Project Summary We are building a Precancer Atlas of colorectal cancer from Familial Adenomatous Polyposis (FAP) patients. We have built a biobank containing thousands of samples from 78 donors. We have applied genomic, epigenomic, proteomic, lipidomic, metabolomic, transcriptomic, and spatial assays to characterize the molecular changes occurring during the progression from normal mucosa to cancer. We propose to use an integrated approach to further develop our Precancer Atlas. By profiling multiple polyps from the same patient, our Precancer Atlas enables characterization of the early events driving colorectal cancer. We will: 1) Complete procurement of longitudinal tissue samples from 100 donors during surveillance colonoscopy and during prophylactic surgical colectomy, including whole blood, serum, normal colonic tissue, colon microbiome, benign pre-cancerous polyps, dysplastic precancerous polyps and colon adenocarcinomas. The material will be used for our own center and will also be available to the Human Tumor Atlas Network (HTAN). Medical records, longitudinal samples and all relevant metadata will also be collected. 2) Characterize the tissue samples with state-of-the-art omics and imaging technologies. 3) Integrate results from -omics, imaging and medical information, to build a spatiotemporal, multidimensional, integrative multi-omics cancer atlas, and develop longitudinal and predictive models for PreCancer biology and progression. 4) Complete our establishment of multi-omics technologies, finishing our CODEX, snRNA-seq and organoid profiling. 5) Complete the publication of our “multiscale deep data analysis” on a large number of samples from a few people. Use this information to guide additional data collection, including our follow- up snRNA-seq experiments and our hypothesis-testing experiments in organoid models. 6) Identify factors (e.g. germline genetics, immune dysfunction) contributing to polyp heterogeneity and build disease progression models based on these data. 7) Make all biospecimens, information, protocols and software available to the PCA, HTAN and the general scientific community.