OTORHINOLARYNGOLOGICAL SOCIETY OF NIGERIA

ORLSON

ANNUAL GENERAL MEETING AND SCIENTIFIC CONFERENCE

OLUYOLE 2014

28 NOVEMBER 2014

GENETIC BASIS OF HEAD AND NECK

CANCER

E.E.U. Akang FMCPath, FWACPB. Kolude FWACS, MSc University College Hospital, Ibadan

Introduction

•Head and neck cancers share common anatomy, natural history, epidemiology, risk factors and morphology

•Particularly distressing because of complex functional anatomy

• Two-thirds of patients present with advanced disease at the time of diagnosis

Risk factors for Head and Neck CancerHeterogeneous group of neoplasms that differ in aetiology, pathogenesis and eventual outcome

• SUBSTANCE ABUSETobacco, Alcohol, Areca nut, Betel leaf• DIETARYSalted fish/meat, Hypovitaminosis A, Fe/Zn/Se deficiency, Low BMI• VIRUSESHPV16/18, EBV• OCCUPATIONALAsbestos, Ni, Cr, Ra, mustine, leather tanning, woodworking

TUMOUR METASTASIS SUPPRESSOR GENES IN HEAD AND NECK CANCER

Metastasis suppressor genes suppress in vivo development of metastases without affecting the growth of the primary tumour.NM23 suppresses metastasis via three mechanisms: 1. demethylation of specific CPG islands2. reduced motility of tumour cells3. down regulation of MMP2 to inhibit metastasis. Expression of NM23-H1 homologue is associated with decreased lymph node metastasis, while reduced NM23-H1 expression is associated with increased cisplatin resistance in head and neck cancer

ROLE OF MICRORNAS IN HEAD AND NECK CANCER

miRNAs are small non-coding RNAs and genetic regulators, grouped as oncogenic or tumour suppressorOncogenic microRNAs include miR-21, miR-31, and miR-210Tumour suppressor microRNAs include miR-99, miR-133a, and miR-375Mutations involving these 2 broad classes of microRNAs are associated with metastasis and poor prognosis in HNSCC

NUT MIDLINE CARCINOMA

Nuclear protein in Testis (NUT) midline carcinoma (NMC) is an aggressive, poorly-differentiated squamous cell carcinomas characterized by t(15;19) translocation. One-third of NMCs involve head and neck; other sites include mediastinum, urinary bladder, iliac bone, pancreas, parotid gland, and lung has been reported. This usually underdiagnosed tumour can be identified by immunohistochemical demonstration of nuclear reactivity for NUT using a commercially available monoclonal antibody

CONCLUSION

Increasing knowledge of molecular genetics is paving the way to development of therapies with greater potency and less toxicity. It is anticipated that further research shall result in the identification of additional genetically defined subsets of head and neck cancer that can be targeted using novel therapeutic methodsThere is a wide vista for collaborative research into this heterogeneous group of neoplasms in the West African sub region

LIST OF REFERENCES1. Adeyemi BF, Adekunle LV, Kolude BM, Akang EE, Lawoyin JO. Head and neck cancer--a clinicopathological study in a tertiary care center. J Natl Med Assoc 2008 Jun;

100(6):690-7.2. Bhurgri Y, Bhurgri A, Usman A, Pervez S, Kayani N, Bashir I, et al. Epidemiological review of head and neck cancers in Karachi. Asian Pac J Cancer Prev 2006 Apr; 7(2):195-

200.3. Barnes L, Everson J, Reichart P, Sidransky D. Pathology and genetics of head and neck tumours. Lyon: IARC Press; 2005.4. Adeyemi BF, Kolude BM, Ogun GO, Akang EE. Paediatric head and neck malignancies in Ibadan, Nigeria. African Journal of Medicine and Medical Sciences 2009; 38:55-62.5. Vokes EE, Weichselbaum RR, Lippman SM, Hong WK. Head and neck cancer. N Engl J Med 1993 Jan 21; 328(3):184-94.6. Fritz A, Percy C, Jack A, Shanmugaratnam K, Sobin L, Parkin DM, et al. International Classification of Diseases for Oncology. 3rd ed. Geneva: World Health Organization;

2000.7. Chin D, Boyle GM, Porceddu S, Theile DR, Parsons PG, Coman WB. Head and neck cancer: past, present and future. Expert Rev Anticancer Ther 2006 Jul; 6(7):1111-8.8. Leemans CR, Braakhuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer 2011 Jan; 11(1):9-22.9. Parkin DM, Bray F, Ferlay I, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005: 55:74-108.10. Amusa YB, Olabanji JK, Akinpelu VO, Olateju SO, Agbakwuru EA, Ndukwe N, et al. Pattern of head and neck malignant tumours in a Nigerian teaching hospital--a ten year

review. West Afr J Med 2004 Oct; 23(4):280-5.11. Da Lilly-Tariah OB, Somefun AO, Adeyemo WL. Current evidence on the burden of head and neck cancers in Nigeria. Head and Neck Oncology 20091(14)12. Yeole BB, Sunny L, Swaminathan R, Sankaranarayanan R, Parkin DM. Population-based survival from colorectal cancer in Mumbai, (Bombay) India. Eur J Cancer 2001 Jul;

37(11):1402-8.13. Ogunbiyi JO, Fabowale AO, Ladipo AA. Cancer incidence and top ten cancers in eleven local government areas in Ibadan and its environs, 2004-2008: Ibadan Cancer

Registry, Nigeria Technical Report, 2010.14. da Lilly-Tariah OB, Somefun AO, Adeyemo WL. Current evidence on the burden of head and neck cancers in Nigeria. Head Neck Oncol 2009; 1:14.15. Cognetti DM, Weber RS, Lai SY. Head and neck cancer: an evolving treatment paradigm. Cancer 2008 Oct 1; 113(7 Suppl):1911-32.16. Ragin CC, Modugno F, Gollin SM. The epidemiology and risk factors of head and neck cancer: a focus on human papillomavirus. J Dent Res 2007 Feb; 86(2):104-14.17. Oxford Cancer Intelligence Unit. Profile of Head and Neck Cancers in England. Oxford: National Health Service; 2010.18. Cardesa E, Nadal A. Carcinoma of the head and neck in the HPV era. Acta Dermatoven APA 2011; 3:161-73.19. Vokes EE, Weichselbaum RR, Lippman SM, Hong WK. Head and neck cancer. N Engl J Med 1993 Jan 21; 328(3):184-94.20. Boccia S, Hashibe M, Galli P, De FE, Asakage T, Hashimoto T, et al. Aldehyde dehydrogenase 2 and head and neck cancer: a meta-analysis implementing a Mendelian

randomization approach. Cancer Epidemiol Biomarkers Prev 2009 Jan; 18(1):248-54.21. Kreimer AR, Clifford GM, Boyle P, Francheschi S. Human Papillomavirus Types in Head and Neck Squamous Cell Carcinomas Worldwide: A Systematic Review. Cancer

Epidemiol Biomarkers Prev 2005; 14(2):467-75.22. Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. Lancet 2008 May 17; 371(9625):1695-709.23. Marur S, Forastiere AA. Head and neck cancer: changing epidemiology, diagnosis, and treatment. Mayo Clin Proc 2008 Apr; 83(4):489-501.24. Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 2006; 15:176525. Tang M, Lautenberger JA, Gao X, Sezgin E, Hendrickson SL, Troyer JL, et al. The principal genetic determinants for nasopharyngeal carcinoma in China involve the HLA

class I antigen recognition groove. PLOS Genetics 2012; 8(11).26. Kwong RA, Kalish LH, Nguyen TV, Kench JG, Bova RJ, Cole IE, et al. p14ARF protein expression is a predictor of both relapse and survival in squamous cell carcinoma of the

anterior tongue. Clin Cancer Res 2005; 11: 4107-16.27. Hogg RP, Honorio S, Martinez A, Agathanggelou A, Dallol A, Fullwood P, et al. Frequent 3p allele loss and epigenetic inactivation of the RASSF1A tumour suppressor gene

from region 3p21.3 in head and neck squamous cell carcinoma. Eur J Cancer 2002; 38:1585-92.28. Noguchi T, Takeno S, Kimura Y, Uchida Y, Daa T, Yokoyama S, et al. FHIT expression and hypermethylation in esophageal squamous cell carcinoma. Int J Mol Med 2003;

11:441-7.29. Kuroki T, Trapasso F, Yendamuri S, Matsuyama A, Alder H, Mori M, et al. Allele loss and promoter hypermethylation of VHL, RARbeta,RASSF1A, and FHIT tumour-

suppressor genes on chromosome 3p in esophageal squamous cell carcinoma. Cancer Res 2003; 63:3724-8.30. Osman I, Sherman E, Singh B, Venkatraman E, Zelefsky M, Bosl G, et al. Alteration of p53 pathway in squamous cell carcinoma of the head and neck: impact on treatment

outcome in patients treated with larynx preservation intent. J Clin Oncol 2002; 20: 2980-7.31. Garber K. China approves the world’s first oncolytic virus therapy for cancer treatment. J Natl Cancer Inst 2006; 98:298-300.32. Michalides R, van Veelen N, Hart A, Loftus B, Wientjens E, Balm A. Overexpression of cyclin D1 correlates with recurrence in a group of 47 operable squamous cell

carcinomas of the head and neck. Cancer Res 1995; 55:975-8.33. Callender T, el-Naggar AK, Lee MS, Frankenthaler R, Luna MA, Batsakis JG. PRAD-1 (CCND1)/cyclin D1 oncogene amplification in primary head and neck squamous cell

carcinoma. Cancer 1994; 74: 152-8.34. Masuda M, Suzui M, Yasumatu R, Nakashima T, Kuratomi Y, Azuma K, et al. Constitutive activation of signal transducers and activators of transcription 3 (STAT3)

correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer Res 2002; 62:3351-5.35. van Oijen MG, Slootweg PJ. Oral field cancerization: carcinogen-induced independent events or micrometastatic deposits? Cancer Epidemiol Biomarkers Prev 2000;

9:249-56.36. Braakhuis BJ, Tabor MP, Leemans CR, van der Waal I, Snow GB, Brakenhoff RH. Second primary tumours and field cancerization in oral and oropharyngeal cancer:

molecular techniques provide new insights and definitions. Head Neck 2002; 24:198-206.37. van Houten VM, Leemans CR, Kummer JA, Dijkstra J, Kuik DJ, van den Brekel MW, et al. Molecular diagnosis of surgical margins and local recurrence in head and neck

cancer patients: prospective study. Clin Cancer Res 2004; 10:3614-20.38. van der Toorn PP, Veltman JA, Bot FJ, de Jong JM, Manni JJ, Ramaekers FC, et al. Mapping of resection margins of oral cancer for p53 overexpression and chromosome

instability to detect residual (pre)malignant cells. J Pathol 2001; 193:66-72

39. Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, Jan JS, et al. Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med 2004; 350:2461-70.

40. Nathan CO, Sanders K, Abreo FW, Nassar R, Glass J. Correlation of p53 and the proto-oncogene eIF4E in larynx cancers: prognostic implications. Cancer Res 2000; 60:3599-604

41. Ryerson AB, Peters ES, Coughlin SS, Chen VW, Gillison ML, Reichman ME, et al. Burden of potentially human papilloma virus associated cancers of the oropharynx and oral cavity in the US, 1998-2003. Cancer 2008; 113(10):2901-9.

42. Robinson KL, Macferlane GJ. Oropharyngeal cancer incidence and mortality in Scotland: are rates still increasing? Oral Oncol 2003; 39:31-6.43. Klussman JP, Weissenborn SJ, Weiland U. Prevalence, distribution and viral load of human papilloma virus 16 DNA in tonsillar carcinomas. Cancer 2001; 92:2875-84.44. Wiest T, Schwarz E, Enders C, Fletchenmacher C, Bosch FX. Involvement of intact HPV 16 E6/E7 gene expression in head and neck cancers with unaltered p53 status and

perturbed pRb cell cycle control. Oncogene 2002: 21:1510-7.45. Pathmanathan R, Prasad U, Sadler R, Flynn K, Raab-Traub N. Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal

carcinoma. N Engl J Med 1995; 333:693-8.46. Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002; 2(8):563-72.47. Rinker-Schaeffer CW, O’Keefe JP, Welch DR, Theodorescu D. Metastasis suppressor proteins: discovery, molecular mechanisms, and clinical application. Clin Cancer Res

2006; 12:3882-9.48. Shevde LA, Welch DR. Metastasis suppressor pathways: an evolving paradigm. Cancer Lett 2003; 198:1-20.49. Steeg PS, Bevilacqua G, Kopper L, Thorgeirsson UP, Talmadge JE, Liotta LA, et al. Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer

Inst. 1988; 80(3):200-4.50. Iizuka N, Miyamoto K, Tangoku A, Hayashi H, Hazama S, Yoshino S, et al Downregulation of intracellular nm23-H1 prevents cisplatin-induced DNA damage in oesophageal

cancer cells: possible association with Na+, K+-ATPase. Br J Cancer 2000; 83:1209-15.51. Prabhu VV, Siddikuzzaman, Berlin Grace VM, Guruvayoorappan C. Targeting tumour metastasis by regulating Nm23 gene expression. Asian Pacific J Cancer Prev 2012;

13:3539-48.52. Darido C, Georgy SR, Wilanowski T, Dworkin S, Auden A, Zhao Q, et al. Targeting of the tumour suppressor GRHL3 by a miR-21-dependent proto-oncogenic network

results in PTEN loss and tumorigenesis. Cancer Cell 2011; 20:635-48.53. Bourguignon LY, Earle C, Wong G, Spevak CC, Krueger K. Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemo resistance in

hyaluronan/CD44-activated head and neck squamous cell carcinoma cells. Oncogene 2012; 31:149-60.54. Tu HF, Lin SC, Chang KW. MicroRNA aberrances in head and neck cancers: pathogenetic and clinical significance. Curr Opin Otolaryngol Head Neck Surg 2013, 21:104-11.55. Gee HE, Camps C, Buffa FM, Patiar S, Winter SC, Betts G, et al. hsa-mir-210 is a marker of tumour hypoxia and a prognostic factor in head and neck cancer. Cancer 2010;

116:2148-58.56. Chen Z, Jin Y, Yu D, Wang A, Mahjabeen I, Wang C, et al. Down-regulation of the microRNA-99 family members in head and neck squamous cell carcinoma. Oral Oncol

2012; 48(8):686-91.57. Mutallip M, Nohata N, Hanazawa T, Kikkawa N, Horiguchi S, Fujimura L, et al. Glutathione S-transferase P1 (GSTP1) suppresses cell apoptosis and its regulation by miR-

133 alpha in head and neck squamous cell carcinoma (HNSCC). Int J Mol Med 2011; 27:345-52.58. Nohata N, Hanazawa T, Kikkawa N, Mutallip M, Fujimura L, Yoshino H, et al. Caveolin-1 mediates tumour cell migration and invasion and its regulation by miR-133a in

head and neck squamous cell carcinoma. Int J Oncol 2011; 38:209-17.59. Harris T, Jimenez L, Kawachi N, Fan JB, Chen J, Belbin T, et al. Low-level expression of miR-375 correlates with poor outcome and metastasis while altering the invasive

properties of head and neck squamous cell carcinomas. Am J Pathol 2012; 180:917-28.60. Nohata N, Hanazawa T, Kikkawa N, Mutallip M, Sakurai D, Fujimura L, et al. Tumor suppressive microRNA-375 regulates oncogene AEG-1/MTDH in head and neck

squamous cell carcinoma (HNSCC). J Hum Genet 2011; 56:595-601.61. Avissar M, Christensen BC, Kelsey KT, Marsit CJ. MicroRNA expression ratio is predictive of head and neck squamous cell carcinoma. Clin Cancer Res 2009; 15:2850-5.62. Bauer DE, Mitchell CM, Strait KM, Lathan CS, Stelow EB, Luer SC, et al. Clinicopathological features and long term outcomes of NUT midline carcinoma. Clin Cancer Res

2012; 18:5773-9.63. French CA. The importance of diagnosing NUT midline carcinoma. Head Neck Pathol 2013; 7:11-6.64. Park HS, Bae YS, Yoon SO, Lim BJ, Hong HJ, Ro JY, et al. Usefulness of Nuclear protein in Testis (NUT) immunohistochemistry in the cytodiagnosis of NUT midline

carcinoma: a brief case report. Kor J Pathol 2014; 48:335-8.65. Kim MM, Califano JA. Molecular pathology of head and neck cancer. Int J Cancer 2004; 112:545-53.66. Uno M, Otsuki T, Kurebayashi J, Sakaguchi H, Isozaki Y, Ueki A, et al. Anti- HER2-antibody enhances irradiation-induced growth inhibition in head and neck carcinoma. Int

J Cancer 2001; 94:474-9.67. Shin DM, Donato NJ, Perez-Soler R, Shin HJ, Wu JY, Zhang P, et al. Epidermal growth factor receptor–targeted therapy with C225 and cisplatin in patients with head-and-

neck cancer. Clin Cancer Res 2001; 7:1204-13.68. Nemunaitis J, Cunningham C, Buchanan A, Blackburn A, Edelman G, Maples P, et al. Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer

patients: safety, feasibility and biological activity. Gene Ther 2001; 8(10):746-59.69. Xia ZJ, Chang JH, Zhang L, Jiang WQ, Guan ZZ, Liu JW, et al. Phase III randomized clinical trial of intratumoral injection of E1B gene-deleted adenovirus (H101) combined

with cisplatin-based chemotherapy in treating squamous cell cancer of head and neck or esophagus. Ai Zheng 2004; 23(12):1666-70.

Thanks for listening!