المؤلفون: Houlahan, Kathleen E, Livingstone, Julie, Fox, Natalie S, Kurganovs, Natalie, Zhu, Helen, Sietsma Penington, Jocelyn, Jung, Chol-Hee, Yamaguchi, Takafumi N, Heisler, Lawrence E, Jovelin, Richard, Costello, Anthony J, Pope, Bernard J, Kishan, Amar U, Corcoran, Niall M, Bristow, Robert G, Waszak, Sebastian M, Weischenfeldt, Joachim, He, Housheng H, Hung, Rayjean J, Hovens, Christopher M, Boutros, Paul C

المصدر: Journal of the National Cancer Institute. 115(4)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Genetics, Aging, Prostate Cancer, Urologic Diseases, Prevention, Genetic Testing, Human Genome, Good Health and Well Being, Male, Humans, Prostatic Neoplasms, Risk Factors, Prognosis, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Oncology and carcinogenesis

الوصف: Prostate cancer is one of the most heritable cancers. Hundreds of germline polymorphisms have been linked to prostate cancer diagnosis and prognosis. Polygenic risk scores can predict genetic risk of a prostate cancer diagnosis. Although these scores inform the probability of developing a tumor, it remains unknown how germline risk influences the tumor molecular evolution. We cultivated a cohort of 1250 localized European-descent patients with germline and somatic DNA profiling. Men of European descent with higher genetic risk were diagnosed earlier and had less genomic instability and fewer driver genes mutated. Higher genetic risk was associated with better outcome. These data imply a polygenic "two-hit" model where germline risk reduces the number of somatic alterations required for tumorigenesis. These findings support further clinical studies of polygenic risk scores as inexpensive and minimally invasive adjuncts to standard risk stratification. Further studies are required to interrogate generalizability to more ancestrally and clinically diverse populations.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/4tq5083qTest

المؤلفون: Sjöström, Martin, Zhao, Shuang G, Levy, Samuel, Zhang, Meng, Ning, Yuhong, Shrestha, Raunak, Lundberg, Arian, Herberts, Cameron, Foye, Adam, Aggarwal, Rahul, Hua, Junjie T, Li, Haolong, Bergamaschi, Anna, Maurice-Dror, Corinne, Maheshwari, Ashutosh, Chen, Sujun, Ng, Sarah WS, Ye, Wenbin, Petricca, Jessica, Fraser, Michael, Chesner, Lisa, Perry, Marc D, Moreno-Rodriguez, Thaidy, Chen, William S, Alumkal, Joshi J, Chou, Jonathan, Morgans, Alicia K, Beer, Tomasz M, Thomas, George V, Gleave, Martin, Lloyd, Paul, Phillips, Tierney, McCarthy, Erin, Haffner, Michael C, Zoubeidi, Amina, Annala, Matti, Reiter, Robert E, Rettig, Matthew B, Witte, Owen N, Fong, Lawrence, Bose, Rohit, Huang, Franklin W, Luo, Jianhua, Bjartell, Anders, Lang, Joshua M, Mahajan, Nupam P, Lara, Primo N, Evans, Christopher P, Tran, Phuoc T, Posadas, Edwin M, He, Chuan, Cui, Xiao-Long, Huang, Jiaoti, Zwart, Wilbert, Gilbert, Luke A, Maher, Christopher A, Boutros, Paul C, Chi, Kim N, Ashworth, Alan, Small, Eric J, He, Housheng H, Wyatt, Alexander W, Quigley, David A, Feng, Felix Y

المصدر: Cancer Research. 82(21)

مصطلحات موضوعية: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Aging, Prostate Cancer, Human Genome, Urologic Diseases, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Male, Humans, 5-Methylcytosine, Prostatic Neoplasms, Prostate, Biopsy, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis

الوصف: Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease.SignificanceIn prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880.

الوصول الحر: https://escholarship.org/uc/item/4mx5410zTest

المؤلفون: Zhao, Shuang G, Chen, William S, Li, Haolong, Foye, Adam, Zhang, Meng, Sjöström, Martin, Aggarwal, Rahul, Playdle, Denise, Liao, Arnold, Alumkal, Joshi J, Das, Rajdeep, Chou, Jonathan, Hua, Junjie T, Barnard, Travis J, Bailey, Adina M, Chow, Eric D, Perry, Marc D, Dang, Ha X, Yang, Rendong, Moussavi-Baygi, Ruhollah, Zhang, Li, Alshalalfa, Mohammed, Laura Chang, S, Houlahan, Kathleen E, Shiah, Yu-Jia, Beer, Tomasz M, Thomas, George, Chi, Kim N, Gleave, Martin, Zoubeidi, Amina, Reiter, Robert E, Rettig, Matthew B, Witte, Owen, Yvonne Kim, M, Fong, Lawrence, Spratt, Daniel E, Morgan, Todd M, Bose, Rohit, Huang, Franklin W, Li, Hui, Chesner, Lisa, Shenoy, Tanushree, Goodarzi, Hani, Asangani, Irfan A, Sandhu, Shahneen, Lang, Joshua M, Mahajan, Nupam P, Lara, Primo N, Evans, Christopher P, Febbo, Phillip, Batzoglou, Serafim, Knudsen, Karen E, He, Housheng H, Huang, Jiaoti, Zwart, Wilbert, Costello, Joseph F, Luo, Jianhua, Tomlins, Scott A, Wyatt, Alexander W, Dehm, Scott M, Ashworth, Alan, Gilbert, Luke A, Boutros, Paul C, Farh, Kyle, Chinnaiyan, Arul M, Maher, Christopher A, Small, Eric J, Quigley, David A, Feng, Felix Y

المصدر: Nature Genetics. 52(8)

مصطلحات موضوعية: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Urologic Diseases, Cancer, Prostate Cancer, Human Genome, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Aged, Aged, 80 and over, Carcinogenesis, DNA Methylation, Epigenomics, Gene Expression Regulation, Neoplastic, Genome, Humans, Male, Middle Aged, Mutation, Prospective Studies, Prostatic Neoplasms, Sequence Analysis, DNA, Exome Sequencing, Whole Genome Sequencing, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology

الوصف: Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome approaches. Notably, we observed that 22% of tumors exhibited a novel epigenomic subtype associated with hypermethylation and somatic mutations in TET2, DNMT3B, IDH1 and BRAF. We also identified intergenic regions where methylation is associated with RNA expression of the oncogenic driver genes AR, MYC and ERG. Finally, we showed that differential methylation during progression preferentially occurs at somatic mutational hotspots and putative regulatory regions. This study is a large integrated study of whole-genome, whole-methylome and whole-transcriptome sequencing in metastatic cancer that provides a comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/7h17w53vTest

المؤلفون: Houlahan, Kathleen E, Shiah, Yu-Jia, Gusev, Alexander, Yuan, Jiapei, Ahmed, Musaddeque, Shetty, Anamay, Ramanand, Susmita G, Yao, Cindy Q, Bell, Connor, O’Connor, Edward, Huang, Vincent, Fraser, Michael, Heisler, Lawrence E, Livingstone, Julie, Yamaguchi, Takafumi N, Rouette, Alexandre, Foucal, Adrien, Espiritu, Shadrielle Melijah G, Sinha, Ankit, Sam, Michelle, Timms, Lee, Johns, Jeremy, Wong, Ada, Murison, Alex, Orain, Michèle, Picard, Valérie, Hovington, Hélène, Bergeron, Alain, Lacombe, Louis, Lupien, Mathieu, Fradet, Yves, Têtu, Bernard, McPherson, John D, Pasaniuc, Bogdan, Kislinger, Thomas, Chua, Melvin LK, Pomerantz, Mark M, van der Kwast, Theodorus, Freedman, Matthew L, Mani, Ram S, He, Housheng H, Bristow, Robert G, Boutros, Paul C

المصدر: Nature Medicine. 25(10)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Urologic Diseases, Genetics, Aging, Cancer, Human Genome, Aetiology, 2.1 Biological and endogenous factors, DNA Methylation, Epigenome, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genome, Human, Germ-Line Mutation, Humans, Male, Neoplasm Recurrence, Local, Prostatic Neoplasms, Proto-Oncogene Proteins c-akt, Quantitative Trait Loci, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences

الوصف: Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor's epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. These tumor methylation quantitative trait loci influence chromatin structure, as well as RNA and protein abundance. One prominent tumor methylation quantitative trait locus is associated with AKT1 expression and is predictive of relapse after definitive local therapy in both discovery and validation cohorts. These data reveal intricate crosstalk between the germ line and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/46s9h5q0Test

المؤلفون: Kothari, Vishal, Goodwin, Jonathan F, Zhao, Shuang G, Drake, Justin M, Yin, Yi, Chang, S Laura, Evans, Joseph R, Wilder-Romans, Kari, Gabbara, Kristina, Dylgjeri, Emanuela, Chou, Jonathan, Sun, Grace, Tomlins, Scott A, Mehra, Rohit, Hege, Kristen, Filvaroff, Ellen H, Schaeffer, Edward M, Karnes, R Jeffrey, Quigley, David A, Rathkopf, Dana E, He, Housheng H, Speers, Corey, Spratt, Daniel E, Gilbert, Luke A, Ashworth, Alan, Chinnaiyan, Arul M, Raj, Ganesh V, Knudsen, Karen E, Feng, Felix Y

المصدر: Clinical Cancer Research. 25(18)

مصطلحات موضوعية: Prostate Cancer, Urologic Diseases, Genetics, Aging, Cancer, 2.1 Biological and endogenous factors, Aetiology, Animals, Biomarkers, Tumor, Cell Line, Tumor, Cell Movement, DNA-Activated Protein Kinase, Disease Models, Animal, Disease Progression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Heterografts, Humans, Male, Mice, Neoplasm Metastasis, Phenotype, Prostatic Neoplasms, Protein Binding, RNA, Small Interfering, Transcription, Genetic, Wnt Signaling Pathway, Oncology and Carcinogenesis, Oncology & Carcinogenesis

الوصف: PURPOSE:Protein kinases are known to play a prominent role in oncogenic progression across multiple cancer subtypes, yet their role in prostate cancer progression remains underexplored. The purpose of this study was to identify kinases that drive prostate cancer progression.Experimental Design: To discover kinases that drive prostate cancer progression, we investigated the association between gene expression of all known kinases and long-term clinical outcomes in tumor samples from 545 patients with high-risk disease. We evaluated the impact of genetic and pharmacologic inhibition of the most significant kinase associated with metastatic progression in vitro and in vivo. RESULTS:DNA-dependent protein kinase (DNAPK) was identified as the most significant kinase associated with metastatic progression in high-risk prostate cancer. Inhibition of DNAPK suppressed the growth of both AR-dependent and AR-independent prostate cancer cells. Gene set enrichment analysis nominated Wnt as the top pathway associated with DNAPK. We found that DNAPK interacts with the Wnt transcription factor LEF1 and is critical for LEF1-mediated transcription. CONCLUSIONS:Our data show that DNAPK drives prostate cancer progression through transcriptional regulation of Wnt signaling and is an attractive therapeutic target in aggressive prostate cancer.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/80v3h3x9Test

المؤلفون: 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 M, Playdle, Denise, Barnard, Travis J, Zhang, Li, Zhang, Jin, Youngren, Jack F, Cieslik, Marcin P, Parolia, Abhijit, Beer, Tomasz M, Thomas, George, Chi, Kim N, Gleave, Martin, Lack, Nathan A, Zoubeidi, Amina, Reiter, Robert E, Rettig, Matthew B, Witte, Owen, Ryan, Charles J, Fong, Lawrence, Kim, Won, Friedlander, Terence, 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, Gehring, Julian S, Hakenberg, Jörg, Liao, Arnold, Febbo, Philip G, Shon, John, Sickler, Brad, Batzoglou, Serafim, Knudsen, Karen E, He, Housheng H, Huang, Jiaoti, Wyatt, Alexander W, Dehm, Scott M, Ashworth, Alan, Chinnaiyan, Arul M, Maher, Christopher A, Small, Eric J, Feng, Felix Y

المصدر: Cell. 174(3)

مصطلحات موضوعية: Humans, Prostatic Neoplasms, Neoplasm Metastasis, Cyclin-Dependent Kinases, Proto-Oncogene Proteins c-myc, BRCA2 Protein, Receptors, Androgen, Gene Expression Profiling, Genomics, Tandem Repeat Sequences, Mutation, Aged, Aged, 80 and over, Middle Aged, Male, Tumor Suppressor Protein p53, Genomic Structural Variation, DNA Copy Number Variations, Exome, Whole Genome Sequencing, BRCA2, androgen receptor, castration resistant prostate cancer, chromothripsis, gene fusion, genomics, metastases, structural variation, tandem duplication, whole-genome sequencing, Biological Sciences, Medical and Health Sciences, Developmental Biology

الوصف: While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/796124qbTest

المؤلفون: Teng, Mona, Zhou, Stanley, Cai, Changmeng, Lupien, Mathieu, He, Housheng H

الوصف: Prostate cancer is the most commonly diagnosed non-cutaneous cancers in North American men. While androgen deprivation has remained as the cornerstone of prostate cancer treatment, resistance ensues leading to lethal disease. Forkhead box A1 (FOXA1) encodes a pioneer factor that induces open chromatin conformation to allow the binding of other transcription factors. Through direct interactions with the Androgen Receptor (AR), FOXA1 helps to shape AR signaling that drives the growth and survival of normal prostate and prostate cancer cells. FOXA1 also possesses an AR-independent role of regulating epithelial-to-mesenchymal transition (EMT). In prostate cancer, mutations converge onto the coding sequence and cis-regulatory elements (CREs) of FOXA1, leading to functional alterations. In addition, FOXA1 activity in prostate cancer can be modulated post-translationally through various mechanisms such as LSD1-mediated protein demethylation. In this review, we describe the latest discoveries related to the function and regulation of FOXA1 in prostate cancer, pointing to their relevance to guide future clinical interventions.

العلاقة: https://doi.org/10.1007/s13238-020-00786-8Test; http://hdl.handle.net/1807/102254Test

الإتاحة: https://doi.org/10.1007/s13238-020-00786-8Test
http://hdl.handle.net/1807/102254Test

المؤلفون: Meyer, Clifford A., He, Housheng H., Brown, Myles, Liu, X. Shirley

مصطلحات موضوعية: GENOME ANALYSIS

الوصف: Summary: Transcription factor binding events are frequently associated with a pattern of nucleosome occupancy changes in which nucleosomes flanking the binding site increase in occupancy, while those in the vicinity of the binding site itself are displaced. Genome-wide information on enhancer proximal nucleosome occupancy can be readily acquired using ChIP-seq targeting enhancer-related histone modifications such as H3K4me2. Here, we present a software package, BINOCh that allows biologists to use such data to infer the identity of key transcription factors that regulate the response of a cell to a stimulus or determine a program of differentiation. Availability: The BINOCh open source Python package is freely available at http://liulab.dfci.harvard.edu/BINOChTest under the FreeBSD license. Contact: cliff@jimmy.harvard.edu ; xsliu@jimmy.harvard.edu Supplementary information: Supplementary data are available at Bioinformatics online.

وصف الملف: text/html

العلاقة: http://bioinformatics.oxfordjournals.org/cgi/content/short/27/13/1867Test; http://dx.doi.org/10.1093/bioinformatics/btr279Test

الإتاحة: https://doi.org/10.1093/bioinformatics/btr279Test
http://bioinformatics.oxfordjournals.org/cgi/content/short/27/13/1867Test

المؤلفون: Hua, Junjie T., Chen, Sujun, He, Housheng H.

المصدر: Trends in Genetics ; volume 35, issue 11, page 840-851 ; ISSN 0168-9525

مصطلحات موضوعية: Genetics

الإتاحة: https://doi.org/10.1016/j.tig.2019.08.004Test
https://api.elsevier.com/content/article/PII:S0168952519301660?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0168952519301660?httpAccept=text/plainTest

المؤلفون: Houlahan, Kathleen E, Shiah, Yu-Jia, Gusev, Alexander, Yuan, Jiapei, Ahmed, Musaddeque, Shetty, Anamay, Ramanand, Susmita G, Yao, Cindy Q, Bell, Connor, O'Connor, Edward, Huang, Vincent, Fraser, Michael, Heisler, Lawrence E, Livingstone, Julie, Yamaguchi, Takafumi N, Rouette, Alexandre, Foucal, Adrien, Espiritu, Shadrielle Melijah G, Sinha, Ankit, Sam, Michelle, Timms, Lee, Johns, Jeremy, Wong, Ada, Murison, Alex, Orain, Michèle, Picard, Valérie, Hovington, Hélène, Bergeron, Alain, Lacombe, Louis, Lupien, Mathieu, Fradet, Yves, Têtu, Bernard, McPherson, John D, Pasaniuc, Bogdan, Kislinger, Thomas, Chua, Melvin LK, Pomerantz, Mark M, van der Kwast, Theodorus, Freedman, Matthew L, Mani, Ram S, He, Housheng H, Bristow, Robert G, Boutros, Paul C

المصدر: Nature medicine, vol 25, iss 10

مصطلحات موضوعية: Urologic Diseases, Male, Aging, Immunology, Quantitative Trait Loci, Medical and Health Sciences, Epigenome, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Aetiology, Germ-Line Mutation, Cancer, Neoplastic, Genome, Genome, Human, Prostate Cancer, Gene Expression Profiling, Human Genome, Prostatic Neoplasms, DNA Methylation, Gene Expression Regulation, Neoplastic, Neoplasm Recurrence, Local, Gene Expression Regulation, Neoplasm Recurrence, Local, Proto-Oncogene Proteins c-akt, Human

الوصف: Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor's epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. These tumor methylation quantitative trait loci influence chromatin structure, as well as RNA and protein abundance. One prominent tumor methylation quantitative trait locus is associated with AKT1 expression and is predictive of relapse after definitive local therapy in both discovery and validation cohorts. These data reveal intricate crosstalk between the germ line and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::cce33a40bf682db7648fc2eb0290b120Test
https://pubmed.ncbi.nlm.nih.gov/31659333Test