Gene expression profiling within pathologically defined malignancy uncovers new categories of cancer classes, including head and neck squamous cell carcinomas (HNSCC).Genome-wide cDNA microarray profiling of a panel HNSCC cell lines revealed novel gene expression signatures which distinguished cancer cell subsets associated with their p53 status.The promoter regions of these gene clusters exhibited distinct patterns and prevalence of transcription factor binding sites for p53, NF-B, AP-1, STAT3 and EGR1.Novel transcriptional regulatory modules were identified using a newly developed computational strategy COGRIM (Clustering Of Gene Regulons using Integrated Modeling).We examined NF-κB regulons (a set of genes under regulation of the same transcription factor) in 1265 genes differentially expressed by head and neck cancer cell lines differing in p53 status.748 NF-κB targets were predicted and individually annotated for RELA, NFkB1 or cRel regulation, and a prevalence of RELA related genes was observed in over-expressed clusters in a tumor subset.Using Ingenuity Pathway Analysis, the NF-κB targets were reverse-engineered into annotated signature networks and pathways, revealing relationships broadly altered in cancer lines (activated proinflammatory and down-regulated Wnt/β-catenin and TGF-β pathways), or specifically defected in cancer subsets (growth factors, cytokines, integrins, receptors and intermediate kinases).