Abstract LB-376: Prediction of clinical outcome using NFkB target gene expression based classifier in head and neck patients with different HPV status
Authors: Gupta Seema , Koru-Sengul Tulay , Philip Sakhi , Brown Robert , Pellitteri Phillip , Goodwin Jarrad W. , Ahmed Mansoor M. 
Published: August 2014

Purpose: Mutations and polymorphisms in various genes, tobacco/alcohol abuse as well as Human Papillomavirus (HPV) are shown to be associated with pathogenesis of Squamous Cell Carcinomas of the Head and Neck (SCCHN). NFkB is one of the common significant players in both HPV and tobacco/alcohol related carcinogenesis. Our objective is to develop a classifier based on the NFkB signaling pathway gene expression profiles that predicts the clinical outcome to chemo-radiation therapy of SCCHN patients with different HPV status.

Methods: Expression levels of HPV16, p16 and 84 NFkB signaling pathway genes were determined using real time RT PCR in 29 SCCHN patient samples and 4 SCCHN cell lines that were either resistant or sensitive to radiation and chemotherapy. A gene expression pattern that correlated to chemo-radiation response was identified in the cell lines. The cell line model was blindly tested in untreated SCCHN patients to predict their clinical outcome to chemo-radiation based upon the individual tumor gene expression.

Results: The gene-based predicted clinical outcome compared with patients' actual observed clinical outcome correctly identified the clinical response in 73% (21 of 29) of the cases (95% Confidence Interval: 55%, 84%). Several important genes were identified that correlated with the clinical outcome. Further, it was observed that 8 out of 11 recurrent patients (73%) were HPV16 negative and 13 out of 18 responders (72%) were HPV16 positive thus confirming that patients with HPV positive tumors respond better than HPV negative tumors to the treatment (p-value=0.01). Further, mean gene expression levels for HPV positive and negative samples for each of the 84 genes in the NFkB signaling pathway were compared by independent two-sample t-test to identify the significantly differentially expressed gene list. We identified a group of genes that were differentially expressed in HPV16 positive and negative tumors. Most of the 35 up-regulated genes in HPV positive recurrent patients had pro-survival function compared to only one gene that was up-regulated in HPV positive responder patients. These results suggest that up-regulation of NFkB target genes with pro-survival function leads to recurrence. Conclusions: We demonstrated that therapeutic response to chemo-radiation can be predicted based on NFkB signaling pathway gene expression profiles. Ongoing analyses will identify the pro-survival/pro-apoptotic genes that were significantly up-regulated in tumor samples from recurrent patients by correlating them to the patients HPV status. These genes can then be used as markers of treatment failure or success.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-376. doi:10.1158/1538-7445.AM2011-LB-376