BRCA1 and MDM2 as independent blood-based biomarkers of head and neck cancer.

Abstract

We investigated the role of BRCA1, MDM2, and p53 in the pathogenesis of head and neck cancer (HNC) and evaluated their potential utility as blood-based predictive biomarkers of HNC. Immunostaining of tissue biopsies and whole blood lymphocytes (WBL) of 36 HNC patients were evaluated by immunohistochemistry (IHC) and immunocytochemistry (ICC), respectively. The staining intensities of BRCA1 and MDM2 in matched tissue and blood samples were significantly associated with cancer stage. Furthermore, the cellular levels of BRCA1, MDM2, and p53 were evaluated in peripheral blood lymphocytes (PBL) of 134 HNC patients and 126 controls by slot blotting. Expression levels of all three proteins in PBL of HNC patients varied significantly with respect to those of controls (p<0.0001) with BRCA1 downregulated to 75% of control and MDM2 and p53 upregulated to 1.7- and 1.4-fold the control level, respectively. Moreover, positive correlation was observed between expression levels of BRCA1, MDM2, and p53 in matched tissue biopsies-WBL (r s=0.840, 0.754, and 0.806, respectively), tissue biopsies-PBL (r s=0.745, 0.736, and 0.776, respectively), and PBL-WBL (r s=0.709, 0.758, and 0.740, respectively), validating the hypothesis that these proteins may serve as blood-based biomarkers of HNC. Bias-corrected and accelerated (BCa) bootstrap cross-validation estimation of receiver operating characteristics (ROC) analysis established BRCA1 (AUC=0.726, sensitivity=89%, NPV=82%) and MDM2 (AUC=0.827, sensitivity=85%, NPV=81%) as predictive biomarkers for HNC. In conclusion, this study suggests that BRCA1 and MDM2 play a crucial role in the pathogenesis of HNC and could be used independently as predictive biomarkers for HNC.