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prostate cancer genomic sequencing

Michael T Schweizer, Heather H Cheng, Maria S Tretiakova, Funda Vakar-Lopez, Nola Klemfuss, Eric Q Konnick, Elahe A Mostaghel, Peter S Nelson, Evan Y Yu, R Bruce Montgomery, Lawrence D True, Colin C Pritchard
Precision oncology entails making treatment decisions based on a tumor's molecular characteristics. For prostate cancer, identifying clinically relevant molecular subgroups is challenging, as molecular profiling is not routine outside of academic centers. Since histologic variants of other cancers correlates with specific genomic alterations, we sought to determine if ductal adenocarcinoma of the prostate (dPC) - a rare and aggressive histopathologic variant - was associated with any recurrent actionable mutations...
October 15, 2016: Oncotarget
Daniel Nava Rodrigues, Gunther Boysen, Semini Sumanasuriya, George Seed, Angelo M De Marzo, Johann de Bono
Prostate cancer (PCa) is a clinically heterogeneous disease and current treatment strategies are based largely on anatomical and pathological parameters. In the recent past, several DNA sequencing studies of primary and advanced PCa have revealed recurrent patterns of genomic aberrations that expose mechanisms of resistance to available therapies and potential new drug targets. Suppression of androgen receptor (AR) signalling is the cornerstone of advanced prostate cancer treatment. Genomic aberrations of the androgen receptor or alternative splicing of its mRNA are increasingly recognized as biomarkers of resistance to AR-targeted therapy such as abiraterone or enzalutamide...
October 18, 2016: Journal of Pathology
Daniel H Hovelson, Scott A Tomlins
Molecular biomarkers play little role in the current treatment of metastatic castration-resistant prostate cancer (CRPC). The advent of next-generation sequencing (NGS) has enabled the comprehensive molecular characterization of the genomic and transcriptomic landscape of both untreated primary prostate cancer and CRPC. Recent studies demonstrating the feasibility of interinstitution studies obtaining and NGS profiling of metastatic biopsies, targeted NGS approaches applicable to routine formalin-fixed, paraffin-embedded specimens, and NGS approaches applicable to circulating DNA and circulating tumor cells portend near-term adoption of NGS approaches in the management and treatment of CRPC...
September 2016: Cancer Journal
Tsuyoshi Hamada, NaNa Keum, Reiko Nishihara, Shuji Ogino
Molecular pathological epidemiology (MPE) is an integrative field that utilizes molecular pathology to incorporate interpersonal heterogeneity of a disease process into epidemiology. In each individual, the development and progression of a disease are determined by a unique combination of exogenous and endogenous factors, resulting in different molecular and pathological subtypes of the disease. Based on "the unique disease principle," the primary aim of MPE is to uncover an interactive relationship between a specific environmental exposure and disease subtypes in determining disease incidence and mortality...
October 13, 2016: Journal of Gastroenterology
Anton M F Kalsbeek, Eva F K Chan, Judith Grogan, Desiree C Petersen, Weerachai Jaratlerdsiri, Ruta Gupta, Ruth J Lyons, Anne-Maree Haynes, Lisa G Horvath, James G Kench, Phillip D Stricker, Vanessa M Hayes
Prostate cancer management is complicated by extreme disease heterogeneity, which is further limited by availability of prognostic biomarkers. Recognition of prostate cancer as a genetic disease has prompted a focus on the nuclear genome for biomarker discovery, with little attention given to the mitochondrial genome. While it is evident that mitochondrial DNA (mtDNA) mutations are acquired during prostate tumorigenesis, no study has evaluated the prognostic value of mtDNA variation. Here we used next-generation sequencing to interrogate the mitochondrial genomes from prostate tissue biopsies and matched blood of 115 men having undergone a radical prostatectomy for which there was a mean of 107 months clinical follow-up...
October 5, 2016: Aging
Thomas Schmidt, Andreas Leha, Gabriela Salinas-Riester
The hypomethylation of DNA may support tumor progression; however, the mechanism underlying this relationship is not clear. Several studies have demonstrated that the in vitro application of the methyl donor S-adenosylmethionine (SAM) leads to promoter remethylation and the downregulation of proto-oncogene expression in cancer cells. It is not clear if this represents a general mechanism of SAM or is limited to selected genes. We examined this problem using new bisulfite sequencing and transcriptomic technologies...
September 26, 2016: Gene
Marjo Malinen, Einari A Niskanen, Minna U Kaikkonen, Jorma J Palvimo
Inflammatory processes and androgen signaling are critical for the growth of prostate cancer (PC), the most common cancer among males in Western countries. To understand the importance of potential interplay between pro-inflammatory and androgen signaling for gene regulation, we have interrogated the crosstalk between androgen receptor (AR) and NF-κB, a key transcriptional mediator of inflammatory responses, by utilizing genome-wide chromatin immunoprecipitation sequencing and global run-on sequencing in PC cells...
September 26, 2016: Nucleic Acids Research
Damien A Leach, Suzanne M Powell, Charlotte Bevan
Prostate cancer has, for decades, been treated by inhibiting androgen signalling. This is effective in the majority of patients, but inevitably resistance develops and patients progress to life-threatening metastatic disease - hence the quest for new effective therapies for "castrate-resistant" prostate cancer (CRPC). Studies into what pathways can drive tumour recurrence under these conditions has identified several other nuclear receptor signalling pathways as potential drivers or modulators of CRPC. The nuclear receptors constitute a large (48 members) superfamily of transcription factors sharing a common modular functional structure...
September 19, 2016: Endocrine-related Cancer
Sari Toropainen, Einari A Niskanen, Marjo Malinen, Päivi Sutinen, Minna U Kaikkonen, Jorma J Palvimo
Androgen receptor (AR) is a male sex steroid-activated transcription factor (TF) that plays a critical role in prostate cancers, including castration-resistant prostate cancers (CRPC) that typically express amplified levels of the AR. CRPC-derived VCaP cells display an excessive number of chromatin AR-binding sites (ARBs) most of which localize to distal inter- or intragenic regions. Here, we analyzed direct transcription programs of the AR in VCaP cells using global nuclear run-on sequencing (GRO-seq) and integrated the GRO-seq data with the ARB and VCaP cell-specific TF-binding data...
2016: Scientific Reports
Damien A Leach, Vasilios Panagopoulos, Claire Nash, Charlotte Bevan, Axel A Thomson, Luke A Selth, Grant Buchanan
Androgen receptor (AR) signalling in fibroblasts is important in prostate development and carcinogenesis, and is inversely related to prostate cancer mortality. However, the molecular mechanisms of AR action in fibroblasts and other non-epithelial cell types are largely unknown. The genome-wide DNA binding profile of AR in human prostate fibroblasts was identified by chromatin immunoprecipitation sequencing (ChIP-Seq), and found to be common to other fibroblast lines but disparate from AR cistromes of prostate cancer cells and tissue...
September 12, 2016: Molecular and Cellular Endocrinology
Stephen Wilson, Jianfei Qi, Fabian V Filipp
Sequence motifs are short, recurring patterns in DNA that can mediate sequence-specific binding for proteins such as transcription factors or DNA modifying enzymes. The androgen response element (ARE) is a palindromic, dihexameric motif present in promoters or enhancers of genes targeted by the androgen receptor (AR). Using chromatin immunoprecipitation sequencing (ChIP-Seq) we refined AR-binding and AREs at a genome-scale in androgen-insensitive and androgen-responsive prostate cancer cell lines. Model-based searches identified more than 120,000 ChIP-Seq motifs allowing for expansion and refinement of the ARE...
2016: Scientific Reports
Sam Behjati, Gunes Gundem, David C Wedge, Nicola D Roberts, Patrick S Tarpey, Susanna L Cooke, Peter Van Loo, Ludmil B Alexandrov, Manasa Ramakrishna, Helen Davies, Serena Nik-Zainal, Claire Hardy, Calli Latimer, Keiran M Raine, Lucy Stebbings, Andy Menzies, David Jones, Rebecca Shepherd, Adam P Butler, Jon W Teague, Mette Jorgensen, Bhavisha Khatri, Nischalan Pillay, Adam Shlien, P Andrew Futreal, Christophe Badie, Ultan McDermott, G Steven Bova, Andrea L Richardson, Adrienne M Flanagan, Michael R Stratton, Peter J Campbell
Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1-100 base pairs often with microhomology at the junction...
September 12, 2016: Nature Communications
Yuanhang Liu, Desiree Wilson, Robin J Leach, Yidong Chen
BACKGROUND: Since its initial discovery in 1975, DNA methylation has been intensively studied and shown to be involved in various biological processes, such as development, aging and tumor progression. Many experimental techniques have been developed to measure the level of DNA methylation. Methyl-CpG binding domain-based capture followed by high-throughput sequencing (MBDCap-seq) is a widely used method for characterizing DNA methylation patterns in a genome-wide manner. However, current methods for processing MBDCap-seq datasets does not take into account of the region-specific genomic characteristics that might have an impact on the measurements of the amount of methylated DNA (signal) and background fluctuation (noise)...
2016: BMC Genomics
Can Kockan, Faraz Hach, Iman Sarrafi, Robert H Bell, Brian McConeghy, Kevin Beja, Anne Haegert, Alexander W Wyatt, Stanislav V Volik, Kim N Chi, Colin C Collins, S Cenk Sahinalp
MOTIVATION: Successful development and application of precision oncology approaches require robust elucidation of the genomic landscape of a patient's cancer and, ideally, the ability to monitor therapy-induced genomic changes in the tumour in an inexpensive and minimally invasive manner. Thanks to recent advances in sequencing technologies, "liquid biopsy", the sampling of patient's bodily fluids such as blood and urine, is considered as one of the most promising approaches to achieve this goal...
August 16, 2016: Bioinformatics
Gennadi V Glinsky
Somatic mutations and chromosome instability are hallmarks of genomic aberrations in cancer cells. Aneuploidies represent common manifestations of chromosome instability, which is frequently observed in human embryos and malignant solid tumors. Activation of human endogenous retroviruses (HERV)-derived loci is documented in preimplantation human embryos, hESC, and multiple types of human malignancies. It remains unknown whether the HERV activation may highlight a common molecular pathway contributing to the frequent occurrence of chromosome instability in the early stages of human embryonic development and the emergence of genomic aberrations in cancer...
October 10, 2016: Cancer Letters
Mathias Stiller, Antje Sucker, Klaus Griewank, Daniela Aust, Gustavo Bruno Baretton, Dirk Schadendorf, Susanne Horn
DNA derived from formalin-fixed and paraffin-embedded (FFPE) tissue has been a challenge to large-scale genomic sequencing, due to its low quality and quantities. Improved techniques enabling the genome-wide analysis of FFPE material would be of great value, both from a research and clinical perspective.Comparing a single-strand DNA library preparation method originally developed for ancient DNA to conventional protocols using double-stranded DNA derived from FFPE material we obtain on average 900-fold more library molecules and improved sequence complexity from as little as 5 ng input DNA...
July 24, 2016: Oncotarget
Lei Wei, Jianmin Wang, Erika Lampert, Simon Schlanger, Adam D DePriest, Qiang Hu, Eduardo Cortes Gomez, Mitsuko Murakam, Sean T Glenn, Jeffrey Conroy, Carl Morrison, Gissou Azabdaftari, James L Mohler, Song Liu, Hannelore V Heemers
BACKGROUND: Next-generation sequencing is revealing genomic heterogeneity in localized prostate cancer (CaP). Incomplete sampling of CaP multiclonality has limited the implications for molecular subtyping, stratification, and systemic treatment. OBJECTIVE: To determine the impact of genomic and transcriptomic diversity within and among intraprostatic CaP foci on CaP molecular taxonomy, predictors of progression, and actionable therapeutic targets. DESIGN, SETTING, AND PARTICIPANTS: Four consecutive patients with clinically localized National Comprehensive Cancer Network intermediate- or high-risk CaP who did not receive neoadjuvant therapy underwent radical prostatectomy at Roswell Park Cancer Institute in June-July 2014...
July 20, 2016: European Urology
Sompol Permpongkosol, Kalayanee Khupulsup, Supatra Leelaphiwat, Sarawan Pavavattananusorn, Supranee Thongpradit, Thanom Petchthong
INTRODUCTION: The long-term effects of long-acting testosterone undecanoate (TU) and androgen receptor CAG repeat lengths in Thai men with late-onset hypogonadism (LOH) have not been reported. AIM: To analyze the 8-year follow-up effects of intramuscular TU therapy on metabolic parameters, urinary symptoms, bone mineral density, and sexual function and investigate CAG repeat lengths in men with LOH. METHODS: We reviewed the medical records of 428 men with LOH who had been treated with TU and 5 patients were diagnosed with prostate cancer during TU therapy...
August 2016: Journal of Sexual Medicine
Xibei Dang, Amar Singh, Brian D Spetman, Krystal D Nolan, Jennifer S Isaacs, Jonathan H Dennis, Stephen Dalton, Alan G Marshall, Nicolas L Young
Histone variants are known to play a central role in genome regulation and maintenance. However, many variants are inaccessible by antibody-based methods or bottom-up tandem mass spectrometry due to their highly similar sequences. For many, the only tractable approach is with intact protein top-down tandem mass spectrometry. Here, ultra-high-resolution FT-ICR MS and MS/MS yield quantitative relative abundances of all detected HeLa H2A and H2B isobaric and isomeric variants with a label-free approach. We extend the analysis to identify and relatively quantitate 16 proteoforms from 12 sequence variants of histone H2A and 10 proteoforms of histone H2B from three other cell lines: human embryonic stem cells (WA09), U937, and a prostate cancer cell line LaZ...
September 2, 2016: Journal of Proteome Research
S Q Zhang, G Q Zhang, L Zhang
Prostate cancer is a common malignant tumor in males with an unclear pathogenic mechanism. As one epigenetic regulation mechanism, DNA methylation of the whole genome and specific gene(s) plays critical roles in pathogenesis, progression, diagnosis, and treatment of prostate cancer. The E-Cadherin gene is involved in cell metabolism and has been suggested to be related with malignancy of multiple tumors. This study investigated the correlation between E-Cadherin methylation and malignancy of prostate cancer...
2016: Genetics and Molecular Research: GMR
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