Aging dictates tumor-specific genomic alterations across cancer types

Cancer risk increases exponentially with age. As the world's population grows older, the absolute number of cancer diagnoses and cancer-related deaths continues to rise globally, despite declines in age-adjusted cancer mortality in many high-income countries. However, there is still little known about how molecular features of tumors differ according to patient age and how these genomic alterations may impact the treatment of patients of advanced age compared to younger patients who are diagnosed with malignancy. In this study, we survey the largest clinically- and genomically-annotated database available and identify age-associated mutations across distinct cancer types, defined as genes whose mutation rates in cross-sectional cancer populations differ by age. By interrogating paired clinical and genomic data from the AACR Project GENIE database across brain, breast, colorectum, lung, pancreas, and skin cancers, we identified somatic mutations in tumors with distinct age-dependent patterns. We also uncovered age-specific associations in the co-mutation patterns among these genes, demonstrating relationships among mutations that strengthen or weaken with age, as well as connections between age-specific mutation patterns and environmental covariates. Finally, in an exploratory analysis, we observed age-associated trends between PTPRT mutations in lung cancer and clinical response to immune checkpoint inhibitors, highlighting the possibility that certain genomic alterations may differentially associate with outcomes across patient age groups.