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Journal of Molecular Diagnostics: JMD

Stephen E Lincoln, Rebecca Truty, Chiao-Feng Lin, Justin M Zook, Joshua Paul, Vincent H Ramey, Marc Salit, Heidi L Rehm, Robert L Nussbaum, Matthew S Lebo
Orthogonal confirmation of next-generation sequencing (NGS)-detected germline variants has been standard practice, although published studies have suggested that confirmation of the highest quality calls may not always be necessary. The key question is how laboratories can establish criteria that consistently identify those NGS calls that require confirmation. Most prior studies addressing this question have limitations: These studies are generally small, omit statistical justification, and explore limited aspects of the underlying data...
January 2, 2019: Journal of Molecular Diagnostics: JMD
Avni Santani, Birgitte B Simen, Marian Briggs, Matthew Lebo, Jason D Merker, Marina Nikiforova, Patricia Vasalos, Karl Voelkerding, John Pfeifer, Birgit Funke
Comprehensive next-generation sequencing (NGS) tests are increasingly used as first-line tests in the evaluation of patients with suspected heritable disease. Despite major technical simplifications, these assays still pose significant challenges for molecular testing laboratories. Existing professional guidelines and recommendations provide a framework for laboratories implementing such tests, but in-depth, concrete guidance is generally not provided. Consequently, there is variability in how laboratories interpret and subsequently implement these regulatory frameworks...
December 31, 2018: Journal of Molecular Diagnostics: JMD
Christopher J Troll, Nicholas H Putnam, Paul D Hartley, Brandon Rice, Marco Blanchette, Sameed Siddiqui, Javkhlan-Ochir Ganbat, Martin P Powers, Ramesh Ramakrishnan, Christian A Kunder, Carlos D Bustamante, James L Zehnder, Richard E Green, Helio A Costa
The clinical management and therapy of many solid tumor malignancies is dependent on detection of medically actionable or diagnostically relevant genetic variation. However, a principal challenge for genetic assays from tumors is the fragmented and chemically damaged state of DNA in formalin-fixed, paraffin-embedded (FFPE) samples. From highly fragmented DNA and RNA there is no current technology for generating long-range DNA sequence data as is required to detect genomic structural variation or long-range genotype phasing...
December 31, 2018: Journal of Molecular Diagnostics: JMD
Maria E Arcila, Wayne Yu, Mustafa Syed, Hannah Kim, Lidia Maciag, JinJuan Yao, Caleb Ho, Kseniya Petrova, Christine Moung, Paulo Salazar, Ivelise Rijo, Tessara Baldi, Ahmet Zehir, Ola Landgren, Jae Park, Mikhail Roshal, Ahmet Dogan, Khedoudja Nafa
Immunoglobulin heavy chain (IGH) clonality testing by next-generation sequencing (NGS) offers unique advantages over current low-throughput methods in the diagnosis and monitoring of B-cell lineage neoplasms. However, clinical use remains limited as assays are not standardized and validation/implementation guidelines not yet developed. Here, we describe our clinical validation and implementation of NGS IGH clonality testing and summarize our experience based on extensive routine use. NGS-based clonality testing targeting IGH FR1, FR2, FR3, and the conserved leader sequence upstream of FR1, were validated using commercially available kits...
December 24, 2018: Journal of Molecular Diagnostics: JMD
Christina Grimm, Axel Fischer, Angela M Farrelly, Roshni Kalachand, Roberta Castiglione, Elena Wasserburger, Michelle Hussong, Anne M Schultheis, Janine Altmüller, Holger Thiele, Hans C Reinhardt, Kai Hauschulz, Bryan T Hennessy, Ralf Herwig, Matthias Lienhard, Reinhard Buettner, Michal R Schweiger
Current molecular tumor diagnostics encompass panel sequencing to detect mutations, copy number alterations, and rearrangements. However, tumor suppressor genes can also be inactivated by methylation within their promoter region. These epigenetic alterations are so far rarely assessed in the clinical setting. Therefore, we established the AllCap protocol facilitating the combined detection of mutations and DNA methylation at the coding and promoter regions of 342 DNA repair genes in one experiment. We demonstrate the use of the protocol by applying it to ovarian cancer cell lines with different responsiveness to PARP inhibition...
December 18, 2018: Journal of Molecular Diagnostics: JMD
Sounak Gupta, Chad M Vanderbilt, Paolo Cotzia, Javier A Arias Stella, Jason C Chang, Ahmet Zehir, Ryma Benayed, Khedouja Nafa, Pedram Razavi, David M Hyman, José Baselga, Michael F Berger, Marc Ladanyi, Maria E Arcila, Dara S Ross
Genomic amplification at 9p24.1, including the loci for JAK2, PD-L1, and PD-L2, has recently been described as a mechanism of resistance in post-chemotherapy, triple-negative breast cancer. This genomic signature holds significant promise as a prognostic biomarker and has implications for targeted therapy with JAK2 inhibitors, as well as with immunotherapy. To guide future screening strategies, we determined the frequency of these alterations. A total of 5,399 cases were included in the study. This encompassed 2,890 institutional cases tested by the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets assay and 2,509 cases from The Cancer Genome Atlas (TCGA)...
December 18, 2018: Journal of Molecular Diagnostics: JMD
Carmen M Alonso, Marta Llop, Claudia Sargas, Laia Pedrola, Joaquín Panadero, David Hervás, José Cervera, Esperanza Such, Mariam Ibáñez, Rosa Ayala, Joaquín Martínez-López, Esther Onecha, Inmaculada de Juan, Sarai Palanca, David Martínez-Cuadrón, Rebeca Rodríguez-Veiga, Blanca Boluda, Pau Montesinos, Guillermo Sanz, Miguel A Sanz, Eva Barragán
Next-generation-sequencing (NGS) has redefined the genetic landscape of acute myeloid leukemia (AML) providing new molecular markers for diagnostic and prognostic classifications. However, its application in the clinical setting is still challenging. We hypothesized that a 19-gene AML-targeted NGS panel could be a valid approach to obtain clinically relevant information. Thus, we assessed the ability of this panel to classify AML patients according to diagnostic and prognostic indexes in a cohort of 162 patients...
December 18, 2018: Journal of Molecular Diagnostics: JMD
Mahadeo A Sukhai, Maksym Misyura, Mariam Thomas, Swati Garg, Tong Zhang, Natalie Stickle, Carl Virtanen, Philippe L Bedard, Lillian L Siu, Tina Smets, Gert Thijs, Steven Van Vooren, Suzanne Kamel-Reid, Tracy L Stockley
A common approach in clinical diagnostic laboratories to variant assessment from tumor molecular profiling is sequencing of genomic DNA extracted from both tumor (somatic) and normal (germline) tissue, with subsequent variant comparison to identify true somatic variants with potential impact on patient treatment or prognosis. However, challenges exist in paired tumor-normal testing, including increased cost of dual sample testing and identification of germline cancer predisposing variants. Alternatively, somatic variants can be identified by in silico tumor-only variant filtration precluding the need for matched normal testing...
December 18, 2018: Journal of Molecular Diagnostics: JMD
Guilin Tang, Shimin Hu, Sa A Wang, Wei Xie, Pei Lin, Jie Xu, Gokce Toruner, Ming Zhao, Jun Gu, Madison Doty, Shaoying Li, L Jeffrey Medeiros, Zhenya Tang
t(3;8)(q26.2;q24) is a rare recurrent cytogenetic abnormality that is associated with myeloid neoplasms. We report 20 patients with t(3;8)(q26.2,q24): eight had therapy-related acute myeloid leukemia (AML), three therapy-related myelodysplastic syndrome, four blast phase of chronic myeloid leukemia, one relapsed AML, one AML transformed from chronic myelomonocytic leukemia, one blast phase of an unclassifiable myeloproliferative neoplasm, one de novo myelodysplastic syndrome, and one de novo AML. Nineteen patients presented with cytopenia...
December 18, 2018: Journal of Molecular Diagnostics: JMD
Suk Wai Lam, David G P van IJzendoorn, Anne-Marie Cleton-Jansen, Karoly Szuhai, Judith V M G Bovée
Although classic histomorphology is the cornerstone of bone tumor diagnostics, this field has rapidly evolved since the advance of new molecular techniques. The identification of novel genetic alterations in bone tumors has led to more insight into the genetic background of these tumors, which resulted in a more prominent role of molecular pathology in daily practice. Numerous studies have been conducted in the last decades and illustrated that based on molecular alterations, bone tumors are roughly divided into tumors with simple and complex karyotypes...
December 17, 2018: Journal of Molecular Diagnostics: JMD
Viacheslav Y Fofanov, Kinnari Upadhyay, Alexander Pearlman, Johnny Loke, Vivian O, Yongzhao Shao, Stephen Freedland, Harry Ostrer
Prostate cancer is the most commonly diagnosed male cancer and the second leading cause of cancer deaths among men in the United States, with approximately 220,000 new diagnoses and approximately 27,000 deaths each year. Men with clinical low-risk disease can receive active surveillance to safely preserve quality of life, provided that the risk of an undetected aggressive cancer can be managed. Thus, prediction of a tumor's metastatic potential, ideally using only a biopsy sample, is critical to choosing appropriate treatment...
December 6, 2018: Journal of Molecular Diagnostics: JMD
Ling-Shan Yu, Jesus Rodriguez-Manzano, Kenny Malpartida-Cardenas, Thomas Sewell, Oliver Bader, Darius Armstrong-James, Matthew C Fisher, Pantelis Georgiou
Invasive human fungal infections caused by multi-azole resistant Aspergillus fumigatus are associated with increasing rates of mortality in susceptible patients. Current methods of diagnosing infections caused by multi-azole resistant A. fumigatus are, however, not well suited for use in clinical point-of-care testing or in the field. Loop-mediated isothermal amplification (LAMP) is a widely used method of nucleic acid amplification with rapid and easy-to-use features, making it suitable for use in different resource settings...
December 4, 2018: Journal of Molecular Diagnostics: JMD
Richard A Blidner, Brian C Haynes, Stephen Hyter, Sarah Schmitt, Ziyan Y Pessetto, Andrew K Godwin, Dan Su, Patrick Hurban, Léon C van Kempen, Maria L Aguirre, Shobha Gokul, Robyn D Cardwell, Gary J Latham
Lung cancer accounts for approximately 14% of all newly diagnosed cancers and is the leading cause of cancer-related deaths. Chimeric RNA resulting from gene fusions (RNA fusions) and other RNA splicing errors are driver events and clinically addressable targets for non-small-cell lung cancer (NSCLC). The reliable assessment of these RNA markers by next-generation sequencing requires integrated reagents, protocols, and interpretive software that can harmonize procedures and assure consistent results across laboratories...
December 4, 2018: Journal of Molecular Diagnostics: JMD
Dale Muzzey, Shera Kash, Jillian I Johnson, Laura M Melroy, Piotr Kaleta, Kelly A Pierce, Kaylene Ready, Hyunseok P Kang, Kevin R Haas
Clinical genomic tests increasingly utilize a next-generation sequencing (NGS) platform due in part to the high fidelity of variant calls, yet rare errors are still possible. In germline DNA screening, failure to correct such errors could have serious consequences for patients, who may follow an unwarranted screening or surgical-management path. It has been suggested that routine orthogonal confirmation via Sanger sequencing is required to verify NGS results, especially low-confidence positives with depressed allele fraction (<30% of alternate allele)...
December 4, 2018: Journal of Molecular Diagnostics: JMD
Miguel Alcaide, Matthew Cheung, Kevin Bushell, Sarah E Arthur, Hui-Li Wong, Joanna Karasinska, Daniel Renouf, David F Schaeffer, Suzan McNamara, Mathilde Couetoux du Tertre, Gerald Batist, Hagen F Kennecke, Aly Karsan, Ryan D Morin
Recurrent activating point mutations in KRAS are critical drivers in pancreatic cancer and have been attributed to resistance to anti-epidermal growth factor receptor therapy in colorectal cancer. Although KRAS genotyping provides limited clinical utility in the diagnosis and management of pancreatic cancer patients at present, inferences about the fractional abundance of KRAS mutations may inform on tumor purity in traditionally challenging clinical specimens and their potential use in precision medicine. KRAS genetic testing has indeed become an essential tool to guide treatment decisions in colorectal cancer, but there is an unmet need for methods standardization...
November 22, 2018: Journal of Molecular Diagnostics: JMD
James T Lu, Matthew Ferber, Jill Hagenkord, Elissa Levin, Sarah South, Hyunseok P Kang, Kimberly A Strong, David P Bick
The increasing quality and diminishing cost of next-generation sequencing has transformed our ability to interrogate large quantities of genetic information. This has led to a dramatic increase in the number of elective genomic tests performed. In this article elective test denotes a test that a patient chooses to undertake without a clinical indication. The variety of elective genomic testing options is considerable. Because these offerings provide differing levels of sensitivity and specificity it can be difficult to choose among them...
November 16, 2018: Journal of Molecular Diagnostics: JMD
Weihua Huang, Changhong Yin, Guiqing Wang, Jeremy Rosenblum, Sankaran Krishnan, Nevenka Dimitrova, John T Fallon
Compared to conventional serological, culture-, and molecular-based diagnostic tests, next-generation sequencing (NGS) provides sequence-evidenced detection of various microbes, without prior knowledge, and is thus becoming a novel diagnostic approach. We describe here a RNA-based metatranscriptomic NGS (mtNGS) protocol for culture-independent detection of potential infectious pathogens, using clinical bronchoalveolar lavage specimens as an example. We present both an optimized workflow for experimental sequence data collection and a simplified pipeline for bioinformatics sequence data processing...
October 30, 2018: Journal of Molecular Diagnostics: JMD
Jeong Eun Kim, Sung-Min Chun, Yong Sang Hong, Kyu-Pyo Kim, Sun Young Kim, Jihun Kim, Chang-Ohk Sung, Eun Jeong Cho, Tae Won Kim, Se Jin Jang
Next-generation sequencing (NGS) panels are widely used for defining tumor mutation profiles and determining treatment approaches. We performed targeted NGS with 382 genes in colorectal cancer with known microsatellite instability (MSI) status. After exclusion of germline alterations, load of somatic mutations and small insertion/deletion (indel) alterations were determined. In the test set, 79 patients with 41 microsatellite-stable (MSS) and 38 MSI tumors were included. There were 120 MSS and eight MSI-high tumors in the validation set...
October 30, 2018: Journal of Molecular Diagnostics: JMD
Jacqueline Maier, Thoralf Lange, Michael Cross, Kathrin Wildenberger, Dietger Niederwieser, Georg-Nikolaus Franke
Quantitative real-time PCR methods are commonly used to monitor BCR-ABL transcript levels in patients with chronic myelogenous leukemia. However, standard techniques involve separate measurements of target and reference DNAs, require standard curves, and are susceptible to PCR inhibition. An optimized duplex droplet digital PCR (ddPCR) should provide absolute quantification without the need for standard curves. The combination of high sensitivity and low background is particularly important for reliable monitoring of minimal residual disease...
October 19, 2018: Journal of Molecular Diagnostics: JMD
Michael J Kluk, Adam Bagg
This commentary highlights the article by Patel et al that reports a novel custom next-generation sequencing platform for fast detection of select genes in hematologic malignancies.
October 19, 2018: Journal of Molecular Diagnostics: JMD
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