Cancer is a genetic disease caused by an interaction between genetic and environmental factors. Understanding this complex interaction and the degree to which factors contribute to cancer in individual patients will impact risk assessment, prevention and treatment. The role of microbes as environmental contributors to cancer has been well documented, causing >20% of cancers worldwide. Colorectal cancer (CRC) occurs at the tissue exposed to the highest concentration of microorganisms, and the surface location of its tumorigenesis implies that some CRC may result from this exposure. Despite efforts to understand the role of pathogens in CRC, exploration has been limited because comprehensive tools to study infection history are lacking. Next-gen sequencing (NGS) has greatly advanced our knowledge of microbiome changes in CRC patients. We are proposing an immunoproteomics study that complements existing NGS studies and hypothesize that a proteome-scale, comprehensive study of the humoral immune response against microbial antigens will yield specific antibody biomarkers with clinical utilities. Our overarching goal is t identify antibody markers that detect pathogen-associated cancer early or identify subjects at high risk of developing cancer. We will select candidate pathogens using three different resources including: the available literature, our own analysis of NGS data, and our large collection of microbial genes. We will identify antibody markers in cancers by profiling serum against thousands of microbial proteins in a large number of cancer patients using our innovative protein microarray platform, namely Nucleic Acid Programmable Protein Array (NAPPA) (22,23). Protein microarrays provide a multiplexed, high-throughput platform to profile host antibody immune responses against thousands of proteins in parallel. Despite the strong potential of harnessing antibody responses to detect pathogen-associated cancers, protein microarrays have never been applied to this purpose. Our NAPPA overcomes some challenges associated with conventional high-density protein arrays in terms of cost and programmability and enables quantitative antibody profiling at the proteome level in the discovery phase. Top candidate antibody markers will be further verified blindly with an independent sample set using the closer-to-clinic ELISA immunoassay to ensure rigor. Cancer specificity will also be assessed by assaying the performance of validated antibodies in non-malignant inflammatory bowel disease (IBD) patients. Our research team comprises experts on disease proteomics, statisticians, microbiologists and GI oncologists. High quality samples collected at diagnosis with detailed clinical information are available for this study. Thus, we can ensure technical excellence to solve clinically important questions with potential impact on patient management. Improved knowledge of the link between infectious agents and cancers may help identify cancer diagnostics, manage risks and develop vaccine and prevention strategies.