Phenome-Wide Association Study of Pre-Cancer Diagnosis Electronic Health Records Identifies Risk and Inverse Associations in the All of Us Research Program

Background: The All of Us Research Program represents a rich resource for cancer epidemiology research, with over 400,000 participants with whole genome sequences linked to electronic health records (EHR). Large cancer datasets often focus exclusively on cases without controls and neglect pre-diagnosis healthcare occurrences. Here, we perform a phenome-wide association study (PheWAS) of EHR data at least 1 year pre-diagnosis between cancer cases and matched controls, revealing co-occurring and mutually exclusive phenotypes. Methods: We identified 55,000+ cancer cases across 21 cancer types in All of Us version 8. To eliminate age-related confounding, we implemented a two-stage matching and censoring strategy: loose matching on demographics to establish index dates and cohort comparability, followed by right-censoring of EHR data (excluding 1 year pre-diagnosis/index), then 1:2 matching to address residual demographic imbalance. We tested associations between 23,193 cancer cases, 46,386 matched controls and approximately 1,600 clinical phenotypes using logistic regression adjusted for sex at birth, self-reported race, age at diagnosis/index date, and two censored EHR metrics: observation window and unique condition count, with Bonferroni correction for multiple testing. Results: Our analysis identified 232 significantly associated phenotypes, confirming established cancer risk factors including elevated prostate specific antigen (OR = 2.92, 95% CI: 2.65-3.23; p-value=1.8x10-101) and multinodular goiter (OR = 1.73, 95% CI: 1.56-1.91; p-value=6.7x10-27). Further investigation into the relationship between several phenotypes with seeming inverse effects is warranted. Conclusions: This PheWAS of EHR data at least 1 year pre-diagnosis leveraged the diversity of All of Us to examine how clinical phenotypes prior to cancer diagnosis vary across cancer types and racial groups. Our findings validate All of Us as a robust platform for cancer epidemiology research, confirming established risk factors at scale across diverse populations. This work provides methodological insights for EHR-based susceptibility analyses and demonstrates the value of agnostic phenome-wide approaches for generating hypotheses in precision medicine.