Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

Quigley, David A.; Dang, Ha X.; Zhao, Shuang G.; Lloyd, Paul; Aggarwal, Rahul; Alumkal, Joshi J.; Foye, Adam; Kothari, Vishal; Perry, Marc D.; Bailey, Adina; Playdle, Denise; Barnard, Travis J.; Zhang, Li; Zhang, Jin; Youngren, Jack; Cieślik, Marcin; Parolia, Abhijit; Beer, Tomasz M.; Thomas, George V.; N., Kim; Gleave, Martin; Lack, Nathan A.; Zoubeidi, Amina; Reiter, Robert E.; Rettig, Matthew B.; Witte, Owen N.; Ryan, Charles J.; Fong, Lawrence; Kim, Won; Friedlander, Terence W.; Chou, Jonathan; Li, Haolong; Das, Rajdeep; Li, Hui; Moussavi-Baygi, Ruhollah; Goodarzi, Hani; Gilbert, Luke A.; Lara, Primo N.; Evans, Christopher P.; Goldstein, Theodore C.; Stuart, Joshua M.; Tomlins, Scott A.; Spratt, Daniel E.; Cheetham, R. Keira; Cheng, Donavan T.; Farh, Kyle Kai‐How; Gehring, Julian; Hakenberg, Jörg; Liao, Arnold; Febbo, Philip G.; Shon, John; Sickler, Brad; Batzoglou, Serafim; Knudsen, Karen E.; He, Housheng Hansen; Huang, Jiaoti; Wyatt, Alexander W.; Dehm, Scott M.; Ashworth, Alan; Chinnaiyan, Arul M.; Maher, Christopher A.; Small, Eric J.; Feng, Felix Y.

doi:10.1016/j.cell.2018.06.039

Cited by 545 publications

(741 citation statements)

References 73 publications

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“…CDK6, CCND1; Supplementary Fig. 3) consistent with the CDK12-associated tandem duplication genotype [19,20]. We also identified truncating mutations in RAD51C and ATR, but in neither case was deletion or mutation of the second allele evident (unlike all deleterious BRCA2 and ATM mutations; Supplementary Fig.…”

Section: Aggressive Genomic Features With Frequent Tp53 Mutations Andsupporting

confidence: 55%

Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer

et al. 2019

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Word count abstract: 293Word count text: 2592 This is the accepted manuscript of the article, which has been published in European Urology. 2019, 75(4), 667-675. http://dx. AbstractBackground: Several systemic therapeutic options exist for metastatic castratesensitive prostate cancer (mCSPC). Circulating tumour DNA (ctDNA) can molecularly profile metastatic castration-resistant prostate cancer (mCRPC) and can influence decision-making, but remains untested in mCSPC. Objective:To determine ctDNA abundance at de novo mCSPC diagnosis and whether ctDNA provides complementary clinically-relevant information to a prostate biopsy. Design, Setting, and Participants:We collected plasma cell-free DNA (cfDNA) from 53 newly diagnosed patients with mCSPC and, where possible, during treatment.Targeted sequencing was performed on cfDNA and DNA from diagnostic prostate tissue. Results and Limitations:Median ctDNA fraction was 11% (range 0-84) among untreated patients but lower (1.0%, range 0-51) in patients after short term (median 22 days) androgen deprivation therapy (ADT). TP53 mutations and DNA repair defects were identified in 47% and 21% of the cohort, respectively. Concordance for mutation detection in matched samples was 80%. Combined ctDNA and tissue analysis identified potential driver alterations in 94% of patients, whereas ctDNA or prostate biopsy alone was insufficient in 19 cases (36%). Limitations include the use of a narrow gene panel and undersampling of primary disease by prostate biopsy.Conclusions: ctDNA provides additional information to a prostate biopsy in men with de novo mCSPC, but ADT rapidly reduces ctDNA availability. Primary tissue and ctDNA share relevant somatic alterations, suggesting that either are suitable for molecular subtyping in de novo mCSPC. The optimal approach for biomarker development should ! 3 utilize both a tissue and liquid biopsy at diagnosis, as neither captures clinically-relevant somatic alterations in all patients. Patient summary:In men with advanced prostate cancer, tumour DNA shed into the bloodstream can be measured by a blood test. The information from this test provides complementary information to a prostate needle biopsy and could be used to guide management strategies.! 4

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Section: Aggressive Genomic Features With Frequent Tp53 Mutations Andsupporting

confidence: 55%

Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer

et al. 2019

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“…Microarray expression data were log 2 -normalized and scaled prior to RBS analysis. Data for the mCRPC cohort were obtained from a previously published study (25). This cohort consisted of 101 patients with deep wholegenome sequencing, whole-transcriptome RNA-seq, and clinical outcomes data available.…”

Section: Characterizing the Prognostic Value Of Rb1 Loss Across Cancementioning

confidence: 99%

Novel RB1-Loss Transcriptomic Signature Is Associated with Poor Clinical Outcomes across Cancer Types

Chen

Alshalalfa

Zhao

et al. 2019

Clinical Cancer Research

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Purpose: Rb-pathway disruption is of great clinical interest, as it has been shown to predict outcomes in multiple cancers. We sought to develop a transcriptomic signature for detecting biallelic RB1 loss (RBS) that could be used to assess the clinical implications of RB1 loss on a pan-cancer scale. Experimental Design: We utilized data from the Cancer Cell Line Encyclopedia (N ¼ 995) to develop the first pancancer transcriptomic signature for predicting biallelic RB1 loss (RBS). Model accuracy was validated using The Cancer Genome Atlas (TCGA) Pan-Cancer dataset (N ¼ 11,007). RBS was then used to assess the clinical relevance of biallelic RB1 loss in TCGA Pan-Cancer and in an additional metastatic castration-resistant prostate cancer (mCRPC) cohort. Results: RBS outperformed the leading existing signature for detecting RB1 biallelic loss across all cancer types in TCGA Pan-Cancer (AUC, 0.89 vs. 0.66). High RBS (RB1 biallelic loss) was associated with promoter hypermethylation (P ¼ 0.008) and gene body hypomethylation (P ¼ 0.002), suggesting RBS could detect epigenetic gene silencing. TCGA Pan-Cancer clinical analyses revealed that high RBS was associated with short progression-free (P < 0.00001), overall (P ¼ 0.0004), and disease-specific (P < 0.00001) survival. On multivariable analyses, high RBS was predictive of shorter progression-free survival in TCGA Pan-Cancer (P ¼ 0.03) and of shorter overall survival in mCRPC (P ¼ 0.004) independently of the number of DNA alterations in RB1. Conclusions: Our study provides the first validated tool to assess RB1 biallelic loss across cancer types based on gene expression. RBS can be useful for analyzing datasets with or without DNA-sequencing results to investigate the emerging prognostic and treatment implications of Rb-pathway disruption. See related commentary by Choudhury and Beltran, p. 4199

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“…Several altered genetic and epigenetic mechanisms contribute to the development of metastatic and drugresistant PCa (Knudsen & Penning 2010, Shen & Abate-Shen 2010, Grasso et al 2012, Robinson et al 2015, Pritchard et al 2016, Baumgart & Haendler 2017, Armenia et al 2018, Cotter & Rubin 2018, Li et al 2018, Quigley et al 2018, Ruggero et al 2018, Karthaus & Sawyers 2019. For example, tandem duplications of an R486 A Jiménez-Panizo et al…”

Section: Genetic Bases Of Drug Resistance In Prostate Cancermentioning

confidence: 99%

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

Jiménez-Panizo

Pérez

Rojas

et al. 2019

Endocrine-Related Cancer

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Nuclear receptors are transcription factors that play critical roles in development, homeostasis and metabolism in all multicellular organisms. An important family of nuclear receptors comprises those members that respond to steroid hormones, and which is subdivided in turn into estrogen receptor (ER) isoforms α and β (NR3A1 and A2, respectively), and a second subfamily of so-called oxosteroid receptors. The latter includes the androgen receptor (AR/NR3C4), the glucocorticoid receptor (GR/NR3C1), the mineralocorticoid receptor (MR/NR3C2) and the progesterone receptor (PR/NR3C3). Here we review recent advances in our understanding of the structure-and-function relationship of steroid nuclear receptors and discuss their implications for the etiology of human diseases. We focus in particular on the role played by AR dysregulation in both prostate cancer (PCa) and androgen insensitivity syndromes (AIS), but also discuss conditions linked to mutations of the GR gene as well as those in a non-steroidal receptor, the thyroid hormone receptor (TR). Finally, we explore how these recent results might be exploited for the development of novel and selective therapeutic strategies.

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Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

Cited by 545 publications

References 73 publications

Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer

Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer

Novel RB1-Loss Transcriptomic Signature Is Associated with Poor Clinical Outcomes across Cancer Types

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

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