Context.—

Genetic profiling data of prostatic adenocarcinoma are derived from predominantly White patients. In African Americans, prostatic adenocarcinoma has a poorer prognosis, raising the possibility of distinct genetic alterations.

Objective.—

To investigate the genomic alterations of prostatic adenocarcinoma metastatic to regional lymph nodes in African American patients, with an emphasis on SPOP mutation.

Design.—

We retrospectively reviewed African American patients with pN1 prostatic adenocarcinoma managed with radical prostatectomy and lymph node dissection. Comprehensive molecular profiling was performed, and androgen receptor signaling scores were calculated.

Results.—

Nineteen patients were included. The most frequent genetic alteration was SPOP mutations (5 of 17; 29.4% [95% CI: 10.3–56.0]). While most alterations were associated with a high androgen receptor signaling score, mutant SPOP was exclusively associated with a low median and interquartile range (IQR) androgen receptor signaling score (0.788 [IQR 0.765–0.791] versus 0.835 [IQR 0.828–0.842], P = .003). In mutant SPOP, mRNA expression of SPOP inhibitor G3BP1 and SPOP substrates showed a significantly decreased expression of AR (33.40 [IQR 28.45–36.30] versus 59.53 [IQR 53.10–72.83], P = .01), TRIM24 (3.95 [IQR 3.28–5.03] versus 9.80 [IQR 7.39–11.70], P = .008), and NCOA3 (15.19 [IQR 10.59–15.93] versus 21.88 [IQR 18.41–28.33], P = .046).

Conclusions.—

African American patients with metastatic prostate adenocarcinoma might have a higher prevalence of mutant SPOP (30%), compared to ∼10% in unselected cohorts with lower expressions of SPOP substrates. In our study, in patients with mutant SPOP, the mutation was associated with decreased SPOP substrate expression and androgen receptor signaling, raising concern for suboptimal efficacy of androgen deprivation therapy in this subset of patients.

Prostatic adenocarcinoma (PCa) is the third most common cancer in the United States, with approximately 1 in 9 men developing PCa during their lifetime.1  At presentation, most PCas are organ-confined, with only ∼10% of patients with metastases to the regional lymph nodes (stage pN1). Prognostic tools based on clinical and histopathologic data have been developed to tailor management, but their plethora, complexity, and suboptimal reliability at flagging high-risk PCa patients have limited their implementation in routine clinical practice.2,3 

Genomic profiling has been increasingly utilized as a prognostic and a predictive tool in malignancies, epitomized by its role in breast cancer management.4  Studies addressing genomic profiling of PCa are primarily derived from White patient cohorts and show molecular heterogeneity.5  Members of the E26 transformation-specific (ETS) family represent 50% of genetic alterations, while 25% of patients harbor somatic point mutations, most commonly involving the speckle-type POZ protein (SPOP).5  Compared to their White counterparts, African Americans have a higher incidence of PCa and present at a younger age, and those who develop PCa display higher-grade features, with poorer prognosis.6  These characteristics raise the possibility of distinct genetic alterations in African Americans.

In this pilot study, our goal was to investigate the differential genetic alterations of PCa metastatic to regional lymph nodes in African Americans, with an emphasis on SPOP mutation.

Patient Selection

We retrospectively identified all African American patients with PCa and regional nodal involvement (pN1) who underwent radical prostatectomy with concomitant lymph node dissection at our institution between 2011 and 2019. Of those, we included patients for whom complete histopathologic specimens were available. Of note, these patients were part of a cohort study addressing risk stratification in advanced PCa, specifically the impact of lymph node tumor burden.7  The study was approved by the Emory University Institutional Review Board (Atlanta, Georgia) and fulfilled the tenets of the declaration of Helsinki.

Histologic Evaluation

The prostatectomy specimens were dissected based on the guidelines set by the International Society of Urologic Pathology,8  and all lymph nodes were entirely submitted for histologic examination.

Histopathologic slides were all rereviewed by one pathologist with expertise in genitourinary pathology. Histologic characterization of the tumor included the 2014 modified Gleason score and Grade Group,9  numbers of submitted and positive lymph nodes, size of the largest regional nodal deposit, extranodal extension, extraprostatic extension, and pathological tumor-node–metastasis stage (based on the 8th edition of the American Joint Committee on Cancer staging manual10).

For immunohistochemistry (IHC), formalin-fixed, paraffin-embedded (FFPE) 5-μm-thick sections of tumor were obtained. Tissue was deparaffinized with xylene and dehydrated with gradient alcohol; antigen retrieval was performed, and tissues were then incubated with anti-G3BP1 (1:5000, Proteintech, Rosemont, Illinois), anti-TRIM24 (1:10, MilliporeSigma, Burlington, Michigan), anti-AR (1:40, Agilent Technology, Santa Clara, California), and anti-BRD4 (1:200, Cell Signaling Technology, Danvers, Massachusetts) antibodies. Sections were counterstained with hematoxylin. Immunostaining was scored by 2 reviewers blinded to the pathological data, based on a modified scoring system previously described.11  The overall score was obtained by multiplying the intensity score (0–4, minus the background score; Figure 1, A through D) by the extent score (0 = <5% positive cells; 1 = 5%–25%; 2 = 26%–50%; 3 = 51%–75%; 4 = >75%), with a maximum score of 12. Additional IHC was performed using anti-PTEN antibodies (clone 138G6, 1:400, Cell Signaling Technology) according to the manufacturer’s instructions, and graded as positive or negative based on a previously published paper.12 

Figure 1

Immunohistochemistry intensity scoring system (example of cytoplasmic expression of G3BP1): (A) intensity 0; (B) intensity 1; (C) intensity 2; (D) intensity 3 (original magnifications ×100 [A, C, and D] and ×200 [B]).

Figure 1

Immunohistochemistry intensity scoring system (example of cytoplasmic expression of G3BP1): (A) intensity 0; (B) intensity 1; (C) intensity 2; (D) intensity 3 (original magnifications ×100 [A, C, and D] and ×200 [B]).

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Clinical and Laboratory Evaluation

Age, prostatic-specific antigen (PSA) levels, and clinical and radiologic follow-up including use of adjuvant treatment (radiation therapy and/or androgen deprivation therapy and/or chemotherapy) were collected by reviewers blinded to the histopathologic findings. The status at last follow-up was categorized as follows: (1) no evidence of disease: PSA levels remain undetectable (<0.01 ng/mL) and there is no evidence of metastatic adenocarcinoma clinically or radiologically; (2) alive with disease: postoperative elevated PSA levels are detected or the patient develops clinical or radiographic recurrence; (3) dead of disease: patient found to have died of the disease clinically; and (4) dead of other causes: patient died of other causes unrelated to PCa.

Next-Generation Sequencing and Analysis

Whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) of DNA and RNA, respectively, isolated from FFPE samples were conducted at a Clinical Laboratory Improvement Amendments–certified laboratory at Caris Life Sciences (Phoenix, Arizona) using Illumina NovaSeq 6000 sequencers. Prior to molecular testing, samples were enriched for tumor via macrodissection of the slides. For WES, a hybrid pull-down assay designed to enrich for >700 clinically relevant genes at high coverage and high read-depth and for an additional >20 000 genes at lower depth were used. All variants were detected with >99% confidence based on allele frequency and amplicon coverage, with an average sequencing depth of coverage being at least 500 and an analytic sensitivity of 10% allele frequency. Genetic variants identified were further interpreted by board-certified molecular geneticists and categorized as “pathogenic,” “likely pathogenic,” “variant of unknown significance,” “likely benign,” or “benign,” according to the American College of Medical Genetics and Genomics standards.13,14  Subsequently, individual genes annotated with “pathogenic” and “likely pathogenic” were counted toward mutations, while the rest of the samples annotated otherwise were considered wild-type.

For WTS, RNA was extracted using a Qiagen RNA FFPE tissue extraction kit and was subjected to cDNA amplification via a bait-targeted polymerase chain reaction (per the manufacturer’s instructions; Qiagen, Germantown, Maryland), which was further sequenced to an average of 60 million reads. Subsequently, raw data were demultiplexed by using the Illumina Dragen BioIT accelerator, trimmed, and counted, with polymerase chain reaction duplicates removed and aligned to human reference genome hg19 by STAR aligner22 for transcription counting. Transcripts per million molecules (TPMs) were used (Salmon expression pipeline23) as units to reflect mRNA expression, and fusion events were captured via the WTS technique.

Androgen Receptor Signaling and Integrated Neuroendocrine Prostate Cancer Scores

Androgen receptor (AR) signaling was evaluated by employing mRNA levels of 30 genes used to define AR pathway activation, as previously described.15  Briefly, RNA extracts from triplicate batches of lymph node carcinoma of the prostate cells, which were known to possess active AR signaling, were used for generating the reference sample: average values of expression of 30 genes across the triplicates were used as a reference vector, and the Spearman correlation coefficients of the TPM value of each tumor specimen to this reference vector were computed and further considered as the “AR signaling” score. A score greater than 0.81 was defined as AR-high.

The integrated neuroendocrine prostate cancer (NEPC) score predicts the likelihood of tumor specimens to have neuroendocrine histologic features.16  The score was computed as the Pearson correlation coefficient between a tested sample and a reference vector based on a set of 70 genes using log2-transformed TPM values as input. The reference vector stemmed from the average of 70 genes across 43 samples with a diagnosed NEPC histology that had a high Pearson correlation coefficient with each other (r > 0.72). A score greater than 0.40 was considered NEPC-high.

Single-Sample Gene Enrichment Analysis

To evaluate pathway enrichment for individual tumors, single-sample gene enrichment analysis was performed to calculate scores of 50 hallmark gene pathways based on mRNA expression without any normalization.17,18  Analysis was performed using the “GSVA” packages in R (version 4.0.2, R Foundation for Statistical Computing, Vienna, Austria).

Statistical Analysis

Continuous variables were compared between groups using the Wilcoxon test, and descriptive statistics including medians and interquartile ranges (IQRs) were reported. The 95% confidence intervals (95% CIs) were obtained by normal approximation to the binomial or by the exact binomial test when appropriate.

For survival analysis, the primary end point was disease-free survival, defined as the time from the date of prostatectomy to biochemical, clinical, or radiographic relapse or cancer-related death. In case of biochemical relapse or recurrence, the date of the first abnormal PSA obtained following surgery was used as the date of the event. Patients with no evidence of disease and those who died from another cause were grouped together and were censored at date of last follow-up. Patients alive with disease and those who died from the disease were grouped together and were considered as “event” data and as having unfavorable outcomes. Survival analysis was performed using the “survival” (version 3.2–7) and the “survminer” (version 0.4.8) packages in R, where disease-free survival curves were derived from the Kaplan-Meier method; differences in disease-free survival between groups were compared using the log-rank test (2-tailed, significance level at 5%).

Baseline Demographic and Prostate Pathologic Findings

Nineteen African American patients (median [IQR] age: 61.0 years old [53.0–62.5]) who underwent radical prostatectomy and lymphadenectomy for PCa with ≥1 positive regional lymph node(s) (pN1 stage) were included. Stage, histopathologic findings, and follow-up are summarized in Table 1. Most patients had a Grade Group of 5 (13 of 19; 68%), stage pT3b (12 of 19; 63%) PCa with metastatic disease confined to the regional lymph nodes (pN1M0; 16 of 19; 84%).

Table 1

Demographics, Staging, and Follow-up Findings in Our 19 Prostatic Adenocarcinoma African American Patients at Baseline

Demographics, Staging, and Follow-up Findings in Our 19 Prostatic Adenocarcinoma African American Patients at Baseline
Demographics, Staging, and Follow-up Findings in Our 19 Prostatic Adenocarcinoma African American Patients at Baseline

Mutations in SPOP, BRD4, TP53, and TMPRSS2-ETS Fusion Were the Most Prevalent Genomic Alterations

Molecular profiling including WES and WTS was performed on the primary tumor of all 19 patients; all detectable coalterations are displayed in Figure 2. SPOP mutations (5 of 17; 29.4% [95% CI: 10.3–56.0], including those in 1 patient with preoperative external beam radiation therapy and 4 treatment-naive patients) were the most prevalent alterations, all of which were missense mutations in the MATH domain, including W131G, F125C, F133L, and 2 F133V. Other common genetic alterations included BRD4 mutations (4 of 15; 26.7% [95% CI: 7.8–55.1]), TP53 mutations (4 of 17; 23.5% [95% CI: 6.8–49.9]), and TMPRSS2-ETS gene fusions (4 of 17; 23.5% [95% CI: 6.8–49.9]). Mutant SPOP (m-SPOP) patients did not have TMPRSS2-ETS fusions. Interestingly, while most alterations were associated with a high AR signaling score (AR-high), m-SPOP PCas were exclusively AR-low (AR signaling score of 0.788 [IQR 0.765–0.791] versus 0.835 [IQR 0.828–0.842], P = .003). The NEPC score was not different between m-SPOP PCa versus wild-type SPOP (wt-SPOP) PCa (0.327 [IQR 0.325–0.382] versus 0.378 [IQR 0.352–0.404], P = .38). Interestingly, while being a frequent mutation in PCa,5  none of the 19 patients had PTEN mutation.

Figure 2

OncoPrint of the androgen receptor (AR) activity, integrated neuroendocrine prostate cancer (NEPC) score, and all genomic alterations (mutation [NGS]; copy number amplification [CNA]) in the primary tumor. Side bars indicate the frequency of individual alteration; green: mutant (mut) (gene) or high (score); grey: wild-type (wt) (gene) or low (score); white: not available.

Figure 2

OncoPrint of the androgen receptor (AR) activity, integrated neuroendocrine prostate cancer (NEPC) score, and all genomic alterations (mutation [NGS]; copy number amplification [CNA]) in the primary tumor. Side bars indicate the frequency of individual alteration; green: mutant (mut) (gene) or high (score); grey: wild-type (wt) (gene) or low (score); white: not available.

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Additional WES was performed on the lymph node metastases of 10 patients, but failed in 7 patients due to insufficient tumor volume; therefore, WES yielded analyzable results in only 3 patients (Supplemental Figure 1; see supplemental digital content, containing 4 figures and 1 table, at https://meridian.allenpress.com/aplm in the March 2024 table of contents).

Impact of SPOP Mutations on mRNA Levels of AR, G3BP1, TRIM24, BRD4, NCOA3, and HOXB13

We further investigated the impact of SPOP mutations on transcriptomic levels of SPOP and its direct negative upstream regulator G3BP1; its substrates AR, TRIM24, BRD4, NCOA3 (also known as CRF-3); and the AR signaling inhibitor HOXB13 (Table 2). Compared to wt-SPOP PCa, m-SPOP mRNA expression showed a significantly decreased expression of AR, TRIM24, and NCOA3 and a trend for a lower expression of G3BP1, BRD4, and HOXB13.

Table 2

Messenger RNA Expression of SPOP, SPOP Regulators, and Substrates and AR Signaling Inhibitor HOXB13 and Immunohistochemistry Scores of SPOP Substratesa

Messenger RNA Expression of SPOP, SPOP Regulators, and Substrates and AR Signaling Inhibitor HOXB13 and Immunohistochemistry Scores of SPOP Substratesa
Messenger RNA Expression of SPOP, SPOP Regulators, and Substrates and AR Signaling Inhibitor HOXB13 and Immunohistochemistry Scores of SPOP Substratesa

Impact of SPOP Mutations on Protein Levels of AR, G3BP1, TRIM24, and BRD4

IHC was performed on 5 of 5 m-SPOP PCas and 6 of 12 wt-SPOP PCas to assess protein levels of AR, G3BP1, TRIM24, and BRD4 (Table 2). Our results showed a trend for lower expression of G3BP1 in m-SPOP PCa. No significant differences of immunohistochemical expression between m-SPOP and wt-SPOP PCa for AR, TRIM24, and BRD4 were observed.

Results for PTEN IHC are available in the Supplemental Table and Supplemental Figure 2.

Associations Between Genomic Alterations and Hallmark Pathway Enrichments

To investigate the association between detected genetic alterations and pathway enrichments at the transcriptomic level, we performed single-sample gene enrichment analysis analysis using hallmark gene sets, which represented and summarized specific well-defined biological states in cancer development. Results are depicted in Supplemental Figure 3.

Survival Analysis

Of the 19 patients, the status at last follow-up was unavailable for 1 patient, and 1 m-SPOP PCa patient died from other causes soon after radical prostatectomy and was excluded. Therefore, 17 patients were included for survival analysis, including 4 m-SPOP patients. Five patients have remained disease-free, with a median follow-up of 23.0 months (IQR 21.7–24.3), and 12 patients experienced a recurrence or died from PCa, with a median follow-up of 31.8 months (IQR 19.9–45.6). Overall median disease-free survival was 4.1 months. Kaplan-Meier curves stratified by SPOP mutational status are depicted in Figure 3. Specific m-SPOP patient data, including follow-up, status at last follow-up, and neoadjuvant and adjuvant therapy, are provided in Table 3.

Figure 3

Comparison of disease-free survival rate of African American patients with pN1 prostate adenocarcinoma stratified by SPOP mutational status. P values for the log-rank test are displayed at the bottom.

Figure 3

Comparison of disease-free survival rate of African American patients with pN1 prostate adenocarcinoma stratified by SPOP mutational status. P values for the log-rank test are displayed at the bottom.

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Table 3

Details Regarding Our 5 Patients With SPOP Mutation

Details Regarding Our 5 Patients With SPOP Mutation
Details Regarding Our 5 Patients With SPOP Mutation

Downloading and Reprocessing of The Cancer Genome Atlas Database

To support our results, we used The Cancer Genome Atlas (TCGA) data set for PCa with annotated race and SPOP mutational status obtained from the supplemental materials of a previously published paper.5  Matched transcriptomic data (normalized using the RNA-seq by expectation-maximization algorithm19) were further downloaded for the same cohort via the Firehose portal by the Broad Institute. Of the 191 patients with available race information, 22 were African American (55.0 years old [IQR 53.3–62.0]), among whom 6 had a SPOP mutation (27.3% [95% CI: 11.6–50.4]). The prevalence of SPOP mutation was lower in non–African American patients (n = 14 of 169, 8.2% [95% CI: 4.8–13.8], P = .03). In m-SPOP African American patients, a trend for lower expression of G3BP1, AR, and BRD4 was noted, which is consistent with our results, with the exception of TRIM24 (Figure 4). For comparison, we similarly processed the data from White patients and White patients with high-risk disease only (Gleason score >7; see Supplemental Figure 4, A and B).

Figure 4

Differential mRNA expression of SPOP, SPOP-negative regulator G3BP1, SPOP substrates AR, TRIM24, BRD4, and NCOA3 and AR signaling inhibitor HOXB13 stratified by SPOP mutational status in African American patients from the The Cancer Genome Atlas data set. Messenger RNA expression is expressed as “expected counts” using the RNA-seq by Expectation-Maximization (RSEM) algorithm (following logarithmic transformation), a method to handle ambiguously mapped reads. Abbreviations: m-SPOP, mutated SPOP; wt-SPOP, wild-type SPOP.

Figure 4

Differential mRNA expression of SPOP, SPOP-negative regulator G3BP1, SPOP substrates AR, TRIM24, BRD4, and NCOA3 and AR signaling inhibitor HOXB13 stratified by SPOP mutational status in African American patients from the The Cancer Genome Atlas data set. Messenger RNA expression is expressed as “expected counts” using the RNA-seq by Expectation-Maximization (RSEM) algorithm (following logarithmic transformation), a method to handle ambiguously mapped reads. Abbreviations: m-SPOP, mutated SPOP; wt-SPOP, wild-type SPOP.

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SPOP is the most commonly mutated gene in PCa, reported in 5% to 15% of localized and metastatic PCa cases.2030  SPOP drives degradation of key oncogene proteins through its function as a substrate adaptor of cullin 3 (CUL3)-based ubiquitin ligase, and therefore acts as a tumor suppressor in several cancers, including PCa.31  Our results suggest that African American patients with metastatic PCa have a high frequency of SPOP mutations (∼30%) with lower expressions of SPOP substrates, including AR, TRIM24, and NCOA3. We found a similar prevalence of SPOP mutation in African Americans (∼27%) after reprocessing a TCGA-derived dataset used in a previously published paper,5  supporting our findings.

The higher incidence and aggressiveness of PCa in African Americans raises concern for interracial molecular heterogeneity. However, most studies regarding the genomic landscape of PCa either did not provide information regarding race2024,2630,32,33  or, when the data were available, did not address racial differences in the genetic alterations of PCa.5,34  To our knowledge, only 4 studies have focused on genetic alteration of PCa in African Americans, yet with inconsistent results.25,3537  In these studies, the percentage of m-SPOP patients varied from 5% to 10%,25,35,36  up to 23% in a study derived from TCGA data.37  Interestingly, 1 study,38  focusing on molecular subtypes, has suggested that PCa in African American patients is more likely to belong to the You PSC1 molecular subtype39  (ie, m-SPOP enriched) compared to PCa in White patients (25% versus 18%). Although random sampling error has certainly contributed to these inconsistent findings given the small size of the different African American cohorts, ranging from 19 (our study) to 88,25,35  other factors, such as the metastatic status, might explain this discrepancy. Indeed, while details regarding the metastatic status were not provided in the other reports addressing race,25,3537  we exclusively included African American patients with aggressive disease, that is, with PCa metastatic to the pelvic lymph node, believing that this subset of patients would harbor a different mutational burden. Our high prevalence of SPOP mutation might stem from our highly selected cohort.

In line with other studies,5,20,35  we have found that SPOP mutations were mutually exclusive with ETS rearrangement, suggesting that m-SPOP might represent an early and divergent driver in prostate carcinogenesis and could define a molecularly distinct class of PCa.20  The fact that SPOP mutations were also identified in high-grade prostatic intraepithelial neoplasia lends support to this hypothesis.20  The immense majority of SPOP mutations in PCa affect highly conserved amino-acid residues in the substrate-binding region (called the MATH domain) of SPOP (as found in our study), disrupting optimal interaction with its substrates, and therefore preventing their degradation (ie, inactivating mutation). The clustering of mutations in the MATH domain of SPOP suggests that m-SPOP tumor cells have a survival advantage by altering the degradation of oncogene substrates,40  including AR, TRIM24, BRD4, and NCOA3, possibly further leading to high AR activity, which is a key pathophysiologic mechanism in prostate carcinogenesis.5  Surprisingly, while we hypothesized increased expression of AR, TRIM24, BRD4, and NCOA3 in m-SPOP PCa,5,41,42  not only did AR, TRIM24, and NCOA3 show significantly lower expression (and BRD4 a trend for lower expression) by transcriptome analysis, but a significantly (and consistently) lower AR signaling score in m-SPOP PCa was also shown. This was not mirrored by IHC results, possibly due to the difficulty of assessing quantitative differences using this method.

To better understand whether the unexpected expression change could be attributed to aberrations in upstream regulators of SPOP, we evaluated the mutational status and expression (mRNA level and IHC) of G3BP1. G3BP1, a well-known oncogene protein, is an inhibitor of the CUL3–SPOP complex by competing with SPOP substrates, leading to upregulation of AR signaling and prostate tumorigenesis.43  In return, G3BP1 is upregulated by AR through a feed-forward G3BP1-SPOP-AR loop.43  G3BP1 is often overexpressed and SPOP often downregulated in PCa,26,43,44  and G3BP1 overexpression is proposed to define a distinct group of PCa patients with compromised SPOP function (regardless of SPOP mutational status), high AR signaling, and sensitivity to AR-targeted therapy.43 

Paradoxically, our results suggest a trend toward decreased G3BP1 (which is consistent with African American patients in the TCGA-derived dataset after reprocessing5) in addition to the lower AR signaling score and lower expression of AR. One hypothesis is that our m-SPOP PCa patients had a gain-of-function of SPOP (leading to increased degradation of AR and therefore lower G3BP1 expression); however, this is unlikely, as all our SPOP mutations were previously reported and associated with loss of function. An alternate hypothesis is that the G3BP1-SPOP-AR axis feed-forward loop is disrupted in this subset of patients, with low AR activity preventing G3BP1 overexpression, in return maintaining the expression of wt-SPOP and preventing SPOP substrate overexpression, raising concern for suboptimal efficacy of androgen deprivation in this subset of patients. To explain this low AR activity (and therefore the disruption of the loop), we hypothesized an overexpression of HOXB13 (an AR signaling inhibitor reported in PCa45), but the data presented here and TCGA data do not support this hypothesis. Alternatively, genetic alterations involving G3BP1 or AR could have explained the low AR activity, but sequencing did not reveal any alteration of these genes in m-SPOP PCa patients. Further investigations into the pathogenesis of the observed findings are warranted.

Although SPOP mutation has been one of the most detectable alterations in PCa, its prognostic value remains unclear given the heterogeneity of the different cohorts, with some suggesting either a better21,34  or a worse33  prognosis in m-SPOP patients, or even no prognostic value of the SPOP mutation.35  A higher percentage of m-SPOP was observed in castrate-resistant prostate carcinoma (20%–30%)21,34  and was associated with high AR signaling21  and better response to androgen deprivation therapy.21,34  However, race was not specified in either of these studies. One hypothesis is that SPOP mutations are present at higher percentages in metastatic prostate carcinoma, but confer a better prognosis due to increased AR signaling and therefore response to androgen deprivation therapy. Although the suboptimal power of our study precluded any meaningful conclusions in terms of outcome, our results may suggest a trend toward a better prognosis in m-SPOP African American patients with pN1 PCa compared to those with wt-SPOP. However, m-SPOP patients in our study were all associated with low AR signaling, and the effects of this finding on androgen therapy response and prognosis are not clear (Table 3).

The strength of our study includes a highly selected population of African American patients with metastatic PCa; the vast majority were treatment-naive, mitigating the effects of radiation therapy and hormone-induced genetic alterations on our results. We acknowledge that the small size of our sample prevents more robust conclusions, but our results are supported by the TCGA-derived data. We believe that further larger-scale studies might shed light on the pathophysiology of PCa in this subset of patients.

African American patients with metastatic PCa might have a higher prevalence of SPOP mutation with disruption of the recently described G3BP1-SPOP-AR axis, of yet unclear origin. Future prospective studies to confirm our results on a larger sample and investigate the significance of low AR signaling on response to androgen deprivation therapy in m-SPOP African American patients would be helpful. Better genetic understanding of the mutational milieu of PCa in African American patients is critical to improving the choices of targeted treatment for this population.

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Author notes

This research was supported in part by the Dunwoody Golf Club Prostate Cancer Research Award, a philanthropic award provided by the Winship Cancer Institute of Emory University.

Supplemental digital content is available for this article at https://meridian.allenpress.com/aplm in the March 2024 table of contents.

Yin and Xiu are employees of Caris Life Sciences. The other authors have no relevant financial interest in the products or companies described in this article.

The contents of this manuscript are original research that was presented as a poster at the United States and Canadian Academy of Pathology meeting; March 22, 2022; Los Angeles, California.

Supplementary data