A Trial of Omeprazole and Low Dose Aspirin to Identify Colorectal Biomarkers of Preventive Efficacy

Inclusion Criteria: * Age 18-75 * Individuals who are due for a standard of care colonoscopy. * Have a prior history of colorectal neoplasia including any ONE of the following: * Multiple (\>=5) colorectal adenomas on most recent colonoscopy * Multiple (\>=5) sessile serrated polyps on most recent colonoscopy * Adenomatous polyps meeting criteria for colon polyposis of unknown etiology (\> 20 lifetime adenomas) * Serrated polyps meeting criteria for serrated polyposis syndrome * History of incompletely resected colorectal polyp(s) (adenoma or sessile serrated polyp) on most recent colonoscopy * Willing to avoid taking non-steroidal anti-inflammatory drugs that are not provided by the study in the 30 days prior to Visit 1 and while on study. * Willing to avoid taking proton pump inhibitors that are not provided by the study in the 30 days prior to Visit 1 and while on study. * Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation since endoscopy is not recommended during pregnancy. * Demonstrate adequate organ and marrow function obtained within the last 60 days as defined below: * Absolute neutrophil count ≥1,000/microliter * Platelets ≥100,000/microliter * Total bilirubin ≤ 1.5 fold of the institutional upper limit of normal Note: Higher total bilirubin levels (≤ 3 mg/dL) can be allowed if due to known benign liver condition such as Gilbert's * AST (SGOT)/ALT (SGPT) ≤3.0 fold of the institutional upper limit of normal * Creatinine ≤1.5 fold of the institutional upper limit of normal * Patients on chronic suppressive antiviral therapy for herpes simplex virus (HSV) are eligible. * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. * Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: * Age 76 or higher since there is an increased risk of GI bleeding and peptic ulcer disease in persons above 75 years of age. * Pathogenic germline variants in adenomatous polyposis coli (APC) and DNA mismatch repair (MMR) genes associated with Lynch Syndrome, or biallelic pathogenic germline variants in the MutY homologue glycosylase (MUTYH) gene. * Have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to proton pump inhibitors and/or aspirin. * Participants may not be receiving any other investigational agents. * Have a history of prior aspirin or NSAID gastritis with bleeding. * Currently taking a proton pump inhibitor and unable/unwilling to discontinue use 30 days prior to Visit 1. * Taking NSAIDs or aspirin \>25% of the time (\>8 days/month) and unable/unwilling to discontinue use 30 days prior to Visit 1 and until Visit 4. * Currently taking medications associated with increased risk for bleeding (warfarin, Eliquis, Plavix, etc.). * Currently taking medications that have interactions with omeprazole: atazanavir, erlotinib, levoketoconazole, nelfinavir, pazopanib, rilpivirine, sparsentan, certain azole antifungals (itraconazole, ketoconazole, and posaconazole). * Have a history of hemophilia, Von Willebrand disease or any other known bleeding diathesis. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Individuals who the site physician investigator assesses as at high risk for bleeding due to heavy alcohol use or comorbid conditions. * Pregnant women are excluded since endoscopy is not recommended while pregnant. * Have invasive cancer or being treated for invasive cancer at the current time or within the past 36 months, with the exception of cancers curatively removed by surgery, other than melanoma, and stage I and II cervical squamous cell cancers.