| Autor: |
Bergom HE; Masonic Cancer Center, and.; Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA., Boytim E; Masonic Cancer Center, and.; Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA., McSweeney S; Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA., Sadeghipour N; Department of Clinical and Translational Research, Caris Life Sciences, Phoenix, Arizona, USA., Elliott A; Department of Clinical and Translational Research, Caris Life Sciences, Phoenix, Arizona, USA., Passow R; Masonic Cancer Center, and.; Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA., Toye E; Masonic Cancer Center, and.; Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA., Li X; Desai Sethi Urology Institute, Sylvester Comprehensive Cancer Center, University of Miami, Florida, USA., Likasitwatanakul P; Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.; Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand., Geynisman DM; Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA., Dehm SM; Masonic Cancer Center, and.; Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA., Halabi S; Department of Biostatistics and Bioinformatics, Duke Cancer Institute, Durham, North Carolina, USA., Sharifi N; Desai Sethi Urology Institute, Sylvester Comprehensive Cancer Center, University of Miami, Florida, USA., Antonarakis ES; Masonic Cancer Center, and.; Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA., Ryan CJ; Masonic Cancer Center, and.; Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA., Hwang J; Masonic Cancer Center, and.; Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA. |
| Abstrakt: |
BACKGROUNDProstate cancer (PC) is driven by aberrant signaling of the androgen receptor (AR) or its ligands, and androgen deprivation therapies (ADTs) are a cornerstone of treatment. ADT responsiveness may be associated with germline changes in genes that regulate androgen production, uptake, and conversion (APUC).METHODSWe analyzed whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) data from prostate tissues (SU2C/PCF, TCGA, GETx). We also interrogated the Caris Precision Oncology Alliance (POA) DNA (592-gene/whole exome) and RNA (whole transcriptome) next-generation sequencing databases. Algorithm for Linking Activity Networks (ALAN) was used to quantify all pairwise gene-to-gene associations. Real-world overall survival was determined from insurance claims data using Kaplan-Meier estimates.RESULTSSix 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 2 subgroups of tumors with differential association with hallmark pathways and cell surface targets.CONCLUSIONSThe APUC-6-high/AR-low tumors represented a subgroup of patients with good clinical outcomes, in contrast with the AR-high or neuroendocrine PCs. 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.FUNDINGNCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279. |
