Prostate cancer (PC) is driven by aberrant signaling of the androgen receptor (AR) or its ligands, and androgen deprivation therapies (ADT) are a cornerstone of treatment. ADT responsiveness may be associated with germline alterations in genes that regulate androgen production, uptake, and conversion (APUC).
We analyzed whole-exome sequencing (WES) and whole transcriptome sequencing (WTS) data from prostate tissues (SU2C/PCF, TCGA, GETx). We also interrogated the Caris POA DNA (592-gene/whole exome) and RNA (whole transcriptome) NGS databases. Algorithm for Linking Activity Networks (ALAN) was used to quantify all pairwise gene-to-gene associations. Real-world overall survival (OS) was determined from insurance claims data using Kaplan-Meier estimates.
Six APUC genes (HSD3B1, HSD3B2, CYP3A43, CYP11A1, CYP11B1, CYP17A1) exhibited coalescent gene behavior in a cohort of metastatic tumors (n = 208). In the Caris POA dataset, the 6 APUC genes (APUC-6) exhibited robust clustering in primary prostate (n = 4,490) and metastatic (n = 2,593) biopsies. Surprisingly, tumors with elevated APUC-6 expression had statically lower expression of AR, AR-V7, and AR signaling scores suggesting ligand-driven disease biology. APUC-6 genes instead associated with the expression of alternative steroid hormone receptors, ESR1/2 and PGR. We used RNA expression of AR or APUC-6 genes to define two subgroups of tumors with differential association with hallmark pathways and cell surface targets.
The APUC-6 high/AR-low tumors represented a subgroup of patients with good clinical outcomes in contrast to the AR-high or neuroendocrine prostate cancers. Altogether, measuring the aggregate expression of APUC-6 genes in current genomic tests identifies PCs that are ligand- (rather than AR-) driven and require distinct therapeutic strategies.
NCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279.
JCI insight. 2024 Aug 29 [Epub ahead of print]
Hannah E Bergom, Ella Boytim, Sean McSweeney, Negar Sadeghipour, Andrew Elliott, Rachel Passow, Eamon Toye, Xiuxiu Li, Pornlada Likasitwatanakul, Daniel M Geynisman, Scott M Dehm, Susan Halabi, Nima Sharifi, Emmanuel S Antonarakis, Charles J Ryan, Justin Hwang
Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, United States of America., Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, United States of America., Department of Clinical and Translational Research, Caris Life Sciences, Phoenix, United States of America., Desai Sethi Urology Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, United States of America., Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, United States of America., Medical Oncology, Fox Chase Cancer Center, Philadelphia, United States of America., Department of Biostatistics and Bioinformatics, Duke Cancer Institute, Durham, United States of America.