Towards Prognostic Profiling of Non-Small Cell Lung Cancer: New Perspectives on the Relevance of Polo-Like Kinase 1 Expression, the TP53 Mutation Status and Hypoxia

Jolien Van den Bossche; Christophe Deben; Ken Op de Beeck; Vanessa Deschoolmeester; Christophe Hermans; Ines De Pauw; Julie Jacobs; Paul Van Schil; Jan Baptist Vermorken; Patrick Pauwels; Marc Peeters; Filip Lardon; An Wouters

doi:10.7150/jca.18455

Towards Prognostic Profiling of Non-Small Cell Lung Cancer: New Perspectives on the Relevance of Polo-Like Kinase 1 Expression, the TP53 Mutation Status and Hypoxia

J Cancer. 2017 May 12;8(8):1441-1452. doi: 10.7150/jca.18455. eCollection 2017.

Authors

Jolien Van den Bossche¹, Christophe Deben^{1

2}, Ken Op de Beeck^{1

3}, Vanessa Deschoolmeester^{1

2}, Christophe Hermans^{1

2}, Ines De Pauw¹, Julie Jacobs^{1

2}, Paul Van Schil⁴, Jan Baptist Vermorken^{1

5}, Patrick Pauwels^{1

2}, Marc Peeters^{1

5}, Filip Lardon¹, An Wouters¹

Affiliations

¹ Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
² Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium.
³ Center of Medical Genetics, University of Antwerp, Antwerp University Hospital, Prins Boudewijnlaan 43, 2650 Edegem, Belgium.
⁴ Department of Thoracic and Vascular Surgery, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium.
⁵ Department of Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium.

Abstract

Background: Currently, prognosis of non-small cell lung cancer (NSCLC) patients is based on clinicopathological factors, including TNM stage. However, there are considerable differences in patient outcome within a similar staging group, even when patients received identical treatments. In order to improve prognostic predictions and to guide treatment options, additional parameters influencing outcome are required. Polo-like kinase 1 (Plk1), a master regulator of mitotic cell division and the DNA damage response, is considered as a new potential biomarker in this research area. While several studies reported Plk1 overexpression in a broad range of human malignancies, inconsistent results were published regarding the clinical significance hereof. A prognostic panel, consisting of Plk1 and additional biomarkers that are related to the Plk1 pathway, might further improve prediction of patient prognosis. Methods: In this study, we evaluated for the first time the prognostic value of Plk1 mRNA and protein expression in combination with the TP53 mutation status (next generation sequencing), induction of apoptotic cell death (immunohistochemistry for cleaved caspase 3) and hypoxia (immunohistochemistry for carbonic anhydrase IX (CA IX)) in 98 NSCLC adenocarcinoma patients. Results: Both Plk1 mRNA and protein expression and CA IX protein levels were upregulated in the majority of tumor samples. Plk1 mRNA and protein expression levels were higher in TP53 mutant samples, suggesting that Plk1 overexpression is, at least partially, the result of loss of functional p53 (<0.05). Interestingly, the outcome of patients with both Plk1 mRNA and CA IX protein overexpression, who also harbored a TP53 mutation, was much worse than that of patients with aberrant expression of only one of the three markers (p=0.001). Conclusion: The combined evaluation of Plk1 mRNA expression, CA IX protein expression and TP53 mutations shows promise as a prognostic panel in NSCLC patients. Moreover, these results pave the way for new combination strategies with Plk1 inhibitors.

Keywords: Carbonic anhydrase IX; Hypoxia.; Non-small cell lung cancer; Polo-like kinase 1; Prognostic biomarker; TP53.