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Next generation sequencing clinical

Davina Gale, Andrew R J Lawson, Karen Howarth, Mikidache Madi, Bradley Durham, Sarah Smalley, John Calaway, Shannon Blais, Greg Jones, James Clark, Peter Dimitrov, Michelle Pugh, Samuel Woodhouse, Michael Epstein, Ana Fernandez-Gonzalez, Alexandra S Whale, Jim F Huggett, Carole A Foy, Gerwyn M Jones, Hadas Raveh-Amit, Karin Schmitt, Alison Devonshire, Emma Green, Tim Forshew, Vincent Plagnol, Nitzan Rosenfeld
INTRODUCTION: Detection and monitoring of circulating tumor DNA (ctDNA) is rapidly becoming a diagnostic, prognostic and predictive tool in cancer patient care. A growing number of gene targets have been identified as diagnostic or actionable, requiring the development of reliable technology that provides analysis of multiple genes in parallel. We have developed the InVision™ liquid biopsy platform which utilizes enhanced TAm-Seq™ (eTAm-Seq™) technology, an amplicon-based next generation sequencing method for the identification of clinically-relevant somatic alterations at low frequency in ctDNA across a panel of 35 cancer-related genes...
2018: PloS One
Peng Yong Sim, V Swetha E Jeganathan, Alan F Wright, Peter Cackett
This case report depicts the clinical course of a female patient with unilateral retinitis pigmentosa, who first presented at the age of 12 years. Fundus photography at the time revealed unilateral pigmentary retinopathy, which was associated with extinguished electroretinogram (ERG) signal. At 35 years of age, fundus examination revealed deterioration of pre-existing unilateral pigmentary retinopathy with progressive visual field defect detected on Goldmann visual field testing. ERG findings remained unchanged and multifocal ERG showed unilateral decrease in amplitude in the affected eye...
March 15, 2018: BMJ Case Reports
Akira Inoue, Tsunekazu Mizushima, Xin Wu, Daisuke Okuzaki, Nanami Kambara, Sho Ishikawa, Jiaqi Wang, Yamin Qian, Haruka Hirose, Yuhki Yokoyama, Ryo Ikeshima, Masayuki Hiraki, Norikatsu Miyoshi, Hidekazu Takahashi, Naotsugu Haraguchi, Taishi Hata, Chu Matsuda, Yuichiro Doki, Masaki Mori, Hirofumi Yamamoto
We previously demonstrated that miR-29b-3p is a hopeful microRNA (miRNA)-based therapies against colorectal cancer (CRC). In this study, we aimed to clarify a value of miR-29b-1-5p as a next generation treatment, especially for KRAS mutant CRC. RT-PCR assay showed that expression of miR-29b-3p was high and its partner strand, miR-29b-1-5p level was only negligible in clinical CRC samples. Mimic-miR-29b-1-5p significantly inhibited proliferation of KRAS mutant CRC cell lines DLD1 and SW480 and KRAS wild type HT29 cells...
March 15, 2018: Molecular Cancer Therapeutics
Sofie Ellebæk Pollmann, Valerie S Calvert, Shruti Rao, Simina M Boca, Subha Madhavan, Ivan D Horak, Andreas Kjaer, Emanuel F Petricoin, Michael Kragh, Thomas Tuxen Poulsen
Failure of clinical trials due to development of resistance to MET-targeting therapeutic agents is an emerging problem. Mechanisms of acquired resistance to MET tyrosine kinase inhibitors are well described, whereas characterization of mechanisms of resistance toward MET-targeting antibodies is limited. This study investigated mechanisms underlying in vivo resistance to two antibody therapeutics currently in clinical development: an analogue of the MET-targeting antibody emibetuzumab and Sym015, a mixture of two antibodies targeting non-overlapping epitopes of MET...
March 15, 2018: Molecular Cancer Therapeutics
Hamid Reza Mirzaei, Hossein Pourghadamyari, Majid Rahmati, Abbas Mohammadi, Javid Sadri Nahand, Abbas Rezaei, Hamed Mirzaei, Jamshid Hadjati
Recently clinical trials utilizing genetically engineered T cells expressing a chimeric antigen receptor (CAR) that is half monoclonal antibody and half T-cell receptor have demonstrated remarkable response in patients with advanced cancers like relapsed or refractory acute lymphoblastic leukemia (ALL) and lymphoma. Moreover, emerging chimeric genome editing tools such as zinc-finger nucleases (ZNFs), transcription activator-like effector nucleases (TALENs) and clustered regulatory interspaced short palindromic repeat (CRISPR)/Cas composed of sequence-specific DNA binding module(s) linked to a non-specific DNA cleavage domain have made possible to dramatically expand the ability to manipulate cells aim to treat and/or study a wide range of diseases including cancer...
March 12, 2018: Cancer Letters
Júlia Perera-Bel, Barbara Hutter, Christoph Heining, Annalen Bleckmann, Martina Fröhlich, Stefan Fröhling, Hanno Glimm, Benedikt Brors, Tim Beißbarth
BACKGROUND: A comprehensive understanding of cancer has been furthered with technological improvements and decreasing costs of next-generation sequencing (NGS). However, the complexity of interpreting genomic data is hindering the implementation of high-throughput technologies in the clinical context: increasing evidence on gene-drug interactions complicates the task of assigning clinical significance to genomic variants. METHODS: Here we present a method that automatically matches patient-specific genomic alterations to treatment options...
March 15, 2018: Genome Medicine
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
Taigo Kato, Tatsuo Matsuda, Yuji Ikeda, Jae-Hyun Park, Matthias Leisegang, Sachiko Yoshimura, Tetsuro Hikichi, Makiko Harada, Makda Zewde, Sho Sato, Kosei Hasegawa, Kazuma Kiyotani, Yusuke Nakamura
Neoantigens are the main targets of tumor-specific T cells reactivated by immune checkpoint-blocking antibodies or when using tumor-infiltrating T cells for adoptive therapy. While cancers often accumulate hundreds of mutations and harbor several immunogenic neoantigens, the repertoire of mutation-specific T cells in patients might be restricted. To bypass suboptimal conditions, which impede the reactivation of existing T cells or the priming of neoantigen-specific T cells in a patient, we employ T cells of healthy donors with an overlapping HLA repertoire to target cancer neoantigens...
February 16, 2018: Oncotarget
Yan Hao, Dawei Chen, Zhiguo Zhang, Ping Zhou, Yunxia Cao, Zhaolian Wei, Xiaofeng Xu, Beili Chen, Weiwei Zou, Mingrong Lv, Dongmei Ji, Xiaojin He
Hearing loss may place a heavy burden on the patient and patient's family. Given the high incidence of hearing loss among newborns and the huge cost of treatment and care (including cochlear implantation), prenatal diagnosis is strongly recommended. Termination of the fetus may be considered as an extreme outcome to the discovery of a potential deaf fetus, and therefore preimplantation genetic diagnosis has become an important option for avoiding the birth of affected children without facing the risk of abortion following prenatal diagnosis...
April 2018: Oncology Letters
Matthew Dankner, April A N Rose, Shivshankari Rajkumar, Peter M Siegel, Ian R Watson
The RAS-RAF-MEK-ERK signaling cascade is among the most frequently mutated pathways in human cancer. Approximately 50% of melanoma patients possess a druggable hotspot V600E/K mutation in the BRAF protein kinase. FDA-approved combination therapies of BRAF and MEK inhibitors are available that provide survival benefits to patients with a BRAF V600 mutation. Non-V600 BRAF mutants are found in many cancers, and are more prevalent than V600 mutations in certain tumor types. For example, between 50-80% of BRAF mutations in non-small cell lung cancer and 22-30% in colorectal cancer encode for non-V600 mutants...
March 15, 2018: Oncogene
James H Suh, Alexa B Schrock, Adrienne Johnson, Doron Lipson, Laurie M Gay, Shakti Ramkissoon, Jo-Anne Vergilio, Julia A Elvin, Abdur Shakir, Peter Ruehlman, Karen L Reckamp, Sai-Hong Ignatius Ou, Jeffrey S Ross, Philip J Stephens, Vincent A Miller, Siraj M Ali
BACKGROUND: In our recent study, of cases positive for epidermal growth factor receptor ( EGFR ) exon 19 deletions using comprehensive genomic profiling (CGP), 17/77 (22%) patients with prior standard of care (SOC) EGFR testing results available were previously negative for exon 19 deletion. Our aim was to compare the detection rates of CGP versus SOC testing for well-characterized sensitizing EGFR point mutations (pm) in our 6,832-patient cohort. MATERIALS AND METHODS: DNA was extracted from 40 microns of formalin-fixed paraffin-embedded sections from 6,832 consecutive cases of non-small cell lung cancer (NSCLC) of various histologies (2012-2015)...
March 14, 2018: Oncologist
Linda R Wang, Adam D McIntyre, Robert A Hegele
BACKGROUND: Abetalipoproteinemia and homozygous hypobetalipoproteinemia are classical Mendelian autosomal recessive and co-dominant conditions, respectively, which are phenotypically similar and are usually caused by bi-allelic mutations in MTTP and APOB genes, respectively. Instances of more complex patterns of genomic variants resulting in this distinct phenotype have not been reported. METHODS: A 43 year-old male had a longstanding severe deficiency of apolipoprotein (apo) B-containing lipoproteins and circulating fat soluble vitamins consistent with either abetalipoproteinemia or homozygous familial hypobetalipoproteinemia (FHBL)...
March 14, 2018: Lipids in Health and Disease
F Pietrantonio, F Di Nicolantonio, A B Schrock, J Lee, F Morano, G Fucà, P Nikolinakos, A Drilon, J F Hechtman, J Christiansen, K Gowen, G M Frampton, P Gasparini, D Rossini, C Gigliotti, S T Kim, M Prisciandaro, J Hodgson, A Zaniboni, V K Chiu, M Milione, R Patel, V Miller, A Bardelli, L Novara, L Wang, S Pupa, G Sozzi, J Ross, M Di Bartolomeo, A Bertotti, S Ali, L Trusolino, A Falcone, F de Braud, C Cremolini
Background: Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC). Patients and methods: In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors...
March 10, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Lara Kujtan, Arif Hussain, Janakiraman Subramanian, Ashiq Masood
PURPOSE OF REVIEW: Recent advances in next-generation sequencing have allowed for detailed molecular analysis of urothelial carcinomas, with potentially significant clinical implications for personalized treatment. Our objective in this review is to highlight studies from the past year that have furthered the understanding of urothelial cancer genomics. RECENT FINDINGS: Recent studies by The Cancer Genome Atlas consortium further characterized urothelial carcinomas via molecular subtyping, and a schema was proposed to match each subtype with potential therapeutic implications...
March 13, 2018: Current Opinion in Oncology
Zehra Aycan, Şenay Savaş-Erdeve, Semra Çetinkaya, Erdal Kurnaz, Melikşah Keskin, Nursel Muratoğlu Şahin, Elvan Bayramoğlu, Gülay Ceylaner
OBJECTIVE: Little is known about the genetic cause of idiopathic central precocious puberty (CPP). The aim of this clinical study was to determine the rate of MKRN3 mutation in cases of familial idiopathic central precocious puberty. METHODS: Potential sequence variations in the maternally imprinted MKRN3 gene were evaluated in 19 participants from 10 families using next-generation sequencing (NGS) analysis. RESULTS: In the whole group, the novel heterozygous mutation NM_005664...
February 28, 2018: Journal of Clinical Research in Pediatric Endocrinology
Ping Hu, Fengchang Qiao, Yan Wang, Lulu Meng, Xiuqing Ji, Chunyu Luo, Tianhui Xu, Ran Zhou, Jingjing Zhang, Bin Yu, Leilei Wang, Ting Wang, Qiong Pan, Dingyuan Ma, Dong Liang, Zhengfeng Xu
OBJECTIVES: This study aimed to determine the diagnostic yield of targeted next-generation sequencing (NGS) in prenatal diagnosis of congenital heart defects (CHDs) and for investigating the possible genetic etiology of prenatal CHD cases. METHODS: Forty-four fetuses with CHDs and normal molecular karyotypes underwent targeted NGS in this study. Fetal genomic DNA was directly extracted from amniotic fluid cells in each prenatal case. A customized targeted NGS panel containing 77 CHD-associated genes was designed to detect variants in the coding regions and the splicing sites of these genes...
March 13, 2018: Ultrasound in Obstetrics & Gynecology
Giorgia Acquaviva, Michela Visani, Dario de Biase, Gianluca Marucci, Enrico Franceschi, Alicia Tosoni, Alba A Brandes, Kerry J Rhoden, Annalisa Pession, Giovanni Tallini
IDH mutational status is required for proper diagnosis according to the WHO criteria revised in 2016. The single nucleotide polymorphism (SNP) rs11554137 (IDH1105GGT ) at codon 105 of IDH1 has been reported in patients with several tumor types, including those with glioma. The aim of this study is to investigate the prevalence of IDH1105GGT in a cohort of brain tumors, and its association with clinicopathologic features and IDH1 and IDH2 missense mutations. Exon 4 of IDH1 and IDH2 was analyzed in a series of brain tumors classified according to current WHO criteria...
March 13, 2018: Scientific Reports
Caterina Fumagalli, Davide Vacirca, Alessandra Rappa, Antonio Passaro, Juliana Guarize, Paola Rafaniello Raviele, Filippo de Marinis, Lorenzo Spaggiari, Chiara Casadio, Giuseppe Viale, Massimo Barberis, Elena Guerini-Rocco
BACKGROUND: Molecular profiling of advanced non-small cell lung cancers (NSCLC) is essential to identify patients who may benefit from targeted treatments. In the last years, the number of potentially actionable molecular alterations has rapidly increased. Next-generation sequencing allows for the analysis of multiple genes simultaneously. AIMS: To evaluate the feasibility and the throughput of next-generation sequencing in clinical molecular diagnostics of advanced NSCLC...
March 13, 2018: Journal of Clinical Pathology
J R Bowers, K L Parise, E J Kelley, D Lemmer, J M Schupp, E M Driebe, D M Engelthaler, P Keim, B M Barker
Coccidioides immitis and Coccidioides posadasii are soil fungi endemic to desert regions of the southwestern United States, and the causative agents of valley fever, or coccidioidomycosis. Studies have shown that the distribution of Coccidioides in soils is sporadic and cannot be explained by soil characteristics alone, suggesting that biotic and other abiotic factors should be examined. However, tools to reliably and robustly screen the large number of soils needed to investigate these potential associations have not been available...
March 8, 2018: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
You-Hong Fang, You-You Luo, Jin-Dan Yu, Jin-Gan Lou, Jie Chen
AIM: To analyze clinical differences between monogenic and nonmonogenic very-early-onset inflammatory bowel disease (VEO-IBD) and to characterize monogenic IBD phenotypically and genotypically via genetic testing. METHODS: A retrospective analysis of children aged 0 to 6 years diagnosed with VEO-IBD in a tertiary hospital in southern China from 2005 to 2017 was performed. Clinical data for VEO-IBD patients were collected, and genetic characteristics were analyzed using whole exome sequencing or target gene panel sequencing...
March 7, 2018: World Journal of Gastroenterology: WJG
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