PROJECT SUMMARY Prostate cancer is the second most common cancer and the second leading cause of cancer death in US men, with African American men having the highest incidence and mortality rates. Prostate cancer is strongly influenced by genetic factors, and polygenic risk scores (PRS) of common genetic variants are highly predictive of prostate cancer risk in men from European, African, East Asian, and Hispanic populations. Rare pathogenic variants also contribute to overall and aggressive prostate cancer risk, with 15% of metastatic cases carrying such variation. However, due to high sequencing costs, our knowledge of the contribution of rare genetic variation to prostate cancer risk is largely based on candidate gene studies, with of the few whole-exome or whole-genome studies conducted to date having sample sizes that are large enough for the discovery of novel rare variants/genes. Further, the majority of men included in common and rare genetic variant investigations of prostate cancer risk have been from European ancestry populations, limiting our knowledge on genetic risk of prostate cancer in other populations. The objective of this research is to elucidate genetic factors that contribute to risk of overall and aggressive prostate cancer across diverse populations and how such factors can be combined with lifestyle, environmental, and socioeconomic factors to more accurately characterize risk of prostate cancer. In Aim 1, we will investigate the contribution of rare and common genetic variants to prostate cancer risk across diverse populations, with the goal of validating known genetic risk factors and discovering novel genetic risk regions. In Aim 2, we will investigate whether genetic risk of prostate cancer, as measured by a PRS of known common genetic risk variants, can be modified by rare pathogenic variant carrier status, lifestyle factors, and socioeconomic factors across diverse populations. This research will be conducted in the All of Us Research Program, combining results from Aim 1 with other large-scale investigations to improve our ability to identify novel genetic risk regions. Findings from this investigation are expected to identify novel mechanisms novel mechanisms to target for preventative measures and improve our understanding of the complex interplay of genetic risk and modifiable risk factors of prostate cancer. Further, this investigation is anticipated to improve our ability to identify men at increased risk of overall and aggressive prostate cancer, which could have important screening and healthcare implications for prostate cancer prevention.

PROJECT NARRATIVE While prostate cancer is strongly influenced by inherited genetic factors, most genetic studies of prostate cancer have been limited to men of European ancestry, limiting our knowledge of genetic risk of prostate cancer in other populations. In this study, we will investigate genetic risk of prostate cancer in the All of Us Research Program across diverse populations, combining findings with previous large-scale prostate cancer genetic studies to strengthen our ability to identify novel genetic risk factors, and we will investigate whether genetic risk of prostate cancer can be modified by lifestyle and socioeconomic factors. We anticipate that findings from this investigation will improve our ability to identify men with increased risk of prostate cancer and aggressive disease, which could have important implications for screening and early detection of prostate cancer.