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WRAP53 beta, survivin and p16(INK4a) expression as potential predictors of radiotherapy/chemoradiotherapy response in T2N0-T3N0 glottic laryngeal cancer
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
Helsinki University Hospital, Finland; University of Helsinki, Finland.
Linköping University, Department of Clinical and Experimental Medicine, Division of Speech language pathology, Audiology and Otorhinolaryngology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
Karolinska University Hospital, Sweden.
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2017 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 38, no 4, p. 2062-2068Article in journal (Refereed) Published
Abstract [en]

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 WRAP53 beta, 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 Linkping 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 WRAP53 beta 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 WRAP53 beta 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.

Place, publisher, year, edition, pages
SPANDIDOS PUBL LTD , 2017. Vol. 38, no 4, p. 2062-2068
Keywords [en]
head and neck cancer; radiotherapy; chemoradiotherapy; survival; recurrence; biomarker; WRAP53 beta; survivin; p16
National Category
Surgery
Identifiers
URN: urn:nbn:se:liu:diva-141926DOI: 10.3892/or.2017.5898ISI: 000411688200017PubMedID: 28849066OAI: oai:DiVA.org:liu-141926DiVA, id: diva2:1149197
Note

Funding Agencies|Swedish Cancer Society [2010/545]; County Council of Ostergotland; Research Funds of Linkoping University Hospital; Finnish Cancer Society; Finnish Medical Foundation; Finnish-Norwegian Medical Foundation; Helsinki University Hospital Research Funds [TYH2015204]

Available from: 2017-10-13 Created: 2017-10-13 Last updated: 2018-05-03
In thesis
1. The impact of Survivin, WRAP53β, and Hypoxia on treatment response in Head and Neck Cancer
Open this publication in new window or tab >>The impact of Survivin, WRAP53β, and Hypoxia on treatment response in Head and Neck Cancer
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Squamous cell carcinoma (SCC) is the most common histological type of cancer in the head and neck region and arises in the epithelial mucosa of the upper aerodigestive tract. Approximately one and a half million people are living with the diagnosis. Despite efforts in prevention and advances in treatment, the 5-year survival rate still lies around 60%, and recurrences and second primary tumors remain a problem. Moreover, treatment responses vary from patient to patient, highlighting the need for individually tailored treatments. To make this possible, biomarkers predicting treatment outcome are needed to better guide treatment decisions.

The aim of this thesis was to evaluate the expression of certain proteins and the frequency of certain SNPs (Single nucleotide polymorphisms) in tumor biopsies and cell cultures of head and neck squamous cell carcinomas (HNSCC), and to explore their potential as biomarkers for treatment outcome. Furthermore, we aimed to study the impact of hypoxia on treatment response, epithelial-tomesenchymal transition (EMT), and induction of cancer stem cells (CSC).

In papers I and II, we investigated two proteins, survivin and WRAP53β, using immunohistochemistry (IHC) in tumor biopsies from 40 patients categorized as Non-responders or Responders to radiotherapy. High expression of survivin and nuclear expression of WRAP53β were significantly more prevalent in the Responder group. The combination of these two factors correlated strongest to overall survival, but not to a significantly higher extent compared to survivin alone. Moreover, when examined separately, a high percentage of p53-stained cells and the presence of the SNP FGFR4 Gln388Arg correlated to improved overall survival, whereas the SNP XPD Lys751Gln was associated with worse overall survival. The latter three showed no significant correlations to radiotherapy response. In paper III, the two most promising proteins identified in papers I and II were analyzed in a study cohort of 149 tumor biopsies of glottic laryngeal SCC, categorized as T2N0-T3N0. In this patient group, no significant associations between survivin expression and survival could be found. However, expression of cytoplasmic WRAP53β was significantly linked to worse disease-free-survival (DSF) compared to nuclear WRAP53β or negative staining for WRAP53β. Positive expression of p16INK4a was found in 7% of the tumors. The prevalence of p16 INK4a was higher in younger patients (<60) and associated with absence of recurrence and longer DSF.

In paper IV, five HNSCC cell lines were cultured in normoxic (20% O2) and hypoxic (1% O2) conditions and changes in treatment response, EMT profile, and expression of CSC markers were examined. As expected, hypoxia induced EMT and to a certain extent expression of CSC markers. Silencing of the hypoxia-inducible-factor-1α (HIF-1α) only partly reversed these effects, suggesting that other mechanisms are involved. Whereas most cell lines became more resistant to treatment in hypoxia, one cell line (LK0412) became more sensitive to cetuximab-treatment in hypoxia, an effect that was revoked by depletion of HIF-1α, suggesting a possible sensitizing effect of HIF-1α to cetuximab-treatment.

Taken together, WRAP53β appears to be a promising biomarker candidate for treatment outcome in HNSCC, but further evaluation especially on the subcellular localization of WRAP53β is required. Even though the role of survivin in radiotherapy response in glottic SCC seems to be insignificant, it might have a more important role in other HNSCC subsites. As far as the effects of hypoxia, it appears that hypoxia might have a sensitizing effect on cetuximab-treatment in certain cases, which seems to be HIF1-α –dependent. Further studies are required to clarify the importance of this observation.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2017. p. 80
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1584
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-142112 (URN)10.3384/diss.diva-142112 (DOI)9789176854709 (ISBN)
Public defence
2017-11-16, Granitsalen, Norra Entrén, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Cancer SocietyRegion ÖstergötlandSwedish Research CouncilÅke Wiberg Foundation
Available from: 2017-10-23 Created: 2017-10-23 Last updated: 2017-11-14Bibliographically approved

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