Biomarker-Directed Therapy in Black and White Men With Metastatic Castration-Resistant Prostate Cancer.

Importance: Black men have higher incidence and mortality from prostate cancer. Whether precision oncology disparities affect Black men with metastatic castration-resistant prostate cancer (mCRPC) is unknown. Objective: To compare precision medicine data and outcomes between Black and White men with mCRPC. Design, Setting, and Participants: This retrospective cohort study used data collected by the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) consortium, a multi-institutional registry with linked clinicogenomic data, from April 2020 to December 2021. Participants included Black and White patients with mCRPC with molecular data. Data were analyzed from December 2021 to May 2023. Exposures: Database-reported race and ethnicity. Main Outcomes and Measures: The primary outcome was the frequency of actionable molecular data, defined as the presence of mismatch repair deficiency (MMRD) or high microsatellite instability (MSI-H), homologous recombination repair deficiency, or tumor mutational burden of 10 mutations per megabase or greater. Secondary outcomes included the frequency of other alterations, the type and timing of genomic testing performed, and use of targeted therapy. Efficacy outcomes were prostate-specific antigen response rate, site-reported radiographic response, and overall survival. Results: A total of 962 eligible patients with mCRPC were identified, including 204 Black patients (21.2%; median [IQR] age at diagnosis, 61 [55-67] years; 131 patients [64.2%] with Gleason scores 8-10; 92 patients [45.1%] with de novo metastatic disease) and 758 White patients (78.8%; median [IQR] age, 63 [57-69] years; 445 patients [58.7%] with Gleason scores 8-10; 310 patients [40.9%] with de novo metastatic disease). Median (IQR) follow-up from mCRPC was 26.6 (14.2-44.7) months. Blood-based molecular testing was more common in Black men (111 men [48.7%]) than White men (317 men [36.4%]; P < .001). Rates of actionable alterations were similar between groups (65 Black men [32.8%]; 215 White men [29.1%]; P = .35), but MMRD or MSI-H was more common in Black men (18 men [9.1]) than White men (36 men [4.9%]; P = .04). PTEN alterations were less frequent in Black men than White men (31 men [15.7%] vs 194 men [26.3%]; P = .003), as were TMPRSS alterations (14 men [7.1%] vs 155 men [21.0%]; P < .001). No other differences were seen in the 15 most frequently altered genes, including TP53, AR, CDK12, RB1, and PIK3CA. Matched targeted therapy was given less frequently in Black men than White men (22 men [33.5%] vs 115 men [53.5%]; P = .008). There were no differences in response to targeted therapy or survival between the two cohorts. Conclusions and Relevance: This cohort study of men with mCRPC found higher frequency of MMRD or MSI-H and lower frequency of PTEN and TMPRSS alterations in Black men compared with White men. Although Black men received targeted therapy less frequently than White men, no differences were observed in clinical outcomes.

ETV6 Deficiency Unlocks ERG-Dependent Microsatellite Enhancers to Drive Aberrant Gene Activation in B-Lymphoblastic Leukemia.

Distal enhancers play critical roles in sustaining oncogenic gene-expression programs. We identify aberrant enhancer-like activation of GGAA tandem repeats as a characteristic feature of B-cell acute lymphoblastic leukemia (B-ALL) with genetic defects of the ETV6 transcriptional repressor, including ETV6-RUNX1+ and ETV6-null B-ALL. We show that GGAA repeat enhancers are direct activators of previously identified ETV6-RUNX1+/- like B-ALL "signature" genes, including the likely leukemogenic driver EPOR. When restored to ETV6-deficient B-ALL cells, ETV6 directly binds to GGAA repeat enhancers, represses their acetylation, downregulates adjacent genes, and inhibits B-ALL growth. In ETV6-deficient B-ALL cells, we find that the ETS transcription factor ERG directly binds to GGAA microsatellite enhancers and is required for sustained activation of repeat enhancer-activated genes. Together, our findings reveal an epigenetic gatekeeper function of the ETV6 tumor suppressor gene and establish microsatellite enhancers as a key mechanism underlying the unique gene-expression program of ETV6-RUNX1+/- like B-ALL. SIGNIFICANCE: We find a unifying mechanism underlying a leukemia subtype-defining gene-expression signature that relies on repetitive elements with poor conservation between humans and rodents. The ability of ETV6 to antagonize promiscuous, nonphysiologic ERG activity may shed light on other roles of these key regulators in hematolymphoid development and human disease. See related commentary by Mercher, p. 2. This article is highlighted in the In This Issue feature, p. 1.

The evolutionarily conserved long non-coding RNA LINC00261 drives neuroendocrine prostate cancer proliferation and metastasis via distinct nuclear and cytoplasmic mechanisms.

Metastatic neuroendocrine prostate cancer (NEPC) is a highly aggressive disease, whose incidence is rising. Long noncoding RNAs (lncRNAs) represent a large family of disease- and tissue-specific transcripts, most of which are still functionally uncharacterized. Thus, we set out to identify the highly conserved lncRNAs that play a central role in NEPC pathogenesis. To this end, we performed transcriptomic analyses of donor-matched patient-derived xenograft models (PDXs) with immunohistologic features of prostate adenocarcinoma (AR+ /PSA+ ) or NEPC (AR- /SYN+ /CHGA+ ) and through differential expression analyses identified lncRNAs that were upregulated upon neuroendocrine transdifferentiation. These genes were prioritized for functional assessment based on the level of conservation in vertebrates. Here, LINC00261 emerged as the top gene with over 3229-fold upregulation in NEPC. Consistently, LINC00261 expression was significantly upregulated in NEPC specimens in multiple patient cohorts. Knockdown of LINC00261 in PC-3 cells dramatically attenuated its proliferative and metastatic abilities, which are explained by parallel downregulation of CBX2 and FOXA2 through distinct molecular mechanisms. In the cell cytoplasm, LINC00261 binds to and sequesters miR-8485 from targeting the CBX2 mRNA, while inside the nucleus, LINC00261 functions as a transcriptional scaffold to induce SMAD-driven expression of the FOXA2 gene. For the first time, these results demonstrate hyperactivation of the LINC00261-CBX2-FOXA2 axes in NEPC to drive proliferation and metastasis, and that LINC00261 may be utilized as a therapeutic target and a biomarker for this incurable disease.

Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer.

ABTRACT: Forkhead box A1 (FOXA1) is a pioneer transcription factor that is essential for the normal development of several endoderm-derived organs, including the prostate gland1,2. FOXA1 is frequently mutated in hormone-receptor-driven prostate, breast, bladder and salivary-gland tumours3-8. However, it is unclear how FOXA1 alterations affect the development of cancer, and FOXA1 has previously been ascribed both tumour-suppressive9-11 and oncogenic12-14 roles. Here we assemble an aggregate cohort of 1,546 prostate cancers and show that FOXA1 alterations fall into three structural classes that diverge in clinical incidence and genetic co-alteration profiles, with a collective prevalence of 35%. Class-1 activating mutations originate in early prostate cancer without alterations in ETS or SPOP, selectively recur within the wing-2 region of the DNA-binding forkhead domain, enable enhanced chromatin mobility and binding frequency, and strongly transactivate a luminal androgen-receptor program of prostate oncogenesis. By contrast, class-2 activating mutations are acquired in metastatic prostate cancers, truncate the C-terminal domain of FOXA1, enable dominant chromatin binding by increasing DNA affinity and-through TLE3 inactivation-promote metastasis driven by the WNT pathway. Finally, class-3 genomic rearrangements are enriched in metastatic prostate cancers, consist of duplications and translocations within the FOXA1 locus, and structurally reposition a conserved regulatory element-herein denoted FOXA1 mastermind (FOXMIND)-to drive overexpression of FOXA1 or other oncogenes. Our study reaffirms the central role of FOXA1 in mediating oncogenesis driven by the androgen receptor, and provides mechanistic insights into how the classes of FOXA1 alteration promote the initiation and/or metastatic progression of prostate cancer. These results have direct implications for understanding the pathobiology of other hormone-receptor-driven cancers and rationalize the co-targeting of FOXA1 activity in therapeutic strategies.

Oncogenic Role of THOR, a Conserved Cancer/Testis Long Non-coding RNA.

Large-scale transcriptome sequencing efforts have vastly expanded the catalog of long non-coding RNAs (lncRNAs) with varying evolutionary conservation, lineage expression, and cancer specificity. Here, we functionally characterize a novel ultraconserved lncRNA, THOR (ENSG00000226856), which exhibits expression exclusively in testis and a broad range of human cancers. THOR knockdown and overexpression in multiple cell lines and animal models alters cell or tumor growth supporting an oncogenic role. We discovered a conserved interaction of THOR with IGF2BP1 and show that THOR contributes to the mRNA stabilization activities of IGF2BP1. Notably, transgenic THOR knockout produced fertilization defects in zebrafish and also conferred a resistance to melanoma onset. Likewise, ectopic expression of human THOR in zebrafish accelerated the onset of melanoma. THOR represents a novel class of functionally important cancer/testis lncRNAs whose structure and function have undergone positive evolutionary selection.