PROJECT SUMMARY/ABSTRACT Research in the Cancer Genes and Pathways (CGP) program focuses on defining essential molecular and biological mechanisms underlying tumor pathogenesis and successful therapy. The primary goal of this basic science program is to discover, characterize, and validate new tumor alterations (genetic, molecular and cellular pathways) to fuel translational cancer research that will lead to improved cancer patient outcomes. This is accomplished through three overlapping research aims centered on the study of 1) structural and functional genetic and nuclear alterations that promote tumorigenesis, 2) intrinsic cellular processes and pathways that drive malignant transformation and tumor progression, and 3) tumor extrinsic factors, such as immune cells and environmental carcinogens, that contribute to cancer development and suppression. Key scientific achievements over the prior funding period include defining the role of RAD52 protein in damaged DNA repair and genome stability, identifying metastatic gene signatures and druggable pathways driving neuroendocrine tumor (NET) pathogenesis, and deciphering fundamental mechanisms by which external mechanical forces influence tumor cell metabolism. CGP membership includes 42 full and nine associate members spanning seventeen departments across four colleges. Annual direct cancer-relevant peer-reviewed funding in the last budget year was $6.7 million with $1.2 million from the NCI. CGP members are highly collaborative, having authored or co-authored 384 cancer-related peer-reviewed publications in the past four years, with 22% (n= 85) intraprogrammatic, 30% (n= 117) interprogrammatic, and 54% (n= 206) inter-institutional publications. 57 manuscripts appeared in high impact journals (Impact Factor >10). Productive intra/interprogrammatic and multi-institutional groups are leading investigations that reflect the breadth of CGP research, including advances in mechanisms of DNA repair and genome instability, genetic and molecular events underlying blood cell transformation, animal tumor model development, druggable pathways in sarcoma, novel targets and therapies for NETs, G-protein signaling in breast cancer stemness and metastasis, immune cell activation and the tumor microenvironment, carcinogenic effects of Iowa environmental toxins, and drug resistance in melanoma. In the context of the CCSG, CGP is the basic science foundation that is guided by and drives translational oncology through its partnership with other Holden Comprehensive Cancer Center (HCCC) programs. This is exemplified by CGP member direction of tumor procurement, CGP provision of integral genomic, immunological, and bioinformatics support for clinical studies involving colleagues in all four HCCC programs, the outstanding number of interprogrammatic publications, and key leadership roles of CGP members on a U01 and two NCI SPORE grants.