PROJECT SUMMARY/ABSTRACT The Cancer Genome Dynamics Program (CGD) investigates how DNA sequence, DNA methylation, chromatin modifications, DNA damage, and 3D chromosomal organization coordinately affect transcriptional output. CGD laboratory scientists gain insight into how alterations at any of these levels initiate and/or promote tumor formation and progression, and CGD clinical investigators translate these discoveries into new prevention strategies, diagnostic technologies, and cutting-edge clinical trials. The Program focuses on major cancer burdens and disparities in our catchment area, guided by formal interactions via the CGD designated Liaison with the Community Outreach and Engagement Core, Program meetings and retreats, and close engagement with PCC Disease Management Groups and Disease Centers. Emphasis is placed on breast cancer, prostate cancer, and multiple myeloma in the Black and Ashkenazi populations of our catchment area. CGD is also home to faculty who investigate the carcinogenic impact of the World Trade Center (WTC) disaster, smoking, air pollution, metals, and other toxic agents. Research in CGD is focused around three thematic aims: Aim 1: To determine fundamental mechanisms of genetic and epigenetic regulation and their dysregulation in cancer, Aim 2: To elucidate the role of DNA damage and repair in tumorigenesis and cancer progression, and Aim 3: To discover changes in chromosome architecture that activate oncogenic transcriptional programs. CGD has 3 co- leaders, Hannah Klein, PhD (Basic), William Carroll, MD (translational) and Faith Davies, MD (clinical). Our 58 Members and 8 Associate Members come from 9 Departments at NYU Grossman School of Medicine, and two other NYU campuses. Current cancer-relevant funding is $27.3M, with 7.7M from the NCI, a 91% increase since 2018, which has led to an increase in the depth and breadth of the Program. Members published 1,094 cancer-related papers (a 52% increase from the last funding cycle), including 21% intra-programmatic, 29% inter-programmatic, and 45% inter-institutional (with other NCI-CCs) collaborative manuscripts. Our basic research resulted in numerous high-impact, paradigm-shifting publications (35% in journals with IF >10; 17% in those with IF>15), new intellectual property, new drug discovery companies, and innovative clinical trials. CGD clinical investigators accrued 2,523 patients to interventional and non-interventional clinical trials during the funding period. Members extensively use and have enhanced PCC Shared Resources with new computational pipelines, humanized mouse models that incorporate custom designed synthetic DNA molecules, ‘on demand’ PDX lines, and single molecule biophotonics. We also develop cutting-edge molecular genetic tests for clinical use.