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. In this study, we performed whole-exome, RNA, and DNA-methylation sequencing of IDC-P, concurrent invasive high-grade PAC lesions, and adjacent normal prostate tissues isolated from 22 radical prostatectomy specimens. Three evolutionary patterns of concurrent IDC-P and PAC were identified: early divergent, late divergent, and clonally distant. In contrast to those with a late divergent evolutionary pattern, tumors with clonally distant and early divergent evolutionary patterns showed higher genomic, epigenomic, transcriptional, and pathological heterogeneity between IDC-P and PAC. Compared to co-existing PAC, IDC-P displayed increased expression of adverse prognosis-associated genes. Survival analysis based on an independent cohort of 505 metastatic prostate cancer patients revealed that IDC-P carriers with lower risk ISUP grade 1-4 adenocarcinoma displayed a castration-resistant free survival as poor as those with the highest risk ISUP grade 5 tumors that lacked concurrent IDC-P. 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. Overall, this study provides a molecular groundwork for the aggressive behavior of IDC-P and could help identify potential strategies to improve treatment of IDC-P.
Cancer research. 2023 Oct 17 [Epub ahead of print]
Jinge Zhao, Sha Zhu, Ling Nie, Mengni Zhang, Linmao Zheng, Nanwei Xu, Diming Cai, Xiaomeng Sun, Junru Chen, Jindong Dai, Yuchao Ni, Zhipeng Wang, Xingming Zhang, Jiayu Liang, Yuntian Chen, Xu Hu, Xiuyi Pan, Xiaoxue Yin, Haoyang Liu, Fengnian Zhao, Bei Zhang, Hao Chen, Jiashun Miao, Cong Qin, Xiaochen Zhao, Jin Yao, Zhenhua Liu, Banghua Liao, Qiang Wei, Xiang Li, Jiyan Liu, Allen C Gao, Haojie Huang, Peng-Fei Shen, Ni Chen, Hao Zeng, Guangxi Sun
West China Hospital, Chengdu, China., Department of Pathology and Laboratory of Pathology, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, China., Pathology Department, West China Hospital, West China Medical School,Sichuan University, Chengdu, China., Department of Pathology, West China Hospital, Sichuan University, China., GloriousMed Clinical Laboratory Co., Ltd., Shanghai, Shanghai, China., institute of urology, chengdu, China., West China Hospital of Sichuan University, Chengdu, Sichuan, China., Sichuan University West China Hospital, Chengdu, China., West China Hospital, West China Medical School, Chengdu, China., 3D Medicines Inc., shanghai, China., 3D Medicines Inc., Shanghai, China., The Medical Department, 3D Medicines Inc. Shanghai, P.R. China, Shanghai, China., West China Hospital of Sichuan University, chengdu, China., West China Hospital of Sichuan University, Chengdu, China., West China Hospital, West China Medical School, Sichuan University, Chengdu, China., University of California, Davis, Sacramento, CA, United States., Mayo Clinic, Rochester, MN, United States.