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Cell-free tumor dna

Vincent Plagnol, Samuel Woodhouse, Karen Howarth, Stefanie Lensing, Matt Smith, Michael Epstein, Mikidache Madi, Sarah Smalley, Catherine Leroy, Jonathan Hinton, Frank de Kievit, Esther Musgrave-Brown, Colin Herd, Katherine Baker-Neblett, Will Brennan, Peter Dimitrov, Nathan Campbell, Clive Morris, Nitzan Rosenfeld, James Clark, Davina Gale, Jamie Platt, John Calaway, Greg Jones, Tim Forshew
Circulating tumor DNA (ctDNA) analysis is being incorporated into cancer care; notably in profiling patients to guide treatment decisions. Responses to targeted therapies have been observed in patients with actionable mutations detected in plasma DNA at variant allele fractions (VAFs) below 0.5%. Highly sensitive methods are therefore required for optimal clinical use. To enable objective assessment of assay performance, detailed analytical validation is required. We developed the InVisionFirst™ assay, an assay based on enhanced tagged amplicon sequencing (eTAm-Seq™) technology to profile 36 genes commonly mutated in non-small cell lung cancer (NSCLC) and other cancer types for actionable genomic alterations in cell-free DNA...
2018: PloS One
Antonio Fadda, Davide Gentilini, Loredana Moi, Ludovic Barault, Vera Piera Leoni, Pia Sulas, Luigi Zorcolo, Angelo Restivo, Francesco Cabras, Federica Fortunato, Cesare Zavattari, Liliana Varesco, Viviana Gismondi, Maria Rosaria De Miglio, Antonio Mario Scanu, Federica Colombi, Pasquale Lombardi, Ivana Sarotto, Eleonora Loi, Francesco Leone, Silvia Giordano, Federica Di Nicolantonio, Amedeo Columbano, Patrizia Zavattari
Colorectal cancer (CRC) develops through the accumulation of both genetic and epigenetic alterations. However, while the former are already used as prognostic and predictive biomarkers, the latter are less well characterized. Here, performing global methylation analysis on both CRCs and adenomas by Illumina Infinium HumanMethylation450 Bead Chips, we identified a panel of 74 altered CpG islands, demonstrating that the earliest methylation alterations affect genes coding for proteins involved in the crosstalk between cell and surrounding environment...
March 15, 2018: International Journal of Cancer. Journal International du Cancer
Kristina M Jordahl, Timothy W Randolph, Xiaoling Song, Cassandra L Sather, Lesley F Tinker, Amanda I Phipps, Karl T Kelsey, Emily White, Parveen Bhatti
BACKGROUND: Differential DNA methylation as measured in blood is a promising marker of bladder cancer susceptibility. However, previous studies have exclusively used post-diagnostic blood samples, meaning that observed associations may be markers of disease rather than susceptibility. METHODS: Genome-wide methylation was measured in pre-diagnostic blood samples, using the Illumina Infinium HumanMethylation450 Bead Array, among 440 bladder cancer cases with the transitional cell carcinoma (TCC) subtype and 440 matched cancer-free controls from the Women's Health Initiative (WHI) cohort...
March 14, 2018: Cancer Epidemiology, Biomarkers & Prevention
Shifu Chen, Ming Liu, Yanqing Zhou
As a major biomarker of liquid biopsy, cell-free tumor DNA (ctDNA), which can be extracted from blood, urine, or other circulating liquids, is able to provide comprehensive genetic information of tumor and better overcome the tumor heterogeneity problem comparing to tissue biopsy. Developed in recent years, next-generation sequencing (NGS) is a widely used technology for analyzing ctDNA. Although the technologies of processing ctDNA samples are mature, the task to detect low mutated allele frequency (MAF) variations from noisy sequencing data remains challenging...
2018: Methods in Molecular Biology
Jun Li, Renzhong Liu, Cuihong Huang, Shifu Chen, Mingyan Xu
Cell-free tumor DNA (ctDNA) is a kind of potential tumor biomarkers originated from cancer lesion in the circulating liquids. Liquid biopsy, as a minimally invasive or noninvasive manner, is a cutting-edge technology to detect ctDNA and other circulating biomarkers in the blood or other body fluids. ctDNA is mostly used for cancer patients to select targeted drugs in clinical application. In addition, ctDNA could also be applied to monitor tumor progression and recurrence. In conclusion, ctDNA is a very promising tumor biomarker for diagnosis and monitoring, which would increasingly become a routine clinical application in recent years...
2018: Methods in Molecular Biology
Meenakshi Mehrotra, Rajesh R Singh, Sanam Loghavi, Dzifa Yawa Duose, Bedia A Barkoh, Carmen Behrens, Keyur P Patel, Mark J Routbort, Scott Kopetz, Russell R Broaddus, L Jeffrey Medeiros, Ignacio I Wistuba, Rajyalakshmi Luthra
A suitable clinical-grade platform is required for detection of somatic mutations with high sensitivity in cell-free DNA (cfDNA) of patients with solid tumors. In this study, we evaluated in parallel ultra-deep NGS with MassARRAY and allele-specific droplet digital PCR (ddPCR) for cfDNA genotyping and correlated cfDNA yield and mutation status with overall survival (OS) of patients. We assessed plasma samples from 46 patients with various advanced metastatic solid tumors and known mutations by deep sequencing using an Ampliseq cancer hotspot panel V2 on Ion Proton...
February 13, 2018: Oncotarget
Elena Castellanos-Rizaldos, Dominik G Grimm, Vasisht Tadigotla, James Hurley, John Healy, Patricia L Neal, Mia Sher, Raajdeep Venkatesan, Chris Karlovich, Mitch Raponi, Anne K Krug, Mikkel Noerholm, Jihane Tannous, Bakhos A Tannous, Luis E Raez, Johan Skog
PURPOSE: About 60% of non-small cell lung cancer (NSCLC) patients develop resistance to targeted epidermal growth factor receptor (EGFR) inhibitor therapy through the EGFR T790M mutation. Patients with this mutation respond well to third generation tyrosine kinase inhibitors, but obtaining a tissue biopsy to confirm the mutation poses risks and is often not feasible. Liquid biopsies using circulating free tumor DNA (cfDNA) have emerged as a non-invasive option to detect the mutation, however sensitivity is low as many patients have too few detectable copies in circulation...
March 13, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Shuai Wang, Junjie Xi, Zongwu Lin, Jiatao Hao, Can Yao, Cheng Zhan, Wei Jiang, Yu Shi, Qun Wang
Ku80 is an important DNA repair protein. Here, this study sought to investigate clinical impacts of Ku80 expression for patients with superficial esophageal squamous cell carcinoma (ESCC). Immunohistochemical analysis of Ku80 expression was carried out in normal esophageal mucosa, squamous epithelial dysplasia, carcinoma in situ, and superficial ESCC. Its relationships with clinicopathological features and survival of superficial ESCC patients were further clarified. Lentivirus-mediated RNA interference was used to silence Ku80 gene in ECA109 and KYSE150 cells...
March 13, 2018: Cancer Medicine
Laura Lupini, Anna Moretti, Cristian Bassi, Alessio Schirone, Massimo Pedriali, Patrizia Querzoli, Roberta Roncarati, Antonio Frassoldati, Massimo Negrini
Approximately 70% of breast cancers (BCs) express estrogen receptor alpha (ERα) and are treated with endocrine therapy. However, the effectiveness of this therapy is limited by innate or acquired resistance in approximately one-third of patients. Activating mutations in the ESR1 gene that encodes ERα promote critical resistance mechanisms. Here, we developed a high sensitivity approach based on enhanced-ice-COLD-PCR for detecting ESR1 mutations. The method produced an enrichment up to 100-fold and allowed the unambiguous detection of ESR1 mutations even when they consisted of only 0...
March 12, 2018: Scientific Reports
Heng Zhao, Ke-Zhong Chen, Ben-Gang Hui, Kai Zhang, Fan Yang, Jun Wang
Lung cancer is one of the most common cancers and the predominant cause of cancer-related death in the world. The low accuracy of early detection techniques and high risk of relapse greatly contribute to poor prognosis. An accurate clinical tool that can assist in diagnosis and surveillance is urgently needed. Circulating tumor DNA (ctDNA) is free DNA shed from tumor cells and isolated from peripheral blood. The genomic profiles of ctDNA have been shown to closely match those of the corresponding tumors. With the development of approaches with high sensitivity and specificity, ctDNA plays a vital role in the management of lung cancer as a result of its reproducible, non-invasive, and easy-to-obtain characteristics...
March 12, 2018: Thoracic Cancer
Christoph Oing, Pierre Tennstedt, Ronald Simon, Jennifer Volquardsen, Kerstin Borgmann, Carsten Bokemeyer, Cordula Petersen, Ekkehard Dikomey, Kai Rothkamm, Wael Y Mansour
Here we report that BCL2 blocks DNA double strand break (DSB) repair via nonhomologous end-joining (NHEJ), through sequestration of KU80 protein outside the nucleus. We find that this effect is associated with a repair switch to the error-prone PARP1-dependent end-joining (PARP1-EJ). We present in-vitro proof-of-concept for therapeutic targeting of this switch using PARP inhibitor to specifically enhance the radiosensitivity of BCL2-overexpressing cells. Given its erroneous behavior, PARP1-EJ might allow for the accumulation of genetic alterations and tumor progression...
March 8, 2018: Cancer Letters
Michael J Levy, Benjamin R Kipp, Dragana Milosevic, Amber R Schneider, Jesse S Voss, Rajeswari Avula, Sarah E Kerr, Michael R Henry, Edward Highsmith, Minetta C Liu, Ferga C Gleeson
BACKGROUND & AIMS: Cellular and nuclear material from tumors disseminates into the bloodstream (tumoremia), but it is not clear whether medical procedures cause release of this material or contribute to formation of metastases. We performed a prospective study of blood samples from patients with pancreatic adenocarcinoma (PDAC) to determine whether endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) associates with markers of tumoremia. METHODS: We obtained peripheral blood from 104 patients (35 with PDAC) before and after EUS-FNA of primary tumors; blood samples from 69 healthy individuals were used as controls...
March 8, 2018: Clinical Gastroenterology and Hepatology
Rebecca C Arend, Angelina I Londono, Allison M Montgomery, Haller J Smith, Zachary C Dobbin, Ashwini A Katre, Alba Martinez, Eddy S Yang, Ronald D Alvarez, Warner K Huh, Kerri S Bevis, J Michael Straughn, Jacob M Estes, Lea Novak, David K Crossman, Sara J Cooper, Charles N Landen, Charles A Leath
While high-grade serous ovarian carcinoma (HGSOC) is the most common histological subtype of ovarian cancer, significant tumor heterogeneity exists. In addition, chemotherapy induces changes in gene expression and alters the mutational profile. To evaluate the notion that patients with HGSOC could be better classified for optimal treatment based on gene expression, we compared genetic variants (by DNA next-generation sequencing [NGS] using a 50 gene Ion Torrent panel) and gene expression (using the NanoString® PanCancer 770 gene Panel) in the tumor from 20 patients with HGSOC before and after neoadjuvant chemotherapy (NACT)...
March 9, 2018: Molecular Cancer Research: MCR
Takuya Yotani, Yuriko Yamada, Eri Arai, Ying Tian, Masahiro Gotoh, Motokiyo Komiyama, Hiroyuki Fujimoto, Michiie Sakamoto, Yae Kanai
The aim of this study was to develop a new methodology that is suitable for DNA methylation diagnostics and to demonstrate its clinical applicability. We developed a new anion-exchange column for high-performance liquid chromatography (HPLC) with electrostatic and hydrophobic properties. Both cytosine and thymine, corresponding to methylated and unmethylated cytosine after bisulfite modification, respectively, are captured by electrostatic interaction and then discriminated from each other by their hydrophobic interactions...
March 9, 2018: Cancer Science
Neeraj Agarwal, Sumanta K Pal, Andrew W Hahn, Roberto H Nussenzveig, Gregory R Pond, Sumati V Gupta, Jue Wang, Mehmet A Bilen, Gurudatta Naik, Pooja Ghatalia, Christopher J Hoimes, Dharmesh Gopalakrishnan, Pedro C Barata, Alexandra Drakaki, Bishoy M Faltas, Lesli A Kiedrowski, Richard B Lanman, Rebecca J Nagy, Nicholas J Vogelzang, Kenneth M Boucher, Ulka N Vaishampayan, Guru Sonpavde, Petros Grivas
BACKGROUND: Biomarker-guided clinical trials are increasingly common in metastatic urothelial carcinoma (mUC), yet patients for whom contemporary tumor tissue is not available are not eligible. Technological advancements in sequencing have made cell-free circulating DNA (cfDNA) next-generation sequencing (NGS) readily available in the clinic. The objective of the current study was to determine whether the genomic profile of mUC detected by NGS of cfDNA is similar to historical tumor tissue NGS studies...
March 8, 2018: Cancer
C K Y Ng, G G Di Costanzo, N Tosti, V Paradiso, M Coto-Llerena, G Roscigno, V Perrina, C Quintavalle, T Boldanova, S Wieland, G Marino-Marsilia, M Lanzafame, L Quagliata, G Condorelli, M S Matter, R Tortora, M H Heim, L M Terracciano, S Piscuoglio
Background: Hepatocellular carcinomas (HCCs) are not routinely biopsied, resulting in a lack of tumor materials for molecular profiling. Here we sought to determine if plasma-derived cell-free DNA (cfDNA) captures the genetic alterations of HCC in patients who have not undergone systemic therapy. Patients and methods: Frozen biopsies from the primary tumor and plasma were synchronously collected from 30 prospectively recruited, systemic treatment-naïve HCC patients...
March 2, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Anna Buder, Maximilian J Hochmair, Sophia Schwab, Tatjana Bundalo, Peter Schenk, Peter Errhalt, Romana E Mikes, Gudrun Absenger, Kurt Patocka, Bernhard Baumgartner, Ulrike Setinek, Otto C Burghuber, Helmut Prosch, Robert Pirker, Martin Filipits
INTRODUCTION: Osimertinib is standard treatment for patients with advanced EGFR T790M-mutated NSCLC who have been pre-treated with EGFR-TKIs. We studied whether cell-free plasma DNA for T790M detection can be used to select patients for osimertinib treatment in clinical routine. METHODS: From April 2015 to November 2016, we included 119 patients with advanced EGFR-mutated NSCLC who had progressed under treatment with an EGFR-TKI. The T790M mutation status was assessed in cell-free plasma DNA by droplet digital PCR (ddPCR) in all patients and by tissue analyses in selected patients...
March 2, 2018: Journal of Thoracic Oncology
Masoud Najafi, Elahe Motevaseli, Alireza Shirazi, Ghazale Graily, Abolhasan Rezaeyan, Farzad Norouzi, Saeed Rezapoor, Hamid Abdollahi
PURPOSE: Cancer treatment is one of the most challenging diseases in the present era. Among a few modalities for cancer therapy, radiotherapy plays a pivotal role in more than half of all treatments alone or combined with other cancer treatment modalities. Management of normal tissue toxicity induced by radiation is one of the most important limiting factors for an appropriate radiation treatment course. The evaluation of mechanisms of normal tissue toxicity has shown that immune responses especially inflammatory responses play a key role in both early and late side effects of exposure to ionizing radiation (IR)...
March 5, 2018: International Journal of Radiation Biology
Ling Lu, Junqin Bi, Liming Bao
Circulating cell-free tumor DNA (ctDNA) in the blood is DNA released from apoptotic, circulating, and living tumor cells. ctDNA is about 140 nt in length and has a half-life of about 1.5 h. ctDNA analysis provides a noninvasive means to assess the genetic profile of cancer in real time. With the advent of molecular technologies, including digital PCR and massively parallel sequencing (MPS), ctDNA analysis has shown promise as a highly sensitive and specific alternative to conventional tissue biopsy in cancer detection, longitudinal monitoring, and precision therapy...
February 5, 2018: Journal of Genetics and Genomics, Yi Chuan Xue Bao
Amir Abbas Mokhtarieh, Jieun Lee, Semi Kim, Myung Kyu Lee
Previously a scalable and extrusion-free method has been developed for efficient liposomal encapsulation of DNA by twice stepwise mixing of lipids in ethanol and DNA solution using T-shape mixing chamber. In this study, we prepared nanoliposomes encapsulating siRNA by simply discontinuous mixing of lipids in ethanol/ether/water mixture and acidic siRNA solution without use of special equipment. The simple mixing siRNA/liposomal particles (siRNA/SMLs) prepared using ethanol/ether/water (3:1:1) mixture showed 120...
February 28, 2018: Biochimica et Biophysica Acta
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