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  • 1
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    Abstract 424: Defining prostate cancer subtypes by genomic features associated with defects in DNA repair processes
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 424-424
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 424-424
    Abstract: Introduction: Prostate cancer (PC) exhibits a spectrum of genomic aberrations, a subset of which associate with responses to specific therapeutics. In particular, mutations in genes involved in DNA repair processes expose therapeutic vulnerabilities that include PARP inhibitors and DNA-damaging chemotherapy for homology-directed repair(HR) defects and immune checkpoint blockade for mismatch repair (MMR) defects. Deploying appropriate therapy is dependent on accurate tumor classification. Experimental Procedures: We evaluated whole-exome sequences derived from localized (n = 465) and metastatic (n = 208) PCs to identify mutations and structural aberrations predicted to disrupt or alter the function of genes involved in DNA repair processes. We annotated all tumors for trinucleotide (COSMIC) mutation signatures by comparing somatic alterations in tumor versus paired normal exomes. We compared the type and frequency of presumed pathogenic mutations, tumor ploidy, copy number aberrations, and mutational signatures between primary and metastatic tumors and evaluated associations between specific DNA repair gene aberrations and mutation signatures. Results: Overall, 54% of localized PCs and 24.5% of metastatic PCs had a component of their somatic mutation burden associated with a mutation signature indicative of a DNA repair defect. Metastatic PCs had significantly higher numbers of somatic mutations (n=223) compared to primary PCs (n=93) (p & lt;0.008). Aneuploid and hypermutated tumors are also more common in metastatic PCs compared to primary PCs. Tumors with high LOH ( & gt;0.1) scores were enriched for pathogenic mutations in BRCA1/2 and lowest LOH scores were observed in tumors with mutation/loss of CDK12, which were near-diploid. In addition to relatively frequent aberrations in BRCA2, BRCA1 and ATM, we found CDK12 mutations in ~1% of primary PCs and 5.3% of metastatic PCs. Tumors with BRCA1/2 loss or ATM and RecQ-Helicase pathway aberration exhibited larger amplifications and loss events, whereas PCs with CDK12 aberrations demonstrated a high number (n & gt;73 to 261) of focal (500b-1mb range) amplifications with rare focal losses. Conclusions: 102 individual metastatic cases with some fraction of HR-defect signature and 41 (~40%) of them are without any bona fide HR pathway mutations. DNA repair gene (DRG) aberrations are common in metastatic PC and associate with distinct mutational signatures and structural aberrations that partition PCs into distinct subtypes. Epigenetic processes may contribute to HR signatures in tumors where DRG mutations were not identified. Preclinical and clinical studies are required to determine if mutation signatures are accurate predictors of responses to therapeutics. Thus, with these signatures, we have proposed a few molecular subcategories of prostate tumors and such information can be harnessed for future precision cancer therapies. Citation Format: Navonil De Sarkar, Emily Kohlbrenner, Ilsa Coleman, Peter S. Nelson. Defining prostate cancer subtypes by genomic features associated with defects in DNA repair processes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 424.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-424
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 2
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    Germline mutations in penetrant cancer predisposition genes are rare in men with prostate cancer selecting active surveillance
    Wiley ; 2022
    In:  Cancer Medicine Vol. 11, No. 22 ( 2022-11), p. 4332-4340
    Details
    In: Cancer Medicine, Wiley, Vol. 11, No. 22 ( 2022-11), p. 4332-4340
    Abstract: Pathogenic germline mutations in several rare penetrant cancer predisposition genes are associated with an increased risk of aggressive prostate cancer (PC). Our objectives were to determine the prevalence of pathogenic germline mutations in men with low‐risk PC on active surveillance, and assess whether pathogenic germline mutations associate with grade reclassification or adverse pathology, recurrence, or metastases, in men treated after initial surveillance. Methods Men prospectively enrolled in the Canary Prostate Active Surveillance Study (PASS) were retrospectively sampled for the study. Germline DNA was sequenced utilizing a hereditary cancer gene panel. Mutations were classified according to the American College of Clinical Genetics and Genomics' guidelines. The association of pathogenic germline mutations with grade reclassification and adverse characteristics was evaluated by weighted Cox proportional hazards modeling and conditional logistic regression, respectively. Results Overall, 29 of 437 (6.6%) study participants harbored a pathogenic germline mutation of which 19 occurred in a gene involved in DNA repair (4.3%). Eight participants (1.8%) had pathogenic germline mutations in three genes associated with aggressive PC: ATM , BRCA1 , and BRCA2 . The presence of pathogenic germline mutations in DNA repair genes did not associate with adverse characteristics (univariate analysis HR = 0.87, 95% CI: 0.36–2.06, p  = 0.7). The carrier rates of pathogenic germline mutations in ATM , BRCA1 , and BRCA2 did not differ in men with or without grade reclassification (1.9% vs. 1.8%). Conclusion The frequency of pathogenic germline mutations in penetrant cancer predisposition genes is extremely low in men with PC undergoing active surveillance and pathogenic germline mutations had no apparent association with grade reclassification or adverse characteristics.
    Type of Medium: Online Resource
    ISSN: 2045-7634 , 2045-7634
    URL: Issue
    URL: Article
    DOI: 10.1002/cam4.v11.22
    DOI: 10.1002/cam4.4778
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 3
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    Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer
    Elsevier BV ; 2018
    In:  Cell Vol. 173, No. 7 ( 2018-06), p. 1770-1782.e14
    Details
    In: Cell, Elsevier BV, Vol. 173, No. 7 ( 2018-06), p. 1770-1782.e14
    Type of Medium: Online Resource
    ISSN: 0092-8674
    URL: Article
    DOI: 10.1016/j.cell.2018.04.034
    RVK:
    XA 36269
    RVK:
    WA 15000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2018
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  • 4
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    Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer
    Massachusetts Medical Society ; 2016
    In:  New England Journal of Medicine Vol. 375, No. 5 ( 2016-08-04), p. 443-453
    Details
    In: New England Journal of Medicine, Massachusetts Medical Society, Vol. 375, No. 5 ( 2016-08-04), p. 443-453
    Type of Medium: Online Resource
    ISSN: 0028-4793 , 1533-4406
    URL: Article
    DOI: 10.1056/NEJMoa1603144
    RVK:
    XA 10000
    Language: English
    Publisher: Massachusetts Medical Society
    Publication Date: 2016
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  • 5
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    Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer
    Springer Science and Business Media LLC ; 2021
    In:  Nature Communications Vol. 12, No. 1 ( 2021-03-30)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-03-30)
    Abstract: Lineage plasticity, the ability of a cell to alter its identity, is an increasingly common mechanism of adaptive resistance to targeted therapy in cancer. An archetypal example is the development of neuroendocrine prostate cancer (NEPC) after treatment of prostate adenocarcinoma (PRAD) with inhibitors of androgen signaling. NEPC is an aggressive variant of prostate cancer that aberrantly expresses genes characteristic of neuroendocrine (NE) tissues and no longer depends on androgens. Here, we investigate the epigenomic basis of this resistance mechanism by profiling histone modifications in NEPC and PRAD patient-derived xenografts (PDXs) using chromatin immunoprecipitation and sequencing (ChIP-seq). We identify a vast network of cis -regulatory elements ( N ~15,000) that are recurrently activated in NEPC. The FOXA1 transcription factor (TF), which pioneers androgen receptor (AR) chromatin binding in the prostate epithelium, is reprogrammed to NE-specific regulatory elements in NEPC. Despite loss of dependence upon AR, NEPC maintains FOXA1 expression and requires FOXA1 for proliferation and expression of NE lineage-defining genes. Ectopic expression of the NE lineage TFs ASCL1 and NKX2-1 in PRAD cells reprograms FOXA1 to bind to NE regulatory elements and induces enhancer activity as evidenced by histone modifications at these sites. Our data establish the importance of FOXA1 in NEPC and provide a principled approach to identifying cancer dependencies through epigenomic profiling.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-021-22139-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 6
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    Nucleosome Patterns in Circulating Tumor DNA Reveal Transcriptional Regulation of Advanced Prostate Cancer Phenotypes
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Discovery Vol. 13, No. 3 ( 2023-03-01), p. 632-653
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 13, No. 3 ( 2023-03-01), p. 632-653
    Abstract: Advanced prostate cancers comprise distinct phenotypes, but tumor classification remains clinically challenging. Here, we harnessed circulating tumor DNA (ctDNA) to study tumor phenotypes by ascertaining nucleosome positioning patterns associated with transcription regulation. We sequenced plasma ctDNA whole genomes from patient-derived xenografts representing a spectrum of androgen receptor active (ARPC) and neuroendocrine (NEPC) prostate cancers. Nucleosome patterns associated with transcriptional activity were reflected in ctDNA at regions of genes, promoters, histone modifications, transcription factor binding, and accessible chromatin. We identified the activity of key phenotype-defining transcriptional regulators from ctDNA, including AR, ASCL1, HOXB13, HNF4G, and GATA2. To distinguish NEPC and ARPC in patient plasma samples, we developed prediction models that achieved accuracies of 97% for dominant phenotypes and 87% for mixed clinical phenotypes. Although phenotype classification is typically assessed by IHC or transcriptome profiling from tumor biopsies, we demonstrate that ctDNA provides comparable results with diagnostic advantages for precision oncology. Significance: This study provides insights into the dynamics of nucleosome positioning and gene regulation associated with cancer phenotypes that can be ascertained from ctDNA. New methods for classification in phenotype mixtures extend the utility of ctDNA beyond assessments of somatic DNA alterations with important implications for molecular classification and precision oncology. This article is highlighted in the In This Issue feature, p. 517
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-22-0692
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 7
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    Abstract PR06: Genomic distinctions between metastatic lower and upper tract urothelial carcinoma revealed through rapid autopsy
    American Association for Cancer Research (AACR) ; 2020
    In:  Clinical Cancer Research Vol. 26, No. 15_Supplement ( 2020-08-01), p. PR06-PR06
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 15_Supplement ( 2020-08-01), p. PR06-PR06
    Abstract: Introduction: Exceedingly little is known about the genomic difference between metastatic urothelial carcinoma (LTUC) and upper tract urothelial carcinoma (UTUC). We evaluated and compared genomic features of primary and metastatic UTUC and LTUC tumors in a cohort of patients with end-stage disease. Methods: We performed whole-exome sequencing on 37 tumor samples from 7 patients with metastatic UC collected between 2015-2017 via rapid autopsy, with matched primary and metastatic tumor samples. Inter- and intrapatient analyses of mutational burden, mutational signatures, predicted deleterious mutations (somatic single nucleotide variations [sSNV] and insertions-deletions), and somatic copy alterations (sCNV) were conducted. Results: We investigated 3 patients with UTUC (3 primary samples, 13 metastases) and 4 patients with LTUC (4 primary samples, 17 metastases). Most patients were men, nonsmokers, and received cisplatin-based therapy. We found that sSNV burden was higher in metastatic LTUC compared to UTUC. Moreover, the APOBEC mutational signature that has been described in localized bladder cancer was pervasive in metastatic LTUC and less so in UTUC. Despite a lower overall sSNV burden, UTUC displayed greater inter- and intraindividual genomic distances at the copy number level between primary and metastatic tumors than LTUC. Our data also indicate that metastatic UTUC lesions can arise from small clonal populations present in the primary cancer. Importantly, putative druggable mutations were found across our patient population with the majority shared across all metastases within a patient. Conclusions: In these patients, metastatic UTUC demonstrated a lower overall mutational burden but greater structural variability compared to LTUC. Our findings suggest that metastatic UTUC displays a greater spectrum of copy number divergence from LTUC, which may in part explain differences in aggressive clinical behavior. Importantly, we identified druggable lesions shared across metastatic samples, which demonstrate a level of targetable homogeneity within individual patients. This abstract is also being presented as Poster B09. Citation Format: Brian R. Winters, Navonil De Sarkar, Sonali Arora, Hamid Bolouri, Sujata Jana, Funda Vakar-Lopez, Heather H. Cheng, Michael T. Schweizer, Evan Y. Yu, Petros Grivas, John K. Lee, Lori Kollath, Sarah K. Holt, Lisa McFerrin, Gavin Ha, Peter S. Nelson, Robert B. Montgomery, Jonathan L. Wright, Hung-Ming Lam, Andrew C. Hsieh. Genomic distinctions between metastatic lower and upper tract urothelial carcinoma revealed through rapid autopsy [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr PR06.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.BLADDER19-PR06
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 8
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    Abstract B004: Genomic loss of TP53 impairs AR-targeted activity in metastatic prostate cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 11_Supplement ( 2023-06-02), p. B004-B004
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 11_Supplement ( 2023-06-02), p. B004-B004
    Abstract: Background: Metastatic prostate cancer (mPC) is notable for a spectrum of recurrent genomic alterations, some associated with overall prognosis and others predicting response to specific therapeutics. Standard mPC interventions are designed to suppress the signaling program regulated by the androgen receptor (AR). These include androgen deprivation therapy (ADT) to reduce AR ligand levels and AR signaling inhibitors (ARSI) that directly impair AR function. While ADT and ARSI produce clinical responses in most patients, the duration and depth of response vary greatly. In addition, specific recurring genomic alterations are associated with shorter responses after ADT and ARSI therapy. Among these are mutations and/or genomic copy loss involving key tumor suppressor genes, including PTEN, RB1 and TP53. However, the mechanistic contribution of TP53 loss to AR signaling and resistance to AR pathway-directed therapy remains unresolved. Methods: Isogenic prostate cancer cell lines with intact and TP53 deletions were constructed using CRISPR/Cas9. The transcriptome profiles were determined by RNA-seq, and ChIP-seq was used to determine the chromatin landscapes of AR localization. In addition, we performed ATAC-seq to assess chromatin accessibility. Finally, to further validate the findings, we comprehensively analyzed AR-regulated gene expression and AR cistromes across a panel of patient-derived xenograft (PDX) models and clinical cohorts of mPC patient samples with respect to TP53 status. Results: Compared to TP53-wild-type (WT) cells, the transcriptional results of isogenic knockout TP53 lines showed impaired AR canonical activity. However, the downregulated AR response pathway is not caused by reduced levels of AR transcript or protein levels. Additionally, a similar trend was also found while comparing TP53-WT PDX models with TP53-loss models. We found that the loss of TP53 can shift the chromatin binding of AR, and the altered AR binding sites correlated with genes involved in neurogenesis pathways, which provide a potential mechanism of how the loss of TP53 might impact AR signaling and promote ADT and ARSI treatment resistance. We also identified additional AR chromatin binding sites that were enriched due to the loss of TP53. The targets potentially regulated by these sites are involved in multiple pathways, including cell morphogenesis involved in differentiation and response to the endogenous stimulus. Conclusions and Future Directions: Overall, the results indicate that in addition to altering DNA damage and repair pathways and contributing to cancer progression, genetic loss of TP53 in mPC may directly impair ADT and ARSI therapies, partially through alteration of AR chromatin activity. In addition, the AR cistrome reprogramming resulting from TP53 loss could also affect other pathways that could be exploited to overcome ARSI treatment resistance. Citation Format: Wanting Han, Michael D. Nyquist, Ilsa Coleman, Navonil De Sarkar, Lisa Ang, Eva Corey, Peter S. Nelson. Genomic loss of TP53 impairs AR-targeted activity in metastatic prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B004.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PRCA2023-B004
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 9
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    Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations
    Wiley ; 2021
    In:  The Prostate Vol. 81, No. 16 ( 2021-12), p. 1382-1389
    Details
    In: The Prostate, Wiley, Vol. 81, No. 16 ( 2021-12), p. 1382-1389
    Abstract: Among men with metastatic prostate cancer, about 10% have germline alterations in DNA damage response genes. Most studies have examined BRCA2 alone or an aggregate of BRCA1/2 and ATM . Emerging data suggest that ATM mutations may have distinct biology and warrant individual evaluation. The objective of this study is to determine whether response to prostate cancer systemic therapies differs between men with germline mutations in ATM (g ATM) and BRCA2 (g BRCA2) . Methods This is an international multicenter retrospective matched cohort study of men with prostate cancer harboring g ATM or g BRCA2 . PSA 50 response (≥50% decline in prostate‐specific antigen) was compared using Fisher's exact test. Results and Limitations The study included 45 g ATM and 45 g BRCA2 patients, matched on stage and year of germline testing. Patients with g ATM and g BRCA2 had similar age, Gleason grade, and PSA at diagnosis. We did not observe differences in PSA 50 responses to abiraterone, enzalutamide, or docetaxel in metastatic castration resistant prostate cancer between the two groups; however, 0/7 with g ATM and 12/14 with g BRCA2 achieved PSA 50 response to PARPi ( p   〈  .001). Median (95% confidence interval) overall survival from diagnosis to death was 10.9 years (9.5‐not reached) versus 9.9 years (7.1‐not reached, p  = .07) for the g ATM and g BRCA2 cohorts, respectively. Limitations include the retrospective design and lack of mutation zygosity data. Conclusions Conventional therapies can be effective in g ATM carriers and should be considered before PARPi, which shows limited efficacy in this group. Men with g ATM mutations warrant prioritization for novel treatment strategies.
    Type of Medium: Online Resource
    ISSN: 0270-4137 , 1097-0045
    URL: Issue
    URL: Article
    DOI: 10.1002/pros.v81.16
    DOI: 10.1002/pros.24236
    Language: English
    Publisher: Wiley
    Publication Date: 2021
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  • 10
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    Genomic correlates of clinical outcome in advanced prostate cancer
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 23 ( 2019-06-04), p. 11428-11436
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 23 ( 2019-06-04), p. 11428-11436
    Abstract: Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor ( AR ) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1 , AR , and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1902651116
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
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