Distinct genomic features and evolutionary relationships between concurrent intraductal carcinoma and adenocarcinoma of the prostate.

Abstract

215 Background: Intraductal carcinoma of the prostate (IDC-P) is a lethal prostate cancer subtype that generally co-exists with invasive high-grade prostate acinar adenocarcinoma (PAC) but exhibits distinct biological features compared to concomitant adenocarcinoma. Till now, the genomic characteristics of IDC-P remain largely unknown. Methods: To explore the genomic features and evolutionary relationships between concurrent IDC-P and PAC, we isolated IDC-P, concurrent invasive high-grade PAC lesions, and adjuvant normal prostate tissues from 22 radical prostatectomy specimens. Whole-exome, RNA, and DNA-methylation sequencing were performed on the acquired tumoral and normal samples. The biological characteristics of IDC-P and concurrent PAC were compared at different molecular levels. Results: Three evolutionary patterns between concurrent IDC-P and PAC were identified. Tumors with clonally distant and early divergent evolutionary patterns showed higher genomic and pathological heterogeneities between concurrent IDC-P and PAC than those with the late-divergent pattern. Compared to co-existing PAC, increased adverse prognosis-associated genes were overexpressed in IDC-P. Besides, IDC-P was similar to Gleason pattern 5 PAC on the transcriptome profile. Survival analysis based on an independent cohort supported IDC-P resembled Gleason pattern 5 tumors. Furthermore, IDC-P exhibited robust cell-cycle progression and androgen receptor activities, characterized by an enrichment of cellular proliferation-associated master regulators and genes involved in intratumoral androgen biosynthesis. Conclusions: Our findings provide a molecular groundwork for the aggressive behavior of IDC-P and contribute to developing potential therapies for tumors with IDC-P.