Metastatic prostate tumors in Hispanic American men carry a distinctly different molecular and immune fingerprint from those of non-Hispanic White men, according to a retrospective clinicogenomic study of 83 patients treated at the University of Arizona Cancer Center between 2015 and 2023. The analysis, published in Cancer Reports, compared 32 Hispanic American (HA) patients with 51 non-Hispanic White (NHW) patients, all diagnosed with metastatic hormone-sensitive prostate adenocarcinoma and profiled with next-generation sequencing of primary prostate tissue before any hormone-directed therapy. The researchers report that HA patients in this cohort presented with more advanced disease, harbored a significantly higher frequency of TMPRSS2 gene fusions, and showed differences in immune cell composition, oncogenic pathway activity, and the expression of genes linked to stemness and treatment resistance. The authors emphasize that, given the modest sample size and retrospective design, all findings are hypothesis-generating and require validation in larger, multi-institutional cohorts.
The clinical picture at presentation differed notably between the groups. Hispanic American patients were more likely to have an Eastern Cooperative Oncology Group performance status of zero, reported in 56 percent compared with 22 percent of NHW patients, a difference the authors note with a p-value of 0.001. At the same time, HA patients presented with higher prostate-specific antigen levels, a median of 111.5 versus 52.6 nanograms per milliliter, and more advanced disease stage, including a higher rate of T4 tumors (41 percent versus 14 percent) and visceral metastases (41 percent versus 16 percent). There were no significant differences in Gleason grade above pattern 4 or in nodal involvement. The two groups were similar in age at presentation, with a median of 66 years, and did not differ significantly in obesity, personal cancer history, or first-degree family history of cancer. HA patients reported higher frequencies of smoking (69 percent versus 54 percent) and of alcohol or drug use (63 percent versus 45 percent), a comparison that reached statistical significance.
On the genomic level, the most striking difference concerned gene fusions involving TMPRSS2. These rearrangements were detected in 46.4 percent of HA tumors compared with 20.0 percent of NHW tumors, a difference the authors report as statistically significant with a p-value of 0.04. The ETS-family fusions observed in the HA cohort included ERG, ETV1, and ETV4 rearrangements, with TMPRSS2 and SLC45A3 serving as fusion partners. The TMPRSS2-ERG fusion is among the most frequent somatic alterations in prostate cancer and is thought to occur early in tumor development. Prior studies have found variable prevalence of ETS fusions across populations, with the highest rates reported in men of European ancestry and lower rates in men of African and Asian ancestry, but the prevalence in Hispanic American men had not been well described. The authors stress that their study was not designed to evaluate the mechanisms underlying fusion frequency differences, and that experimental data linking inflammatory signaling to TMPRSS2-ERG formation remain a possibility rather than an explanation established in this cohort.
Other genomic differences were observed but did not reach statistical significance. Differences in the frequency of TP53, SPOP, and CTNNB1 mutations were seen between the groups, and NHW tumors showed lower absolute frequencies of loss of heterozygosity, CDK12 alterations, and RB1 alterations compared with HA tumors, although none of these comparisons was statistically significant. The sequencing was performed on formalin-fixed paraffin-embedded tissue by a commercial CAP/CLIA-certified laboratory, with variants interpreted according to American College of Medical Genetics and Genomics standards. Tumor mutational burden was assessed with a cutoff of more than 10 mutations per megabase, and there was no significant difference between the groups in the frequency of high tumor mutational burden, PD-L1 positivity, mismatch repair deficiency, or microsatellite instability-high status.
Immune deconvolution of whole-transcriptome sequencing data, performed with the quanTIseq algorithm, revealed differences in the estimated composition of immune cells within the tumors. HA tumors showed higher estimated infiltration of M1 macrophages, at 0.72 percent versus 0 percent, and of natural killer cells, at 4.84 percent versus 3.55 percent, along with lower infiltration of CD8 T cells, at 0 percent versus 0.11 percent, in comparisons that each reached a p-value below 0.05. HA tumors also expressed higher levels of the immunoinhibitory genes PDCD1LG2, which encodes PD-L2, at 1.68-fold, and FOXP3, at 1.45-fold. There was no significant difference between the groups in the T cell inflamed score or the interferon-gamma score. The authors caution that while M1 macrophages and NK cells are generally associated with anti-tumor responses, persistent innate immune activation without effective adaptive immunity has been linked in prior work to tumor-promoting inflammation, and that this study cannot determine whether the immune differences reflect ethnicity-associated biology, differences in disease burden, or other clinical factors.
Gene set enrichment analysis pointed to differences in developmental signaling pathways. Hedgehog signaling was significantly enriched in HA tumors, with a normalized enrichment score of 1.45 and a false discovery rate of 0.04. Trends toward enrichment of NOTCH signaling, with a normalized enrichment score of 1.41 and a false discovery rate of 0.07, and Wnt/beta-catenin signaling, with a score of 1.38 and a false discovery rate of 0.10, were also observed. Expression of pathway-associated genes including WNT1, WNT2, HES1, and NOTCH1 was higher in HA tumors, meeting the study’s thresholds of p below 0.05 and q below 0.10. These pathways have been implicated in prostate cancer stemness, epithelial-to-mesenchymal transition, and resistance to androgen receptor-directed therapies in earlier research, and Wnt/beta-catenin activation has been associated with T-cell exclusion from tumors. The authors explicitly state that the present study cannot establish that pathway enrichment contributed to immune composition, treatment response, or clinical presentation.
The transcriptomic analysis also identified higher expression in HA tumors of stem cell-associated markers, including ALDH1A1 at 2.1-fold, ALDH1A2 at 3-fold, and PROM1 at 1.6-fold, all meeting the statistical thresholds applied. In addition, HA tumors showed higher expression of genes associated with cell cycle regulation (CCND2), inhibition of apoptosis (BIRC2 and XIAP), epithelial-to-mesenchymal transition (TWIST1 and MMP2), and drug efflux (ABCC1 and ABCB1), with fold changes ranging from 1.1 to 1.5 and q-values below 0.10. The authors note that these molecular features have been associated with aggressive tumor behavior and therapeutic resistance in prior studies across cancer types, but that the present analysis cannot establish their relationship to the more advanced clinical presentation observed in the HA cohort.
Treatment patterns and short-term outcomes added a further layer of complexity. The modalities and sequencing of treatment did not differ significantly between the groups, and combination therapy was used as first-line treatment in 84 percent of all patients. HA patients began first-line therapy sooner after diagnosis, with a median of 1 month versus 3 months, and showed lower median PSA levels at three months after treatment initiation, 0.8 versus 3.96 nanograms per milliliter. Yet the median time to initiation of second-line therapy was longer for HA patients, 20 versus 11 months, while the median time to last clinical contact was shorter, 23 versus 44 months. Median overall survival had not been reached at the time of analysis because of limited events and ongoing follow-up. The authors suggest that while HA tumors may initially respond to androgen deprivation, underlying tumor biology may limit response durability, while also acknowledging that delayed recognition of progression, shorter follow-up, and incomplete documentation could contribute to the observed patterns.
The authors are careful to frame the entire study as exploratory. They note that baseline clinical characteristics differed between the groups, including performance status, disease stage, visceral metastatic burden, smoking and substance use history, and duration of follow-up, and that multivariable analyses adjusting for these factors were not feasible given the sample size. The limited number of patients relative to the number of molecular and immune features evaluated would have increased the risk of model overfitting and unstable estimates, so the observed differences should be interpreted as unadjusted associations that may partly reflect differences in disease burden, clinical presentation, tissue selection, or other unmeasured factors rather than ethnicity alone. The retrospective design, selection bias related to sequencing availability, and modest sample size further constrain the conclusions. Even so, the study fills a noted gap: Hispanic American men remain substantially underrepresented in genomic and tumor microenvironment research, and most large-scale genomic studies have predominantly included men of European ancestry. The authors argue that the findings underscore the importance of incorporating Hispanic American men into clinicogenomic research and identify molecular and immune features that warrant further investigation in prospective studies with larger, ethnically diverse cohorts and longer follow-up.
Subject of Research: Genomic, transcriptomic, and tumor microenvironment features of metastatic hormone-sensitive prostate cancer in Hispanic American versus non-Hispanic White men
Article Title: Molecular and Immune Features of Metastatic Prostate Cancer in Hispanic and Non‐Hispanic American Men
Article References: Recio‐Boiles, A., Deshmukh, S. K., Everly, C. J., Wu, S., Estrada‐Mendizabal, R. J., Heath, E., McKay, R. R., Miranti, C., Batai, K., Lee, B. R., & Chipollini, J. (2026). Molecular and Immune Features of Metastatic Prostate Cancer in Hispanic and Non‐Hispanic American Men. Cancer Reports, 9(10), Article e70707. https://doi.org/10.1002/cnr2.70707
Image Credits: AI Generated
DOI: 10.1002/cnr2.70707
Keywords: prostate cancer, Hispanic American, genomic disparities, TMPRSS2 fusion, tumor microenvironment, Hedgehog signaling, immune infiltration, next-generation sequencing, health disparities, hormone-sensitive prostate cancer, retrospective study, gene expression
News Source: Nathaniel Bowman. (October 28, 2026). Prostate Tumors in Hispanic American Men Show Distinct Molecular and Immune Features. Scienmag.
