The Fearon and Vogelstein multistep cancer progression model of colon cancer defines key genetic changes associated with progression from normal colorectal tissue to early/late adenoma, primary carcinoma and metastatic dissemination. Extensive research has defined genetic/epigenetic alterations that drive colorectal cancer progression. However, systematic stage-by-stage assessment of genetic changes associated with colorectal tumor response is limited. Recent emergence of organoid technology has bridged the gap between cancer cell lines and xenografts, and advanced the ability to explore therapeutic responses of tumors cultured ex vivo as organoids derived from freshly- isolated tumor tissue. Furthermore, such patient-derived organoids (PDOs) recapitulate the mutational spectra in colorectal cancer. Here we will employ this technology to characterize the radiation responses of multi-stage colorectal cancer. Our biospecimen protocol (IRB-15-191) to harvest tissue from primary human colorectal cancer and normal colorectal mucosal epithelium pre- and post-neoadjuvant chemoradiotherapy and to grow/study PDOs therefrom has revealed 2 findings: 1) While normal colon and adenoma PDOs are radioresistant, surprisingly adenocarcinoma PDOs are as much as 1-log radiosensitive; and 2) Selection post neo-adjuvant therapy reveals loss of radiosensitivity. To our knowledge, these are the first data demonstrating that colorectal cancers develop inherent radiosensitivity when progressing from normal tissue and adenoma into adenocarcinoma. The goals of this study are: 1) To determine using foci technology the dysfunctional DNA repair mechanism (HR, NHEJ or both) that leads to human colorectal cancer radiosensitivity and to identify its molecular basis and 2) To determine whether the most radiosensitive cancers yield complete response after neo-adjuvant therapy.