Project Summary Survival for breast, prostate and colorectal cancer has improved dramatically over the past three decades as a result of advances in treatment and screening for the detection of these common cancers at an earlier stage. However, African Americans (AAs) still suffer from a higher mortality rate after diagnosis of these cancers compared with other groups. One of the consequences of prolonged survival is the possibility of developing one or more new primary cancers in their lifetime. It has been estimated that overall nearly 10% of cancer survivors will be diagnosed with a second primary cancer, with some variability in estimates across studies which is not thoroughly understood, particularly among AAs, who have been shown to have poorer survival after a second primary diagnosis. Understanding the underlying causes of second primary cancers is critical to design strategies for risk mitigation and early detection. Importantly, the multiple primary cancer (MPC) phenotype can be a used to understand both genetic susceptibility and environmental risk determinants. The proposed investigation will build upon the Detroit Research on Cancer Survivors (ROCS) study, one of the largest cohorts conducted exclusively among AA cancer survivors to understand the multiplex causes of poorer outcomes in the population. We will focus both on breast, prostate and colorectal cancer survivors enrolled in Detroit ROCS who developed a second primary cancer and use the existing infrastructure to enroll new participants diagnosed with MPCs. We will: 1) sequence DNA collected from whole blood or saliva of 1000 participants diagnosed with MPCs (500 AA and 500 non-Hispanic white (NHW)) as well as 500 AA survivors diagnosed with a single primary cancer (SPC) to characterize the mutational landscape overall and compare the spectrum and prevalence of pathogenic and likely pathogenic mutations by race and MPC/SPC status; 2) calculate cancer site-specific polygenic risk scores (PRS) us