A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate–prednisone

Wang, L.; Dehm, Scott M.; Hillman, David W.; Sicotte, Hughes; Tan, Winston; Gormley, Michael; Bhargava, Vipul; Jimenez, Rafael E.; Xie, Fang; Yin, Ping; Qin, Sisi; Quevedo, Fernando; Costello, Brian A.; Pitot, Henry C.; Ho, Thanh P.; Bryce, Alan H.; Ye, Z.; Li, Yingming; Eiken, Patrick W.; Vedell, Peter T.; Barman, Poulami; McMenomy, Brendan P.; Atwell, Thomas D.; Carlson, Rachel E.; Ellingson, Marissa S.; Eckloff, Bruce W.; Qin, Rui; Ou, Fang‐Shu; Hart, Steven N.; Huang, Haojie; Jen, Jin; Wieben, Eric D.; Kalari, Krishna R.; Weinshilboum, Richard M.; Kohli, Manish

doi:10.1093/annonc/mdx689

Cited by 73 publications

(98 citation statements)

References 27 publications

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“…[23][24][25] To appropriately interrogate our main aim, we focused our genomic analysis solely on AR. Future studies could integrate AR CN dichotomization with other molecular markers that have been suggested to be associated with worse outcome, including aberrations of TP53 12,21 or WNT signaling 26 or AR splice variant detection. 27,28 These studies would require larger cohorts of patients to allow multiple testing.…”

Section: Discussionmentioning

confidence: 99%

Plasma Androgen Receptor Copy Number Status at Emergence of Metastatic Castration-Resistant Prostate Cancer: A Pooled Multicohort Analysis

Jayaram

Wingate

Wetterskog

et al. 2019

JCO Precision Oncology

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PURPOSEIncreases in androgen receptor ( AR) copy number (CN) can be detected in plasma DNA when patients develop metastatic castration-resistant prostate cancer. We aim to evaluate the association between AR CN as a continuous variable and clinical outcome.PATIENTS AND METHODSPCR2023 was an international, multi-institution, open-label, phase II study of abiraterone acetate plus prednisolone (AAP) or abiraterone acetate plus dexamethasone that included plasma AR assessment as a predefined exploratory secondary end point. Plasma AR CN data (ClinicalTrials.gov identifier: NCT01867710 ) from this study (n = 133) were pooled with data from the following three other cohorts: cohort A, which was treated with either AAP or enzalutamide (n = 73); the PREMIERE trial (ClinicalTrials.gov identifier: NCT02288936 ) of biomarkers for enzalutamide (n = 94); and a phase II trial from British Columbia (ClinicalTrials.gov identifier: NCT02125357 ) that randomly assigned men to either AAP or enzalutamide (n = 201). The primary outcome measures for the biomarker analysis were overall survival and progression-free survival.RESULTSUsing multivariable fractional polynomials analysis using Cox regression models, a nonlinear relationship between plasma AR CN and outcome was identified for overall survival, where initially for small incremental gains in CN there was a large added hazard ratio that plateaued at higher CN. The CN cut point associated with the highest local hazard ratio was 1.92. A similar nonlinear association was observed with progression-free survival. In an exploratory analysis of PCR2023, the time from start of long-term androgen-deprivation therapy to start of AAP or abiraterone acetate plus dexamethasone was significantly shorter in patients with plasma AR CN of 1.92 or greater than patients with plasma AR CN of less than 1.92 (43 v 130 weeks, respectively; P = .005). This was confirmed in cohort A ( P = .003), the PREMIERE cohort ( P = .03), and the British Colombia cohort ( P = .003).CONCLUSIONPatients with metastatic castration-resistant prostate cancer can be dichotomized by a plasma AR CN cut point of 1.92. Plasma AR CN value of 1.92 or greater identifies aggressive disease that is poorly responsive to AR targeting and is associated with a prior short response to primary androgen-deprivation therapy.

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Section: Discussionmentioning

confidence: 99%

Plasma Androgen Receptor Copy Number Status at Emergence of Metastatic Castration-Resistant Prostate Cancer: A Pooled Multicohort Analysis

Jayaram

Wingate

Wetterskog

et al. 2019

JCO Precision Oncology

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“…More recently, non‐canonical Wnt (Wnt/Ca +2 ) signaling has also been implicated in the pathogenesis of PCa . Due to the involvement of Wnt/β‐catenin pathway in progression, it has been suggested to act as a molecular marker for predicting resistance to several androgen‐dependent therapies . Due to their important role in tumorigenesis and metastasis, genes involved in canonical and non‐canonical Wnt signaling pathways are emerging as promising targets for therapeutic intervention in PCa .…”

Section: Discussionmentioning

confidence: 99%

“…45,48 Due to the involvement of Wnt/β-catenin pathway in progression, it has been suggested to act as a molecular marker for predicting resistance to several androgen-dependent therapies. 49 Due to their important role in tumorigenesis and metastasis, genes involved in canonical and non-canonical Wnt signaling pathways are emerging as promising targets for therapeutic intervention in PCa. 50,51 Future studies are needed to not only understand the mechanism of Wnt signaling driven PCa but also identify race-specific therapeutic potential.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic analysis identifies factors driving racial disparity in prostate cancer

et al. 2018

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Background Prostate cancer (PCa) is the second most leading cause of death in men worldwide. African‐American men (AA) represent more aggressive form of the disease compared to Caucasian (CA) counterparts. Several lines of evidences suggest that biological factors are responsible for the observed racial disparity. Aim This study was aimed at identifying the epigenetic variation among AA and CA PCa patients and whether DNA methylation differences have an association with clinical outcomes in the two races. Methods and results The cancer genome atlas (TCGA) dataset (2015) was used to identify existing epigenetic variation in AA and CA PCa patients. Reduced Representation Bisulfite Sequencing (RRBS) was performed to identify global DNA methylation changes in a small cohort of AA and CA PCa patients. The RRBS data were then used to identify survival and recurrence outcomes in AA and CA PCa patients using publicly available datasets. The TCGA data analysis revealed epigenetic heterogeneity, which could be categorized into four classes. AA associated primarily to methylation cluster 1 (p = 0.048), and CA associated to methylation cluster 3 (p = 0.000146). Enrichment of the Wnt signaling pathway was identified in both the races; however, they were differentially activated in terms of canonical and non‐canonical Wnt signaling. This was further validated using the Decipher Genomics Resource Information Database (GRID). The RRBS data also identified discrete methylation patterns in AA compared with CA and, in part, validated our TCGA findings. Survival analysis using the RRBS data suggested hypomethylated genes to be significantly associated with recurrence of PCa in CA (p = 6.07 × 10−6) as well as in AA (p = 0.0077). Conclusion Overall, we observed epigenetic‐based racial disparity in PCa which could affect survival and should be considered during prognosis and treatment.

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“…More recently, non-canonical Wnt (Wnt/Ca +2 ) signaling has also been implicated in the pathogenesis of prostate cancer [41,44]. The involvement of Wnt/β-catenin pathway in progression could be attributed to its function in proliferation and survival of cancer stem cells and was suggested to act as molecular markers for predicting resistance to several androgen dependent therapies [45]. Lately, genes involved in canonical and non-canonical Wnt signaling pathways are emerging as promising targets for therapeutic intervention in prostate cancer [46,47].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic analysis identifies factors driving racial disparity in prostate cancer

Rai

Yadav

Pan

et al. 2018

Preprint

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Prostate cancer (PCa) is the second most leading cause of death in men worldwide. African American men (AA) represent more aggressive form of PCa as compared to Caucasian (CA) counterparts. Evidence suggests that genetic and other biological factors could account for the observed racial disparity. We analyzed the cancer genome atlas (TCGA) dataset (2015) for existing epigenetic variation in AA and CA prostate cancer patients, and carried out Reduced Representation Bisulphite Sequencing (RRBS) analysis to identify global methylation changes in AA and CA prostate cancer patients. The TCGA dataset analysis revealed that the epigenetic heterogeneity could be categorized into 4 classes, where AA associated primarily to methylation cluster 1 (p value 0.048), and CA associated to methylation cluster 3 (p value 0.000146). We identified enrichment of Wnt signaling genes in both AA and CA, however they were differentially activated in terms of canonical and non-canonical Wnt signaling pathway activation. This was further validated using the GenomeDx expression data. Our RRBS data also suggested distinct methylation patterns in AA compared to CA, and in part validated our TCGA findings. Survival analysis using the RRBS data suggested hypomethylated genes to be significantly associated with recurrence of prostate cancer in CA (p=6.07x10 -6 ) as well as in AA (p=0.0077). Overall, the observed racial disparity in the molecular mechanism involved in the pathogenesis of prostate cancer suggests diverse heterogeneity that potentially could affect survival and should be considered during prognosis and treatment.Prostate cancer (PCa) is one of the most prevalent malignancies affecting men (Fitzmaurice et al., 2013) [1] and the second-most leading cause of cancer-related death for men in the US [2,3].According to Surveillance, Epidemiology, and End Results (SEER) there is a decline in prostate cancer incidence over the past few decades [4]. However, African American men (AA) present early onset of the disease with high-grade tumor, aggressive metastasis potential with increased risk of recurrence, and have worse survival outcomes when compared to their CA counterparts [5][6][7][8]. It is suggested that racial disparity in PCa is influenced by socioeconomic status, diet and lifestyle [9][10][11], but several lines of evidence indicate that biological factors like genetic and epigenetic factors are major contributors to this disparity [8,12]. Such factors include ERG rearrangement, PTEN deletion, SPINK1 overexpression, SPOP mutation and 8q24 SNPs [13,14]. Furthermore, PCa in AA is associated with higher testosterone levels and prominent immune related tumor biology [15][16][17], with tumor microenvironment dynamics associated with more aggressive phenotype in AA when compared to CA [18].Aberrant DNA methylation is an important epigenetic modulation that has been implicated in PCa etiology and disease progression [19]. Methylation changes primarily occur in CpG islands sequestered in the promoter regions [20]. Whole genome methylati...

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A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate–prednisone

Abstract: Wnt/β-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy.

Cited by 73 publications

References 27 publications

Plasma Androgen Receptor Copy Number Status at Emergence of Metastatic Castration-Resistant Prostate Cancer: A Pooled Multicohort Analysis

Plasma Androgen Receptor Copy Number Status at Emergence of Metastatic Castration-Resistant Prostate Cancer: A Pooled Multicohort Analysis

Epigenetic analysis identifies factors driving racial disparity in prostate cancer

Epigenetic analysis identifies factors driving racial disparity in prostate cancer

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