Integrative Genomic Profiling of Newly Diagnosed Prostate Cancers Progressing on Surveillance

作者：Nichelle C. Whitlock, Rebecca Silver, Shana Y. Trostel, Chennan Li, Rosina T. Lis, Julian Custer, Nicholas T. Terrigino, Ross Lake, Cathy D. Vocke, Peter A. Pinto, Adam G. Sowalsky · 发表于：Urology · 年份：2026 · DOI：10.1016/j.urology.2026.06.027 · 研究领域：Prostate Cancer Diagnosis and Treatment、Prostate Cancer Treatment and Research、Cancer Genomics and Diagnostics

OBJECTIVE: To identify molecular features associated with earlier progression to definitive therapy amongst patients with localized prostate cancer (PCa) managed on active surveillance (AS). METHODS: We performed a retrospective pilot study of 7 patients with low- to intermediate-risk PCa undergoing serial multiparametric MRI (mpMRI)-targeted biopsies of the same lesion while on AS, who all proceeded to definitive therapy. Time-to-treatment (TTT) was defined as years from first biopsy on AS to definitive therapy. Laser-capture microdissection was used to separate tumor epithelium, benign glands, high-grade prostatic intraepithelial neoplasia, and stroma in each biopsy specimen. DNA from the tumor and matched benign tissue underwent whole-exome sequencing, and RNA from all compartments underwent whole-transcriptome sequencing. Somatic mutations and copy-number alterations were compared across serial biopsies and used to reconstruct phylogenies and quantify clonal complexity. RESULTS: Tumors exhibited substantial intratumoral heterogeneity, and in 3 of 6 paired cases, serial mpMRI-targeted biopsies showed discordant somatic profiles consistent with sampling distinct major clones over time. By contrast, no single gene-level alteration, and few large-scale chromosomal events, were associated with TTT. High clonal complexity, defined as ≥3 subclones, was associated with significantly shorter TTT than low complexity (median 1.9 vs 7.2 years; P = .0082). Exploratory pathway analyses...