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We present a workflow to identify smoking specific gene co-expression networks and then screen them for specific networks with relationship to oral cancer initiation and development. Interestingly, we found the network with highest activity (based on mutual information metric) is a network uniquely identified from the smoking cohort in pre-cancerous stage, which is consistent with the role of smoking in oral cancer initiation. In addition, this network is highly enriched with oral and esophagus tissue specific genes. The discovery suggests that putative smoking associated genes can also be potential targets for cancer therapeutics.