Androgen production, uptake, and conversion (APUC) genes define prostate cancer patients with distinct clinical outcomes
Issued Date
2024-10-22
Resource Type
eISSN
23793708
Scopus ID
2-s2.0-85204640773
Pubmed ID
39207857
Journal Title
JCI Insight
Volume
9
Issue
20
Rights Holder(s)
SCOPUS
Bibliographic Citation
JCI Insight Vol.9 No.20 (2024)
Suggested Citation
Bergom H.E., Boytim E., McSweeney S., Sadeghipour N., Elliott A., Passow R., Toye E., Li X., Likasitwatanakul P., Geynisman D.M., Dehm S.M., Halabi S., Sharifi N., Antonarakis E.S., Ryan C.J., Hwang J. Androgen production, uptake, and conversion (APUC) genes define prostate cancer patients with distinct clinical outcomes. JCI Insight Vol.9 No.20 (2024). doi:10.1172/jci.insight.183158 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/101867
Title
Androgen production, uptake, and conversion (APUC) genes define prostate cancer patients with distinct clinical outcomes
Corresponding Author(s)
Other Contributor(s)
Abstract
BACKGROUND. Prostate 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). METHODS. We 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. RESULTS. 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 2 subgroups of tumors with differential association with hallmark pathways and cell surface targets. CONCLUSIONS. The 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.