p16, Cyclin D1, and HIF-1α Predict Outcomes of Patients with Oropharyngeal Squamous Cell Carcinoma Treated with Definitive Intensity-Modulated Radiation Therapy

Table 1

Description of biomarkers.

Molecular marker	Description
p16^INK4a	Tumor suppressor protein that acts as a cyclin-dependent kinase inhibitor to regulate the cell cycle and is a demonstrated surrogate marker for infection with HPV [7]. Specifically, overexpression of p16 is considered a biomarker for inactivation of tumor suppressor retinoblastoma protein (pRb) by the HPV E7 oncoprotein. P16 itself is a strong independent positive prognostic indicator in OPSCC [7, 8], even when compared to reliable predictors of survival such as stage and grade [8].
Epithelial growth factor receptor (EGFR)	Transmembrane tyrosine kinase receptor that regulates cell growth in response to activation by growth factor ligands. Its overexpression is associated with increased tumor cell proliferation, angiogenesis, loss of differentiation, and reduced apoptosis [12]. Previous studies have shown that EGFR is significantly related to decreased overall survival in OPSCC [10].
Cyclophilin B	Has peptidyl-prolyl isomerase enzymatic activity that functions as a transcriptional inducer for Stat5 and as a ligand for CD147. It is thought to enhance tumorigenesis and motility through multiple mechanisms [18, 19].
Hypoxia inducible factor-1α (HIF-1α)	Transcription factor that responds to a decrease in oxygen levels within a cell and can be used as an indirect assessment of tumor hypoxia levels. Increased HIF-1α levels have been independently associated with decreased locoregional control, disease-free survival, and overall survival in OPSCC [11].
Major vault protein (MVP)	MVP is a protein that forms part of the ribonucleoprotein particle called vault, which has been implicated in the regulation of cellular signaling cascades and multidrug resistance [13, 14].
Carbonic anhydrase 9	Carbonic anhydrase 9 is an enzyme that is overexpressed in hypoxic tumor cells. High co-expression of carbonic anhydrase 9 and MVP has been associated with a poor probability of locoregional control in patients with head and neck squamous cell carcinoma [14].
p21	Cyclin-dependent kinase inhibitor that regulates the cell cycle at G1 and inhibits cell growth. p21 overexpression has been strongly associated with HPV16-positive tonsillar squamous cell carcinoma and is a favorable prognosticator [15].
Cyclin D1	Cell cycle regulator that participates at the G1-S portion of the cell cycle. HPV-positive tonsillar tumors have been shown to be associated with lower cyclin D levels [15].