LAUSR

Approximately two-thirds of cancer diagnoses globally are attributed to modifiable lifestyle factors such as smoking, diet and inactivity. Conversely, regular exercise is linked to decreased risk of multiple cancers. However, the underlying molecular mechanisms are not fully elucidated. Specifically, how exercise impacts tumor genomic landscapes has not been considered. To address this gap, we integrated clinical annotation of exercise exposure with tumor mutational profiling of 2,879 patients with cancer. Exercise exposure was evaluated by validated questionnaire and tumor genomic profiling of ≥ 505 commonly mutated cancer genes was performed using the Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actional Cancer Targets (MSK-IMPACT) assay. Among the most represented cancer types were breast (n = 623), lung (n = 524), endometrial (n = 260), colorectal (n = 217) and prostate (n = 176). We found that exercise influences the genomic landscapes of tumors in a cancer-type specific manner. For instance, breast, colorectal and lung cancers from exercising patients had significantly lower tumor mutation burden (TMB) compared with non-exercisers. TMB of melanoma was significantly higher in exercisers versus non-exercisers. A pan-cancer analysis showed that mutations in SMAD3 were more frequent among exercisers, while mutations in STK11, KEAP1 and RBM10 were more frequent among non-exercisers. Overall, this study shows that exercise regulates tumor genomic landscapes and does so in a cancer-site specific manner. Citation Format: Brandon L. Tsai, Lydia Y. Liu, Stefan E. Eng, Whitney P. Underwood, Catherine P. Lee, Joshua W. Bliss, Paul C. Boutros, Lee W. Jones. Exercise and tumor genomic landscapes in 2,879 patients with cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3121.