Androgen production, uptake, and conversion (APUC) genes define prostate cancer patients with distinct clinical outcomes

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

doi:10.1172/jci.insight.183158

Androgen production, uptake, and conversion (APUC) genes define prostate cancer patients with distinct clinical outcomes

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

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: 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).

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 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.

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 two 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 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.

FUNDING: NCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279.

Original language	English
Journal	JCI insight
DOIs	https://doi.org/10.1172/jci.insight.183158
State	E-pub ahead of print - Jul 29 2024

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10.1172/jci.insight.183158

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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. (2024). Androgen production, uptake, and conversion (APUC) genes define prostate cancer patients with distinct clinical outcomes. JCI insight. Advance online publication. https://doi.org/10.1172/jci.insight.183158

@article{acf0da18403c4de686d3565d5653dc65,

title = "Androgen production, uptake, and conversion (APUC) genes define prostate cancer patients with distinct clinical outcomes",

abstract = "BACKGROUND: 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).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 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.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 two 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 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.FUNDING: NCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279.",

author = "Bergom, {Hannah E} and Ella Boytim and Sean McSweeney and Negar Sadeghipour and Andrew Elliott and Rachel Passow and Eamon Toye and Xiuxiu Li and Pornlada Likasitwatanakul and Geynisman, {Daniel M} and Dehm, {Scott M} and Susan Halabi and Nima Sharifi and Antonarakis, {Emmanuel S} and Ryan, {Charles J} and Justin Hwang",

year = "2024",

month = jul,

day = "29",

doi = "10.1172/jci.insight.183158",

language = "English",

journal = "JCI insight",

issn = "2379-3708",

publisher = "The American Society for Clinical Investigation",

}

Bergom, HE, Boytim, E, McSweeney, S, Sadeghipour, N, Elliott, A, Passow, R, Toye, E, Li, X, Likasitwatanakul, P, Geynisman, DM, Dehm, SM, Halabi, S, Sharifi, N, Antonarakis, ES, Ryan, CJ & Hwang, J 2024, 'Androgen production, uptake, and conversion (APUC) genes define prostate cancer patients with distinct clinical outcomes', JCI insight. https://doi.org/10.1172/jci.insight.183158

TY - JOUR

T1 - Androgen production, uptake, and conversion (APUC) genes define prostate cancer patients with distinct clinical outcomes

AU - Bergom, Hannah E

AU - Boytim, Ella

AU - McSweeney, Sean

AU - Sadeghipour, Negar

AU - Elliott, Andrew

AU - Passow, Rachel

AU - Toye, Eamon

AU - Li, Xiuxiu

AU - Likasitwatanakul, Pornlada

AU - Geynisman, Daniel M

AU - Dehm, Scott M

AU - Halabi, Susan

AU - Sharifi, Nima

AU - Antonarakis, Emmanuel S

AU - Ryan, Charles J

AU - Hwang, Justin

PY - 2024/7/29

Y1 - 2024/7/29

N2 - BACKGROUND: 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).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 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.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 two 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 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.FUNDING: NCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279.

AB - BACKGROUND: 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).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 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.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 two 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 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.FUNDING: NCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279.

U2 - 10.1172/jci.insight.183158

DO - 10.1172/jci.insight.183158

M3 - Article

C2 - 39207857

SN - 2379-3708

JO - JCI insight

JF - JCI insight

ER -

Androgen production, uptake, and conversion (APUC) genes define prostate cancer patients with distinct clinical outcomes

Abstract

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