Comprehensive Analysis of Fraction of Genome Altered in Prostate Cancer Treatment

ABSTRACT Background Genomic instability is a key feature of cancer and plays a central role in tumor progression. One emerging metric for genomic instability is the fraction of genome altered (FGA), which quantifies the proportion of the genome affected by copy number alterations. Previous studies in various solid tumors have shown that high FGA is associated with aggressive disease and adverse clinical outcomes. However, the clinical significance of FGA in prostate cancer (PC) remains unclear. In this study, we investigated the role of FGA as a potential biomarker of tumor aggressiveness and a poor prognosis in PC using several large‐scale public databases. Methods We analyzed the processed data from previous large‐scale PC studies available through the cBioPortal database: MSK CHORD 2024 ( n = 3211), MSK 2021 ( n = 2069), MSK 2020 mCSPC ( n = 424), SU2C/PCF mCRPC ( n = 444), and AACR Project GENIE ( n = 5306). Associations between FGA and clinical parameters such as T stage, Gleason score (GS), tumor volume, metastatic burden, pathological subtype, and treatment history were evaluated. Kaplan–Meier survival analysis was used to assess the prognostic value of FGA. Results High FGA was significantly associated with aggressive clinical features, including higher T stage, GS, metastatic burden, and neuroendocrine prostate cancer histology. FGA increased after most therapeutic interventions. Patients with high FGA had significantly poorer overall survival across nearly all treatment modalities. An oncoplot analysis revealed a higher frequency of somatic alterations in key driver genes, including AR, PTEN , and TP53 , in high‐FGA tumors. Conclusions FGA was closely associated with tumor aggressiveness, therapy‐induced genomic instability, and a poor prognosis in PC. It may serve as a clinically relevant biomarker across diverse treatment contexts.