtypes of breast cancer. Asian Pac J Cancer Prev 22(6):1899–1905

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. PPP1R16B protein expression summary-the human protein atlas

  15. Obeidat M, Li L, Ballermann BJ (2014) TIMAP promotes angiogenesis by suppressing PTEN-mediated Akt inhibition in human glomerular endothelial cells. Am J Physiol Renal Physiol. https://doi.org/10.1152/ajprenal.00070.2014

    Article  PubMed  Google Scholar 

  16. Yang J, Yin S, Bi F, Liu L, Qin T, Wang H et al (2017) TIMAP repression by TGFβ and HDAC3-associated Smad signaling regulates macrophage M2 phenotypic phagocytosis. J Mol Med. https://doi.org/10.1007/s00109-016-1479-z

    Article  PubMed  Google Scholar 

  17. Csortos C, Czikora I, Bogatcheva NV, Adyshev DM, Poirier C, Olah G et al (2008) TIMAP is a positive regulator of pulmonary endothelial barrier function. Am J Physiol Lung Cell Mol Physiol. https://doi.org/10.1152/ajplung.00325.2007

    Article  PubMed  PubMed Central  Google Scholar 

  18. Abdel-razeq H, Attiga F, Mansour A (2015) Cancer care in Jordan. Hematol Oncol Stem Cell Ther 8(2):64–70

    Article  PubMed  Google Scholar 

  19. Shukr B, Bartelli D, Ward KD, Ray M, Maziak W, Mzayek F (2023) The effect of exposure to tobacco smoking-related media messages on youths’ smoking behavior in Jordan: a longitudinal, school-based study. Prev Med (Baltim). 166:107386

    Article  Google Scholar 

  20. Bodoor K, Almomani R, Alqudah M, Haddad Y, Samouri W (2020) LAT1 (SLC7A5) overexpression in negative her2 group of breast cancer: a potential therapy target. Asian Pacific J Cancer Prev. https://doi.org/10.31557/APJCP.2020.21.5.1453

    Article  Google Scholar 

  21. Lydiatt WM, Patel SG, Osullivan B, Brandwein MS, Ridge JA, Migliacci JC et al (2017) Head and neck cancers—major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 67(2):122

    Article  PubMed  Google Scholar 

  22. Vazquez-Guillen JM, Palacios-Saucedo GC, Alanis-Valdez AY, Huerta-Escobedo A, Zavala-Pompa A, Rivera-Morales LG et al (2023) p16INK4a and pRb expression in laryngeal squamous cell carcinoma with and without infection by EBV or different genotypes of HPV: a retrospective study. Infect Agent Cancer. https://doi.org/10.1186/s13027-023-00514-x

    Article  PubMed  PubMed Central  Google Scholar 

  23. Khanna S, Palackdharry S, Roof L, Wicker CA, Mark J, Zhu Z et al (2020) Determining the molecular landscape and impact on prognosis in HPV-associated head and neck cancer. Cancers Head Neck. https://doi.org/10.1186/s41199-020-00058-2

    Article  PubMed  PubMed Central  Google Scholar 

  24. Wendt M, Hammarstedt-Nordenvall L, Zupancic M, Friesland S, Landin D, Munck-Wikland E et al (2021) Long-term survival and recurrence in oropharyngeal squamous cell carcinoma in relation to subsites, HPV, and p16-status. Cancers (Basel). 13(11):2553

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Bixofis RB, Sassi LM, Patussi C, Jung JE, Ioshii SO, Schussel JL (2014) Significance of p16 positive expression in oropharyngeal cancers. Asian Pacific J Cancer Prev. 15(23):10289

    Article  Google Scholar 

  26. Ukpo OC, Flanagan JJ, Ma XJ, Luo Y, Thorstad WL, Lewis JS (2011) High-risk human papillomavirus E6/E7 mRNA detection by a novel in situ hybridization assay strongly correlates with p16 expression and patient outcomes in oropharyngeal squamous cell carcinoma. Am J Surg Pathol. 35(9):1343–50. https://doi.org/10.1097/pas.0b013e318220e59d

    Article  PubMed  Google Scholar 

  27. Yamashita Y, Ikegami T, Hirakawa H, Uehara T, Deng Z, Agena S et al (2019) Staging and prognosis of oropharyngeal carcinoma according to the 8th Edition of the American Joint Committee on Cancer Staging Manual in human papillomavirus infection. Eur Arch Otorhinolaryngol. 276(3):827–836

    Article  PubMed  Google Scholar 

  28. AJCC (2020) AJCC Cancer Staging Manual 8th Edition. In: Definitions [Internet]. Qeios. https://doi.org/10.32388/b30ldk

  29. Alsbeih G, Al-Harbi N, Bin Judia S, Al-Qahtani W, Khoja H, El-Sebaie M et al (2019) Prevalence of human papillomavirus (HPV) infection and the association with survival in Saudi patients with head and neck squamous cell carcinoma. Cancers (Basel). 11(6):820

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Hanna GJ, Kacew A, Chau NG, Shivdasani P, Lorch JH, Uppaluri R et al (2018) Improved outcomes in PI3K-pathway-altered metastatic HPV oropharyngeal cancer. JCI Insight. 3(17):e122799

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kwon HJ, Brasch HD, Benison S, Marsh RW, Itinteang T, Titchener GW et al (2016) Changing prevalence and treatment outcomes of patients with p16 human papillomavirus related oropharyngeal squamous cell carcinoma in New Zealand. Br J Oral Maxillofac Surg. 54(8):898–903. https://doi.org/10.1016/j.bjoms.2016.05.033

    Article  PubMed  CAS  Google Scholar 

  32. Berman TA, Schiller JT (2017) Human papillomavirus in cervical cancer and oropharyngeal cancer: one cause, two diseases. Cancer. 123:2219

    Article  PubMed  Google Scholar 

  33. Carlander AF, Jakobsen KK, Bendtsen SK, Garset-Zamani M, Lynggaard CD, Jensen JS et al (2021) A contemporary systematic review on repartition of HPV-positivity in oropharyngeal cancer worldwide. Viruses. 13(7):1326

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Goulart J, Hay J, Thomson T (2009) 102 the prognostic value of P16 status in advanced stage oropharyngeal carcinoma according to treatment regime. Radiother Oncol. 92:S33. https://doi.org/10.1016/s0167-8140(12)72489-1

    Article  Google Scholar 

  35. Sinha P, Karadaghy OA, Doering MM, Tuuli MG, Jackson RS, Haughey BH (2018) Survival for HPV-positive oropharyngeal squamous cell carcinoma with surgical versus non-surgical treatment approach: a systematic review and meta-analysis. Oral Oncol. 86:121–131. https://doi.org/10.1016/j.oraloncology.2018.09.018

    Article  PubMed  Google Scholar 

  36. Lewis JS Jr, Thorstad WL, Chernock RD, Haughey BH, Yip JH, Zhang Q et al (2010) p16 positive oropharyngeal squamous cell carcinoma: an entity with a favorable prognosis regardless of tumor HPV status. Am J Surg Pathol. 34(8):1088–1096

    Article  PubMed  Google Scholar 

  37. Culié D, Lisan Q, Leroy C, Modesto A, Schiappa R, Chamorey E et al (2021) Oropharyngeal cancer: first relapse description and prognostic factor of salvage treatment according to p16 status, a GETTEC multicentric study. Eur J Cancer. 143:168–177. https://doi.org/10.1016/j.ejca.2020.10.034

    Article  PubMed  Google Scholar 

  38. Anantharaman D, Muller DC, Lagiou P, Ahrens W, Holcátová I, Merletti F et al (2016) Combined effects of smoking and HPV16 in oropharyngeal cancer. Int J Epidemiol. 45(3):752

    Article  PubMed  PubMed Central  Google Scholar 

  39. Bouland C, Dequanter D, Lechien JR, Hanssens C, De Saint Aubain N, Digonnet A et al (2021) Prognostic significance of a scoring system combining p16, smoking, and drinking status in a series of 131 patients with oropharyngeal cancers. Int J Otolaryngol. https://doi.org/10.1155/2021/8020826

    Article  PubMed  PubMed Central  Google Scholar 

  40. Mehanna H, Taberna M, von Buchwald C, Tous S, Brooks J, Mena M et al (2023) Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis. Lancet Oncol. 24(3):239

    Article  PubMed  CAS  Google Scholar 

  41. Dahlstrom KR, Song J, Thall PF, Fuller CD, Hutcheson KA, Johnson FM et al (2021) Conditional survival among patients with oropharyngeal cancer treated with radiation therapy and alive without recurrence 5 years after diagnosis. Cancer. 127(8):1228–1237

    Article  PubMed  Google Scholar 

  42. Lai YH, Su CC, Wu SY, Hsueh WT, Wu YH, Chen HHW et al (2022) Impact of alcohol and smoking on outcomes of HPV-related oropharyngeal cancer. J Clin Med. 11(21):6510

    Article  PubMed  PubMed Central  Google Scholar 

  43. Bar Ad V, Wang Z, Mishra M, Ahn P, Cognetti D, Curry J et al (2011) Combination of p16 levels and pre-radiotherapy factors predict for outcome in patients treated for oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 81(2):S500–S501. https://doi.org/10.1016/j.ijrobp.2011.06.1022

    Article  Google Scholar 

  44. Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm T, Alsner J, Overgaard J (2009) Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol. 27(12):1992–1998. https://doi.org/10.1200/jco.2008.20.2853

    Article  PubMed  CAS  Google Scholar 

  45. Gillison ML, D’Souza G, Westra W, Sugar E, Xiao W, Begum S et al (2008) Distinct risk factor profiles for human papillomavirus type 16–positive and human papillomavirus type 16–negative head and neck cancers. J Natl Cancer Inst. 100(6):407–20. https://doi.org/10.1093/jnci/djn025

    Article  PubMed  Google Scholar 

  46. Kelly JR, An Y, Park HSM, Yarbrough W, Burtness BA, Husain ZA (2017) Survival Outcomes Among Human Papillomavirus-Associated Oropharyngeal Squamous Cell Cancer Patients Treated with Upfront Surgery Versus Definitive Chemoradiation Therapy. Int J Radiat Oncol Biol Phys. 99(2):S43–S44. https://doi.org/10.1016/j.ijrobp.2017.06.114

    Article  Google Scholar 

  47. Panda S, Mohanty N, Panda S, Mishra L, Gopinath D, Sahoo A et al (2022) Are survival outcomes different for young and old patients with oral and oropharyngeal squamous cell carcinoma? A systematic review and meta-analysis. Cancers (Basel). 14(8):1886

    Article  PubMed  PubMed Central  Google Scholar 

  48. Choi I, Lee D, Son K, Bae S (2020) Incidence, cost and gender differences of oropharyngeal and noncervical anogenital cancers in South Korea [Internet]. Research Square Platform LLC. https://doi.org/10.21203/rs.2.23463/v1

  49. Simpson DR, Mell LK, Cohen EEW (2015) Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck. Oral Oncol. 51(4):291–8. https://doi.org/10.1016/j.oraloncology.2014.11.012

    Article  PubMed  CAS  Google Scholar 

  50. Janecka-Widła A, Majchrzyk K, Mucha-Małecka A, Biesaga B (2021) EGFR/PI3K/Akt/mTOR pathway in head and neck squamous cell carcinoma patients with different HPV status. Polish J Pathol. 72(4):296–314. https://doi.org/10.5114/pjp.2021.113073

    Article  Google Scholar 

  51. García-Carracedo D, Villaronga MÁ, Álvarez-Teijeiro S, Hermida-Prado F, Santamaría I, Allonca E et al (2016) Impact of PI3K/AKT/mTOR pathway activation on the prognosis of patients with head and neck squamous cell carcinomas. Oncotarget [Internet]. 7(20):29780–93

    Article  PubMed  PubMed Central  Google Scholar 

  52. Iglesias-Bartolome R, Martin D, Gutkind JS (2013) Exploiting the head and neck cancer oncogenome: widespread PI3K-mTOR pathway alterations and novel molecular targets. Cancer Discov. 3(7):722–5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Won HS, Jung CK, Chun SH, Kang JH, Kim YS, Sun DI et al (2012) Difference in expression of EGFR, pAkt, and PTEN between oropharyngeal and oral cavity squamous cell carcinoma. Oral Oncol. 48(10):985–90. https://doi.org/10.1016/j.oraloncology.2012.04.013

    Article  PubMed  CAS  Google Scholar 

  54. Chun SH, Jung CK, Won HS, Kang JH, Kim YS, Kim MS (2014) Divergence of P53, PTEN, PI3K, Akt and mTOR expression in tonsillar cancer. Head Neck. 37(5):636–43. https://doi.org/10.1002/hed.23643

    Article  PubMed  Google Scholar 

  55. Weber SM, Lu S, Wang XJ (2006) 08:00 AM: alterations in the PI3K/AKT pathway in head and neck cancer. Otolaryngol Head Neck Surg. 135(2):P85. https://doi.org/10.1016/j.otohns.2006.06.499

    Article  Google Scholar 

  56. Larque AB, Conde L, Hakim S, Alos L, Jares P, Vilaseca I et al (2015) p16INK4a overexpression is associated with CDKN2A mutation and worse prognosis in HPV-negative laryngeal squamous cell carcinomas. Virchows Archiv. 466(4):375–82. https://doi.org/10.1007/s00428-015-1725-8

    Article  PubMed  CAS  Google Scholar 

  57. Lassen P, Overgaard J, Eriksen JG (2013) Expression of EGFR and HPV-associated p16 in oropharyngeal carcinoma: correlation and influence on prognosis after radiotherapy in the randomized DAHANCA 5 and 7 trials. Radiother Oncol. 108(3):489–94. https://doi.org/10.1016/j.radonc.2013.08.036

    Article  PubMed  CAS  Google Scholar 

  58. Kiessling SY, Broglie MA, Soltermann A, Huber GF, Stoeckli SJ (2018) Comparison of PI3K pathway in HPV-associated oropharyngeal cancer with and without tobacco exposure. Laryngoscope Investig Otolaryngol. 3(4):283–9

    Article  PubMed  PubMed Central  Google Scholar 

  59. Horn D, Freudlsperger C, Holzinger D, Kunzmann K, Plinkert P, Dyckhoff G et al (2017) Upregulation of pAKT(Ser473) expression in progression of HPV-positive oropharyngeal squamous cell carcinoma. Head Neck. 39(12):2397–405. https://doi.org/10.1002/hed.24910

    Article  PubMed  Google Scholar 

  60. Obeidat M, Bodoor K, Alqudah M, Masaadeh A, Barukba M, Almomani R (2021) TIMAP upregulation correlates negatively with survival in HER2-negative subtypes of breast cancer. Asian Pac J Cancer Prev. 22(6):1899–1905 https://doi.org/10.31557/APJCP.2021.22.6.1899

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Funding

Deanship of Scientific Research,Jordan university of science and technology.

Author information

Authors and Affiliations

Authors

Contributions

Conceptualization: MO, WA, and KB; data curation: MO; formal analysis: MO; investigation, MB, IM, FB, and SB; methodology: MO; resources: MO, SB, and WA; validation: MO, KB, SB, and WA; writing––original draft: MO, MB, and WA; Writing––review and editing: MO, KB, and WA.

Corresponding author

Correspondence to Marya Obeidat.

Ethics declarations

Conflict of interest

The authors declare no proprietary or commercial interest in any product mentioned or concept discussed in this article.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Obeidat, M., Algargaz, W., Barukba, M. et al. Clinical and molecular characteristics of Jordanian oropharyngeal cancer patients according to P16 expression: a retrospective study and a report of a novel biomarker. Med Mol Morphol (2024). https://doi.org/10.1007/s00795-024-00383-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00795-024-00383-2

Keywords

Navigation