Discovering New Targets for Colorectal and Endometrial Cancer Risk Reduction

Colorectal cancer (CRC) and endometrial cancer (EC) have a highly heritable component. Approximately 25% of CRC or EC patients have another first or second degree relative who are also affected by CRC or EC, and there are at least 32 known high penetrance CRC/EC germline predisposition genes. The overarching goal of this protocol is to (a) facilitate the discoveries of novel mechanisms in intestinal carcinogenesis and genes inducing genetic predisposition, (b) to help identify new genes and proteins that are amenable to targeted therapy and precision prevention drug intervention and biomarker development in Hereditary Cancer Syndromes, (c) to facilitate understanding and learning about ways of how the immune system can be used to recognize and kill tumor cells that carry mutations. To accomplish these goals, we plan to pursue the following aims: 1. To collect tissue and blood samples for storage, so they can be made available to future research studies and scientist aiming to learn more about the underlying causes of gastrointestinal cancers and endometrial cancers, both in patients with hereditary cancer syndromes and in the general population, 2. To develop organoids from adenocarcinomas, polyps, and normal intestinal mucosa samples in patients with Hereditary Cancer Syndromes and a sporadic cohort as a comparator and control. These organoids will be derived from tissue biopsies of different parts of the intestinal tract, other GI organs, and endometrium in order to perform assessment of drug sensitivity and molecular biology experiments to understand the biology and carcinogenesis of the intestine. To accomplish these goals, we will obtain normal mucosa, polyp tissue and carcinoma (tumor tissue) arising in the upper gastrointestinal tract (mainly the duodenum, but also other potential locations such as the esophagus, GE junction, stomach, and small bowel), lower gastrointestinal tract (mainly the colorectum), paired normal mucosa samples, endometrial tissue, and blood and as a source of genomic DNA, RNA, and protein. The biospecimen samples will be collected in the context of standard of care (SOC) endoscopic procedure(s) and/or from pathologic specimens obtained during gastrointestinal (GI) endoscopy procedures and surgery performed at Weill Cornell or New York Presbyterian Hospital, including diagnostic testing, clinic and/or treatment visit and/or from residual blood. These tissue samples and blood samples were collected in the context of routine care and procedures performed at Weill-Cornell and NYPH. Biospecimen samples will also be collected in the context of SOC transvaginal ultrasound, hysteroscopy and endometrium biopsy performed at Weill Cornell or New York Presbyterian Hospital, including diagnostic testing, clinic and/or treatment visit. Blood samples will be collected at the time blood is taken for clinical care. We will register, collect, process and store frozen blood, frozen normal and diseased tissue and FFPE (formalin fixed paraffin embedded) specimens. This will be an invaluable annotated hereditary CRC/EC registry and tissue repository that will be available to the Weill Cornell Community upon appropriate approval. Subjects that provide informed consent will agree to collection and storage of clinical data. For the purposes of this project, clinical data includes all data collected for standard clinical purposes (e.g., demographics, medical issues, prognostic data, treatment data, outcomes).