WRAP53β, survivin and p16INK4a expression as potential predictors of radiotherapy/chemoradiotherapy response in T2N0-T3N0 glottic laryngeal cancer

Tiefenböck-Hansson,Katharina; Haapaniemi,Aaro; Farnebo,Lovisa; Palmgren,Björn; Tarkkanen,Jussi; Farnebo,Marianne; Munck-Wikland,Eva; Mäkitie,Antti; Garvin,Stina; Roberg,Karin

doi:10.3892/or.2017.5898

WRAP53β, survivin and p16INK4a expression as potential predictors of radiotherapy/chemoradiotherapy response in T2N0-T3N0 glottic laryngeal cancer

Authors:
- Katharina Tiefenböck-Hansson
- Aaro Haapaniemi
- Lovisa Farnebo
- Björn Palmgren
- Jussi Tarkkanen
- Marianne Farnebo
- Eva Munck-Wikland
- Antti Mäkitie
- Stina Garvin
- Karin Roberg
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Affiliations: Division of Otorhinolaryngology and Head and Neck Surgery, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden, Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland, Division of ENT Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden, Department of Pathology, HUSLAB, Helsinki University Hospital and University of Helsinki, Helsinki, Finland, Department of Oncology-Pathology, Cancer Centrum Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden, Department of Clinical Pathology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
Published online on: August 11, 2017 https://doi.org/10.3892/or.2017.5898
Pages: 2062-2068
Copyright: © Tiefenböck-Hansson et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The current treatment recommendation for T2-3N0M0 glottic squamous cell carcinoma (SCC) in the Nordic countries comprises of radiotherapy (RT) and chemoradiotherapy (CRT). Tumor radiosensitivity varies and another option is primary surgical treatment, which underlines the need for predictive markers in this patient population. The aim of the present study was to investigate the relation of the proteins WRAP53β, survivin and p16INK4a to RT/CRT response and ultimate outcome of patients with T2-T3N0 glottic SCC. Protein expression was determined using immunohistochemistry on tumors from 149 patients consecutively treated with RT or CRT at Helsinki University Hospital, Karolinska University Hospital, and Linköping University Hospital during 1999-2010. Our results demonstrate a significantly better 5-year relapse-free survival, disease-free survival (DFS), disease-specific survival and overall survival of patients with T3N0 tumors treated with CRT compared with RT alone. Patients with tumors showing a cytoplasmic staining of WRAP53β revealed significantly worse DFS compared with those with nuclear staining. For survivin, we observed a trend towards better 5-year DFS in patients with strong nuclear survivin expression compared with those with weak nuclear survivin expression (p=0.091). Eleven (7%) tumors showed p16 positivity, with predilection to younger patients, and this age group of patients with p16-positive SCC had a significantly better DFS compared with patients with p16-negative SCC. Taken together, our results highlight WRAP53β as a potential biomarker for predicting RT/CRT response in T2-T3N0 glottic SCC. p16 may identify a small but distinct group of glottic SCC with favorable outcome. Furthermore, for T3N0 patients better outcome was observed following CRT compared to RT alone.

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1	Engholm G, Ferlay J, Christensen N, Bray F, Gjerstorff ML, Klint A, Køtlum JE, Olafsdóttir E, Pukkala E and Storm HH: NORDCAN - a Nordic tool for cancer information, planning, quality control and research. Acta Oncol. 49:725–736. 2010. View Article : Google Scholar : PubMed/NCBI
2	Haapaniemi A, Koivunen P, Saarilahti K, Kinnunen I, Laranne J, Aaltonen LM, Närkiö M, Lindholm P, Grénman R, Mäkitie A, et al: Finnish Head and Neck Oncology Working Group: Laryngeal cancer in Finland: A 5-year follow-up study of 366 patients. Head Neck. 38:36–43. 2016. View Article : Google Scholar : PubMed/NCBI
3	Wennerberg J: A population based perspective on treatment and outcome of glottic laryngeal carcinoma stage T3 and T4 - does organ preservation jeopardize survival?5th World Congress of IFHNOS and the 2014 Annual Meeting of the AHNS. New York: 2014
4	Hoffman HT, Porter K, Karnell LH, Cooper JS, Weber RS, Langer CJ, Ang KK, Gay G, Stewart A and Robinson RA: Laryngeal cancer in the United States: Changes in demographics, patterns of care, and survival. Laryngoscope. 116 Suppl 111:1–13. 2006. View Article : Google Scholar : PubMed/NCBI
5	Olsen KD: Reexamining the treatment of advanced laryngeal cancer. Head Neck. 32:1–7. 2010.PubMed/NCBI
6	Farnebo L, Tiefenbock K, Ansell A, Thunell LK, Garvin S and Roberg K: Strong expression of survivin is associated with positive response to radiotherapy and improved overall survival in head and neck squamous cell carcinoma patients. Int J Cancer. 133:1994–2003. 2013. View Article : Google Scholar : PubMed/NCBI
7	Garvin S, Tiefenböck K, Farnebo L, Thunell LK, Farnebo M and Roberg K: Nuclear expression of WRAP53β is associated with a positive response to radiotherapy and improved overall survival in patients with head and neck squamous cell carcinoma. Oral Oncol. 51:24–30. 2015. View Article : Google Scholar : PubMed/NCBI
8	Garg H, Suri P, Gupta JC, Talwar GP and Dubey S: Survivin: A unique target for tumor therapy. Cancer Cell Int. 16:492016. View Article : Google Scholar : PubMed/NCBI
9	Altieri DC: Targeting survivin in cancer. Cancer Lett. 332:225–228. 2013. View Article : Google Scholar : PubMed/NCBI
10	Li F, Yang J, Ramnath N, Javle MM and Tan D: Nuclear or cytoplasmic expression of survivin: what is the significance? Int J Cancer. 114:509–512. 2005. View Article : Google Scholar : PubMed/NCBI
11	Stauber RH, Mann W and Knauer SK: Nuclear and cytoplasmic survivin: Molecular mechanism, prognostic, and therapeutic potential. Cancer Res. 67:5999–6002. 2007. View Article : Google Scholar : PubMed/NCBI
12	Lo Muzio L, Farina A, Rubini C, Pezzetti F, Stabellini G, Laino G, Santarelli A, Pannone G, Bufo P, de Lillo A, et al: Survivin as prognostic factor in squamous cell carcinoma of the oral cavity. Cancer Lett. 225:27–33. 2005. View Article : Google Scholar : PubMed/NCBI
13	Freier K, Pungs S, Sticht C, Flechtenmacher C, Lichter P, Joos S and Hofele C: High survivin expression is associated with favorable outcome in advanced primary oral squamous cell carcinoma after radiation therapy. Int J Cancer. 120:942–946. 2007. View Article : Google Scholar : PubMed/NCBI
14	Mahmoudi S, Henriksson S, Corcoran M, Méndez-Vidal C, Wiman KG and Farnebo M: Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage. Mol Cell. 33:462–471. 2009. View Article : Google Scholar : PubMed/NCBI
15	Henriksson S and Farnebo M: On the road with WRAP53β: Guardian of Cajal bodies and genome integrity. Front Genet. 6:912015. View Article : Google Scholar : PubMed/NCBI
16	Hedström E, Pederiva C, Farnebo J, Nodin B, Jirström K, Brennan DJ and Farnebo M: Downregulation of the cancer susceptibility protein WRAP53β in epithelial ovarian cancer leads to defective DNA repair and poor clinical outcome. Cell Death Dis. 6:e18922015. View Article : Google Scholar : PubMed/NCBI
17	Silwal-Pandit L, Russnes H, Borgen E, Skarpeteig V, Vollan Moen HK, Schlichting E, Kåresen R, Naume B, Børresen-Dale AL, Farnebo M, et al: The sub-cellular Localization of WRAP53 has prognostic impact in breast cancer. PLoS One. 10:e01399652015. View Article : Google Scholar : PubMed/NCBI
18	Rassoolzadeh H, Böhm S, Hedström E, Gad H, Helleday T, Henriksson S and Farnebo M: Overexpression of the scaffold WD40 protein WRAP53β enhances the repair of and cell survival from DNA double-strand breaks. Cell Death Dis. 7:e22672016. View Article : Google Scholar : PubMed/NCBI
19	Fischer CA, Zlobec I, Green E, Probst S, Storck C, Lugli A, Tornillo L, Wolfensberger M and Terracciano LM: Is the improved prognosis of p16 positive oropharyngeal squamous cell carcinoma dependent of the treatment modality? Int J Cancer. 126:1256–1262. 2010.PubMed/NCBI
20	Castellsagué X, Alemany L, Quer M, Halec G, Quirós B, Tous S, Clavero O, Alòs L, Biegner T, Szafarowski T, et al: ICO International HPV in Head and Neck Cancer Study Group: HPV involvement in head and neck cancers: Comprehensive assessment of biomarkers in 3680 patients. J Natl Cancer Inst. 108:djv4032016. View Article : Google Scholar : PubMed/NCBI
21	Young RJ, Urban D, Angel C, Corry J, Lyons B, Vallance N, Kleid S, Iseli TA, Solomon B and Rischin D: Frequency and prognostic significance of p16^INK4A protein overexpression and transcriptionally active human papillomavirus infection in laryngeal squamous cell carcinoma. Br J Cancer. 112:1098–1104. 2015. View Article : Google Scholar : PubMed/NCBI
22	Morshed K, Polz-Dacewicz M, Szymański M and Polz D: Short-fragment PCR assay for highly sensitive broad-spectrum detection of human papillomaviruses in laryngeal squamous cell carcinoma and normal mucosa: Clinico-pathological evaluation. Eur Arch Otorhinolaryngol. 265 Suppl 1:S89–S96. 2008. View Article : Google Scholar : PubMed/NCBI
23	Rischin D, Young RJ, Fisher R, Fox SB, Le QT, Peters LJ, Solomon B, Choi J, OSullivan B, Kenny LM, et al: Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol. 28:4142–4148. 2010. View Article : Google Scholar : PubMed/NCBI
24	Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, Glisson B, Trotti A, Ridge JA, Chao C, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 349:2091–2098. 2003. View Article : Google Scholar : PubMed/NCBI
25	Nishimura G, Tsukuda M, Mikami Y, Matsuda H, Horiuchi C, Taguchi T, Takahashi M, Kawakami M, Watanabe M, Niho T, et al: Efficacy of concurrent chemoradiotherapy for T1 and T2 laryngeal squamous cell carcinoma regarding organ preservation. Anticancer Res. 29:661–666. 2009.PubMed/NCBI
26	Akimoto T, Nonaka T, Kitamoto Y, Ishikawa H, Ninomiya H, Chikamatsu K, Furuya N, Hayakawa K, Mitsuhashi N and Nakano T: Radiation therapy for T2N0 laryngeal cancer: A retrospective analysis for the impact of concurrent chemotherapy on local control. Int J Radiat Oncol Biol Phys. 64:995–1001. 2006. View Article : Google Scholar : PubMed/NCBI
27	Berardinelli F, Nieri D, Sgura A, Tanzarella C and Antoccia A: Telomere loss, not average telomere length, confers radiosensitivity to TK6-irradiated cells. Mutat Res. 740:13–20. 2012. View Article : Google Scholar : PubMed/NCBI
28	McCaul JA, Gordon KE, Minty F, Fleming J and Parkinson EK: Telomere dysfunction is related to the intrinsic radio-resistance of human oral cancer cells. Oral Oncol. 44:261–269. 2008. View Article : Google Scholar : PubMed/NCBI
29	Henriksson S, Rassoolzadeh H, Hedström E, Coucoravas C, Julner A, Goldstein M, Imreh G, Zhivotovsky B, Kastan MB, Helleday T, et al: The scaffold protein WRAP53beta orchestrates the ubiquitin response critical for DNA double-strand break repair. Genes Dev. 28:2726–2738. 2014. View Article : Google Scholar : PubMed/NCBI
30	Kalfert D, Celakovsky P, Laco J and Ludvikova M: The role of protein p16^INK4a in glottic laryngeal squamous cell carcinoma. Pathol Oncol Res. 20:909–915. 2014. View Article : Google Scholar : PubMed/NCBI
31	Baumann JL, Cohen S, Evjen AN, Law JH, Vadivelu S, Attia A, Schindler JS, Chung CH, Wirth PS, Meijer CJ, et al: Human papillomavirus in early laryngeal carcinoma. Laryngoscope. 119:1531–1537. 2009. View Article : Google Scholar : PubMed/NCBI
32	Jouhi L, Hagström J, Atula T and Mäkitie A: Is p16 an adequate surrogate for human papillomavirus status determination? Curr Opin Otolaryngol Head Neck Surg. 25:108–112. 2017. View Article : Google Scholar : PubMed/NCBI