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1
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Lu W, Zhou Q, Chen Y. Impact of RNA degradation on next-generation sequencing transcriptome data. Genomics 2022; 114:110429. [PMID: 35810931 DOI: 10.1016/j.ygeno.2022.110429] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 06/16/2022] [Accepted: 07/06/2022] [Indexed: 11/04/2022]
Abstract
RNA sequencing is an innovative technology to study transcriptomes in both biological and clinical research. However, clinical specimens from patients undergoing surgical operations have a major challenge due to sample degradation. This study replicated the process of RNA degradation by maintaining cells at room temperature to achieve none, slight, middle, and high levels of RNA degradation with decreasing RNA integrity numbers (RIN) of approximately 9.8, 6.7, 4.4, and 2.5, respectively. Next, the differential expression of mRNA and long non-coding RNA (lncRNA) was analyzed in the four degradation groups along with pathway enrichment analysis. The results showed that the similarity of lncRNAs exhibited significant differences even for a slight level of RNA degradation compared with the non-degraded RNA sample. Also, the RNA degradation process was found to be universal, global, and random; the differentially expressed genes increased with an increase in degradation but the pathway enrichment phenomenon was not significantly observed.
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Affiliation(s)
- Wenxiang Lu
- State Key Lab of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu 210096, China
| | - Qin Zhou
- Department of Obstetrics and Gynecology, Kunshan Hospital of Traditional Chinese Medicine, Kunshan 215300, China
| | - Yi Chen
- Department of Obstetrics and Gynecology, Kunshan Hospital of Traditional Chinese Medicine, Kunshan 215300, China.
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2
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Targeted next generation sequencing of parotid gland cancer uncovers genetic heterogeneity. Oncotarget 2016; 6:18224-37. [PMID: 26053092 PMCID: PMC4627247 DOI: 10.18632/oncotarget.4015] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Accepted: 05/14/2015] [Indexed: 12/12/2022] Open
Abstract
Salivary gland cancer represents a heterogeneous group of malignant tumors. Due to their low incidence and the existence of multiple morphologically defined subtypes, these tumors are still poorly understood with regard to their molecular pathogenesis and therapeutically relevant genetic alterations. Performing a systematic and comprehensive study covering 13 subtypes of salivary gland cancer, next generation sequencing was done on 84 tissue samples of parotid gland cancer using multiplex PCR for enrichment of cancer related gene loci covering hotspots of 46 cancer genes. Mutations were identified in 22 different genes. The most frequent alterations affected TP53, followed by RAS genes, PIK3CA, SMAD4 and members of the ERB family. HRAS mutations accounted for more than 90% of RAS mutations, occurring especially in epithelial-myoepithelial carcinomas and salivary duct carcinomas. Additional mutations in PIK3CA also affected particularly epithelial-myoepithelial carcinomas and salivary duct carcinomas, occurring simultaneously with HRAS mutations in almost all cases, pointing to an unknown and therapeutically relevant molecular constellation. Interestingly, 14% of tumors revealed mutations in surface growth factor receptor genes including ALK, HER2, ERBB4, FGFR, cMET and RET, which might prove to be targetable by new therapeutic agents. 6% of tumors revealed mutations in SMAD4. In summary, our data provide novel insight into the fundamental molecular heterogeneity of salivary gland cancer, relevant in terms of tumor classification and the establishment of targeted therapeutic concepts.
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Ellis HP, Greenslade M, Powell B, Spiteri I, Sottoriva A, Kurian KM. Current Challenges in Glioblastoma: Intratumour Heterogeneity, Residual Disease, and Models to Predict Disease Recurrence. Front Oncol 2015; 5:251. [PMID: 26636033 PMCID: PMC4644939 DOI: 10.3389/fonc.2015.00251] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 10/29/2015] [Indexed: 12/27/2022] Open
Abstract
Glioblastoma (GB) is the most common primary malignant brain tumor, and despite the availability of chemotherapy and radiotherapy to combat the disease, overall survival remains low with a high incidence of tumor recurrence. Technological advances are continually improving our understanding of the disease, and in particular, our knowledge of clonal evolution, intratumor heterogeneity, and possible reservoirs of residual disease. These may inform how we approach clinical treatment and recurrence in GB. Mathematical modeling (including neural networks) and strategies such as multiple sampling during tumor resection and genetic analysis of circulating cancer cells, may be of great future benefit to help predict the nature of residual disease and resistance to standard and molecular therapies in GB.
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Affiliation(s)
- Hayley P Ellis
- Brain Tumour Research Group, Institute of Clinical Neurosciences, University of Bristol , Bristol , UK
| | - Mark Greenslade
- Bristol Genetics Laboratory, North Bristol NHS Trust , Bristol , UK
| | - Ben Powell
- School of Mathematics, University of Bristol , Bristol , UK
| | - Inmaculada Spiteri
- Centre for Evolution and Cancer, The Institute of Cancer Research , London , UK
| | - Andrea Sottoriva
- Centre for Evolution and Cancer, The Institute of Cancer Research , London , UK
| | - Kathreena M Kurian
- Brain Tumour Research Group, Institute of Clinical Neurosciences, University of Bristol , Bristol , UK
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Breveglieri G, Finotti A, Borgatti M, Gambari R. Recent patents and technology transfer for molecular diagnosis of β-thalassemia and other hemoglobinopathies. Expert Opin Ther Pat 2015; 25:1453-76. [PMID: 26413795 DOI: 10.1517/13543776.2015.1090427] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
INTRODUCTION Biological tests and genetic analyses for diagnosis and characterization of hematological diseases in health laboratories are designed with the aim of meeting the major medical needs of hospitals and pharmaceutical companies involved in this field of applied biomedicine. Genetic testing approaches to perform diagnosis consist of molecular techniques, which should be absolutely reproducible, fast, sensitive, cheap, and portable. AREAS COVERED Biological tests analyzed involve adult/newborn subjects, whereas genetic analyses involve adult thalassemia patients, newborns, embryos/fetuses (including non-invasive prenatal diagnosis), pre-implantation embryos, and pre-fertilization oocytes. EXPERT OPINION The most recent findings in the diagnostic approach for β-thalassemias are related to three major fields of investigation: moving towards ultrasensitive methodologies for effective detection of the primary causative mutation of β-thalassemia, including the development of polymerase chain reaction-free approaches and non-invasive prenatal diagnosis; comparing analyses of the genotype of β-thalassemia patients to high-HbF-associated polymorphisms; introducing whole genome association assays and next-generation sequencing. All these issues should be considered and discussed in the context of several aspects, including regulatory, ethical and social issues. DNA sequence data aligned with the identification of genes central to the induction, development, progression, and outcome of β-thalassemia will be a key point for directing personalized therapy.
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Affiliation(s)
- Giulia Breveglieri
- a 1 University of Ferrara, Section of Biochemistry and Molecular Biology, Department of Life Sciences and Biotechnology , Ferrara, Italy
| | - Alessia Finotti
- a 1 University of Ferrara, Section of Biochemistry and Molecular Biology, Department of Life Sciences and Biotechnology , Ferrara, Italy
| | - Monica Borgatti
- a 1 University of Ferrara, Section of Biochemistry and Molecular Biology, Department of Life Sciences and Biotechnology , Ferrara, Italy
| | - Roberto Gambari
- b 2 University of Ferrara, Section of Biochemistry and Molecular Biology, Department of Life Sciences and Biotechnology , Via Fossato di Mortara 74, 44121 Ferrara, Italy +39 05 32 97 44 43 ; +39 05 32 97 45 00 ;
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Petric RC, Pop LA, Jurj A, Raduly L, Dumitrascu D, Dragos N, Neagoe IB. Next generation sequencing applications for breast cancer research. ACTA ACUST UNITED AC 2015; 88:278-87. [PMID: 26609257 PMCID: PMC4632883 DOI: 10.15386/cjmed-486] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 06/26/2015] [Accepted: 06/30/2015] [Indexed: 12/19/2022]
Abstract
For some time, cancer has not been thought of as a disease, but as a multifaceted, heterogeneous complex of genotypic and phenotypic manifestations leading to tumorigenesis. Due to recent technological progress, the outcome of cancer patients can be greatly improved by introducing in clinical practice the advantages brought about by the development of next generation sequencing techniques. Biomedical suppliers have come up with various applications which medical researchers can use to characterize a patient’s disease from molecular and genetic point of view in order to provide caregivers with rapid and relevant information to guide them in choosing the most appropriate course of treatment, with maximum efficiency and minimal side effects. Breast cancer, whose incidence has risen dramatically, is a good candidate for these novel diagnosis and therapeutic approaches, particularly when referring to specific sequencing panels which are designed to detect germline or somatic mutations in genes that are involved in breast cancer tumorigenesis and progression. Benchtop next generation sequencing machines are becoming a more common presence in the clinical setting, empowering physicians to better treat their patients, by offering early diagnosis alternatives, targeted remedies, and bringing medicine a step closer to achieving its ultimate goal, personalized therapy.
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Affiliation(s)
- Roxana Cojocneanu Petric
- Functional Genomics, Proteomics and Experimental Pathology Department, Prof. Dr. I. Chiricuta Oncology Institute, Cluj-Napoca, Romania ; Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania ; Faculty of Biology and Geology, Babes Bolyai Univesity, Cluj-Napoca, Romania
| | - Laura-Ancuta Pop
- Functional Genomics, Proteomics and Experimental Pathology Department, Prof. Dr. I. Chiricuta Oncology Institute, Cluj-Napoca, Romania ; Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ancuta Jurj
- Functional Genomics, Proteomics and Experimental Pathology Department, Prof. Dr. I. Chiricuta Oncology Institute, Cluj-Napoca, Romania
| | - Lajos Raduly
- Functional Genomics, Proteomics and Experimental Pathology Department, Prof. Dr. I. Chiricuta Oncology Institute, Cluj-Napoca, Romania ; University of Agricultural Sciences and Veterinary Medicine, Cluj-Napoca, Romania
| | - Dan Dumitrascu
- 2nd Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Nicolae Dragos
- Taxonomy and Ecology Department, NIRDBS - Institute of Biological Research, Cluj-Napoca, Romania
| | - Ioana Berindan Neagoe
- Functional Genomics, Proteomics and Experimental Pathology Department, Prof. Dr. I. Chiricuta Oncology Institute, Cluj-Napoca, Romania ; Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania ; Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, Texas, USA ; Department of Immunology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Hashmi U, Shafqat S, Khan F, Majid M, Hussain H, Kazi AG, John R, Ahmad P. Plant exomics: concepts, applications and methodologies in crop improvement. PLANT SIGNALING & BEHAVIOR 2015; 10:e976152. [PMID: 25482786 PMCID: PMC4622497 DOI: 10.4161/15592324.2014.976152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2014] [Revised: 08/17/2014] [Accepted: 08/18/2014] [Indexed: 05/17/2023]
Abstract
Molecular breeding has a crucial role in improvement of crops. Conventional breeding techniques have failed to ameliorate food production. Next generation sequencing has established new concepts of molecular breeding. Exome sequencing has proven to be a significant tool for assessing natural evolution in plants, studying host pathogen interactions and betterment of crop production as exons assist in interpretation of allelic variation with respect to their phenotype. This review covers the platforms for exome sequencing, next generation sequencing technologies that have revolutionized exome sequencing and led toward development of third generation sequencing. Also discussed in this review are the uses of these sequencing technologies to improve wheat, rice and cotton yield and how these technologies are used in exploring the biodiversity of crops, providing better understanding of plant-host pathogen interaction and assessing the process of natural evolution in crops and it also covers how exome sequencing identifies the gene pool involved in symbiotic and other co-existential systems. Furthermore, we conclude how integration of other methodologies including whole genome sequencing, proteomics, transcriptomics and metabolomics with plant exomics covers the areas which are left untouched with exomics alone and in the end how these integration will transform the future of crops.
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Key Words
- BAC, bacterial artificial chromosome
- BGR, bacterial grain rot
- CBOL, consortium for 860 the barcode of life
- ETI, effector-triggered immunity
- HPRT, hypoxanthineguanine phosphoribosyl transferase
- MMs, molecular markers
- NGS, next generation sequencing
- NITSR, nuclear internal transcribed spacer region
- OPC, open promoter complex
- QTL, quantitative trait locus
- SMRT, single molecule real time
- SNPs, single nucleotide poly-morphisms
- SOLiD, sequencing by oligonucleotide ligation and detection
- WES, whole exome sequencing
- WGS, whole genome sequencing
- WGS, whole genome shotgun
- biodiversity
- crop improvement
- dNMPs, deoxyribosenucleoside monophosphates
- exome sequencing
- plant biotechnology
- plant-host pathogen interactions
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Affiliation(s)
- Uzair Hashmi
- Atta ur Rahman School of Applied Biosciences; National University of Sciences and Technology; Islamabad, Pakistan
| | - Samia Shafqat
- Atta ur Rahman School of Applied Biosciences; National University of Sciences and Technology; Islamabad, Pakistan
| | - Faria Khan
- Atta ur Rahman School of Applied Biosciences; National University of Sciences and Technology; Islamabad, Pakistan
| | - Misbah Majid
- Atta ur Rahman School of Applied Biosciences; National University of Sciences and Technology; Islamabad, Pakistan
| | - Harris Hussain
- Atta ur Rahman School of Applied Biosciences; National University of Sciences and Technology; Islamabad, Pakistan
| | - Alvina Gul Kazi
- Atta ur Rahman School of Applied Biosciences; National University of Sciences and Technology; Islamabad, Pakistan
| | - Riffat John
- Department of Botany; University of Kashmir; Jammu and Kashmir, India
| | - Parvaiz Ahmad
- Department of Botany; S.P. College Srinagar; Jammu and Kashmir, India
- Correspondence to: Parvaiz Ahmad;
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Abstract
PURPOSE OF REVIEW Next generation sequencing (NGS) allows the rapid analysis of genomes and has brought invaluable information on cancer biology and drug targets. Laboratories have started to provide NGS data to physicians to aid in the prescription of targeted drugs. The review presents the recent clinical experience with NGS. RECENT FINDINGS Clinical studies support the potential of NGS to tailor the treatment of patients to alterations in their cancer genome in a process called precision medicine. Case reports, analyses of early phase trials, and series of lung cancer patients have recently shown superior outcome for the matching of drug to specific molecular alterations. NGS is also useful to detect germline mutations associated with hereditary cancers. SUMMARY NGS and other molecular technologies are transforming the practice of medical oncology and clinical research. Sequencing of primary tumors, metastases, or blood-derived circulating tumor DNA has great potential to guide individualized cancer treatment. However, the integration of NGS as a breakthrough technology is associated with operational challenges such as information processing, medical education and interpretation, and reimbursement.
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Ciombor KK, Haraldsdottir S, Goldberg RM. How Can Next-Generation Sequencing (Genomics) Help Us in Treating Colorectal Cancer? CURRENT COLORECTAL CANCER REPORTS 2014; 10:372-379. [PMID: 25395895 DOI: 10.1007/s11888-014-0244-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Next generation sequencing methods have exponentially increased the amount of genomic information available to scientists and clinicians. This review will explain the evolution of tumor gene sequencing and identify its potential to accelerate therapeutic progress by using colorectal cancer to illustrate the benefits of this type of analysis. A milestone in sequencing occurred when The Cancer Genome Atlas investigators characterized the genomes of 276 colorectal cancer samples, with the resulting information expected to provide future clinical applications and help to guide the treatment of colorectal cancer. Data regarding colorectal cancer mutational frequencies, prognostic and predictive biomarker usefulness, and signaling pathway alterations are emerging from various next generation sequencing platforms. Next generation sequencing methods are also enhancing our understanding of the causes and consequences of both the chromosomal instability and microsatellite instability pathways, as well as expanding our knowledge of the origins of familial colorectal cancer. Limitations to next generation sequencing methods include the need for storage and analysis of massive quantities of data, as well as assurance that the data is of the highest possible quality. However, this genomic technology carries with it the potential to revolutionize our treatment of colorectal cancer patients through better understanding of the underlying disease biology and subsequent development and application of therapeutic approaches targeting the genetic abnormalities specific to individual malignancies.
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Affiliation(s)
- Kristen K Ciombor
- Division of Medical Oncology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Sigurdis Haraldsdottir
- Division of Medical Oncology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Richard M Goldberg
- Division of Medical Oncology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH
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Kononova SK, Sidorova OG, Fedorova SA, Platonov FA, Izhevskaya VL, Khusnutdinova EK. Bioethical issues of preventing hereditary diseases with late onset in the Sakha Republic (Yakutia). Int J Circumpolar Health 2014; 73:25062. [PMID: 25147769 PMCID: PMC4111875 DOI: 10.3402/ijch.v73.25062] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 06/30/2014] [Accepted: 07/02/2014] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Prenatal diagnosis of congenital and hereditary diseases is a priority for the development of medical technologies in Russia. However, there are not many published research results on bioethical issues of prenatal DNA testing. OBJECTIVE The main goal of the article is to describe some of the bioethical aspects of prenatal DNA diagnosis of hereditary diseases with late onset in genetic counselling practice in the Sakha Republic (Yakutia) - a far north-eastern region of Russia. METHODS The methods used in the research are genetic counselling, invasive chorionic villus biopsy procedures, molecular diagnosis, social and demographic characteristics of patients. RESULTS In 10 years, 48 (76%) pregnant women from families tainted with hereditary spinocerebellar ataxia type 1 and 15 pregnant women from families with myotonic dystrophy have applied for medical and genetic counselling in order to undergo prenatal DNA testing. The average number of applications is 7-8 per year. There are differences in prenatal genetic counselling approaches. CONCLUSION It is necessary to develop differentiated ethical approaches depending on the mode of inheritance, age of manifestation, and clinical polymorphism of hereditary disease.
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Affiliation(s)
- Sardana K. Kononova
- Yakutsk Scientific Center of Complex Medical Problems, Siberian Branch of the Russian Academy of Medical Sciences, Yakutsk, Russia
- Institute of Natural Sciences, M. K. Ammosov North-Eastern Federal University, Yakutsk, Russia
| | - Oksana G. Sidorova
- Yakutsk Scientific Center of Complex Medical Problems, Siberian Branch of the Russian Academy of Medical Sciences, Yakutsk, Russia
| | - Sardana A. Fedorova
- Yakutsk Scientific Center of Complex Medical Problems, Siberian Branch of the Russian Academy of Medical Sciences, Yakutsk, Russia
- Institute of Natural Sciences, M. K. Ammosov North-Eastern Federal University, Yakutsk, Russia
| | - Fedor A. Platonov
- Institute of Natural Sciences, M. K. Ammosov North-Eastern Federal University, Yakutsk, Russia
| | - Vera L. Izhevskaya
- Research Centre for Medical Genetics of the Russian Academy of Medical Sciences, Moscow, Russia
| | - Elza K. Khusnutdinova
- Institute for Biochemistry and Genetics, Ufa Scientific Centre of the Russian Academy of Sciences, Ufa, Russia
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Cheng DT, Cheng J, Mitchell TN, Syed A, Zehir A, Mensah NYT, Oultache A, Nafa K, Levine RL, Arcila ME, Berger MF, Hedvat CV. Detection of mutations in myeloid malignancies through paired-sample analysis of microdroplet-PCR deep sequencing data. J Mol Diagn 2014; 16:504-518. [PMID: 25017477 DOI: 10.1016/j.jmoldx.2014.05.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 04/24/2014] [Accepted: 05/09/2014] [Indexed: 01/10/2023] Open
Abstract
Amplicon-based methods for targeted resequencing of cancer genes have gained traction in the clinic as a strategy for molecular diagnostic testing. An 847-amplicon panel was designed with the RainDance DeepSeq system, covering most exons of 28 genes relevant to acute myeloid leukemia and myeloproliferative neoplasms. We developed a paired-sample analysis pipeline for variant calling and sought to assess its sensitivity and specificity relative to a set of samples with previously identified mutations. Thirty samples with known mutations in JAK2, NPM1, DNMT3A, MPL, IDH1, IDH2, CEBPA, and FLT3, were profiled and sequenced to high depth. Variant calling using an unmatched Hapmap DNA control removed a substantial number of artifactual calls regardless of algorithm used or variant class. The removed calls were nonunique, had lower variant frequencies, and tended to recur in multiple unrelated samples. Analysis of sample replicates revealed that reproducible calls had distinctly higher variant allele depths and frequencies compared to nonreproducible calls. On the basis of these differences, filters on variant frequency were chosen to select for reproducible calls. The analysis pipeline successfully retrieved the associated known variant in all tested samples and uncovered additional mutations in some samples corresponding to well-characterized hotspot mutations in acute myeloid leukemia. We have developed a paired-sample analysis pipeline capable of robust identification of mutations from microdroplet-PCR sequencing data with high sensitivity and specificity.
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Affiliation(s)
- Donavan T Cheng
- Molecular Diagnostics Service, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
| | - Janice Cheng
- Molecular Diagnostics Service, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Talia N Mitchell
- Molecular Diagnostics Service, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Aijazuddin Syed
- Molecular Diagnostics Service, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Ahmet Zehir
- Molecular Diagnostics Service, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Nana Yaa T Mensah
- Molecular Diagnostics Service, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Alifya Oultache
- Molecular Diagnostics Service, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Khedoudja Nafa
- Molecular Diagnostics Service, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Ross L Levine
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Maria E Arcila
- Molecular Diagnostics Service, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Michael F Berger
- Molecular Diagnostics Service, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Cyrus V Hedvat
- Molecular Diagnostics Service, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
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De Mattos-Arruda L, Bidard FC, Won HH, Cortes J, Ng CKY, Peg V, Nuciforo P, Jungbluth AA, Weigelt B, Berger MF, Seoane J, Reis-Filho JS. Establishing the origin of metastatic deposits in the setting of multiple primary malignancies: the role of massively parallel sequencing. Mol Oncol 2014; 8:150-8. [PMID: 24220311 PMCID: PMC5528499 DOI: 10.1016/j.molonc.2013.10.006] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Revised: 10/08/2013] [Accepted: 10/11/2013] [Indexed: 01/03/2023] Open
Abstract
In this proof-of-principle study, we sought to define whether targeted capture massively parallel sequencing can be employed to determine the origin of metastatic deposits in cases of synchronous primary malignancies and metastases in distinct anatomical sites. DNA samples extracted from synchronous tumor masses in the breast, adnexal, and pelvic-peritoneal regions from a 62-year-old BRCA1 germline mutation carrier were subjected to targeted massively parallel sequencing using a platform comprising 300 cancer genes known to harbor actionable mutations. In addition to BRCA1 germline mutations, all lesions harbored somatic loss of the BRCA1 wild-type allele and TP53 somatic mutations. The primary breast cancer displayed a TP53 frameshift (p.Q317fs) mutation, whereas and the adnexal lesion harbored a TP53 nonsense (p.R213*) mutation, consistent with a diagnosis of two independent primary tumors (i.e. breast and ovarian cancer). The adnexal tumor and all pelvic-peritoneal implants harbored identical TP53 (p.R213*) and NCOA2 (p.G952R) somatic mutations. Evidence of genetic heterogeneity within and between lesions was observed, both in terms of somatic mutations and copy number aberrations. The repertoires of somatic genetic aberrations found in the breast, ovarian, and pelvic-peritoneal lesions provided direct evidence in support of the distinct origin of the breast and ovarian cancers, and established that the pelvic-peritoneal implants were clonally related to the ovarian lesion. These observations were consistent with those obtained with immunohistochemical analyses employing markers to differentiate between carcinomas of the breast and ovary, including WT1 and PAX8. Our results on this case of a patient with BRCA1-mutant breast and ovarian cancer demonstrate that massively parallel sequencing may constitute a useful tool to define the relationship, clonality and intra-tumor genetic heterogeneity between primary tumor masses and their metastatic deposits in patients with multiple primary malignancies and synchronous metastases.
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Affiliation(s)
- Leticia De Mattos-Arruda
- Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Francois-Clement Bidard
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Department of Medical Oncology, Institut Curie, Paris, France
| | - Helen H Won
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Javier Cortes
- Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain; Medica Scientia Innovation Research (MedSIR), Barcelona, Spain
| | - Charlotte K Y Ng
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Vicente Peg
- Universitat Autònoma de Barcelona, Barcelona, Spain; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Paolo Nuciforo
- Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Achim A Jungbluth
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Britta Weigelt
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Michael F Berger
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Joan Seoane
- Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
| | - Jorge S Reis-Filho
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
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12
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Affiliation(s)
- Joanne Mason
- West Midlands Regional Genetics Laboratory, Birmingham Women’s NHS Foundation Trust, Edgbaston, Birmingham, B15 2TG, UK
| | - Michael Griffiths
- West Midlands Regional Genetics Laboratory, Birmingham Women’s NHS Foundation Trust, Edgbaston, Birmingham, B15 2TG, UK
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13
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Viray H, Li K, Long TA, Vasalos P, Bridge JA, Jennings LJ, Halling KC, Hameed M, Rimm DL. A Prospective, Multi-Institutional Diagnostic Trial to Determine Pathologist Accuracy in Estimation of Percentage of Malignant Cells. Arch Pathol Lab Med 2013; 137:1545-9. [DOI: 10.5858/arpa.2012-0561-cp] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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14
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Jones MA, Rhodenizer D, da Silva C, Huff IJ, Keong L, Bean LJH, Coffee B, Collins C, Tanner AK, He M, Hegde MR. Molecular diagnostic testing for congenital disorders of glycosylation (CDG): detection rate for single gene testing and next generation sequencing panel testing. Mol Genet Metab 2013; 110:78-85. [PMID: 23806237 DOI: 10.1016/j.ymgme.2013.05.012] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 05/20/2013] [Accepted: 05/20/2013] [Indexed: 11/19/2022]
Abstract
Congenital disorders of glycosylation (CDG) are comprised of over 60 disorders with the majority of defects residing within the N-glycosylation pathway. Approximately 20% of patients do not survive beyond five years of age due to widespread organ dysfunction. A diagnosis of CDG is based on abnormal glycosylation of transferrin but this method cannot identify the specific gene defect. For many individuals diagnosed with CDG the gene defect remains unknown. To improve the molecular diagnosis of CDG we developed molecular testing for 25 CDG genes including single gene testing and next generation sequencing (NGS) panel testing. From March 2010 through November 2012, a total of 94 samples were referred for single gene testing and 68 samples were referred for NGS panel testing. Disease causing mutations were identified in 24 patients resulting in a molecular diagnosis rate of 14.8%. Coverage of the 24 CDG genes using panel testing and whole exome sequencing (WES) was compared and it was determined that many exons of these genes were not adequately covered using a WES approach and a panel approach may be the preferred first option for CDG patients. A collaborative effort between physicians, researchers and diagnostic laboratories will be very important as NGS testing using panels and exome becomes more widespread. This technology will ultimately improve the molecular diagnosis of patients with CDG in hard to solve cases.
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Affiliation(s)
- Melanie A Jones
- Emory Genetics Laboratory, 2165 N. Decatur Road, Decatur, GA 30033, USA.
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15
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Cheng L, Quek CYJ, Sun X, Bellingham SA, Hill AF. The detection of microRNA associated with Alzheimer's disease in biological fluids using next-generation sequencing technologies. Front Genet 2013; 4:150. [PMID: 23964286 PMCID: PMC3737441 DOI: 10.3389/fgene.2013.00150] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Accepted: 07/21/2013] [Indexed: 02/06/2023] Open
Abstract
Diagnostic tools for neurodegenerative diseases such as Alzheimer's disease (AD) currently involve subjective neuropsychological testing and specialized brain imaging techniques. While definitive diagnosis requires a pathological brain evaluation at autopsy, neurodegenerative changes are believed to begin years before the clinical presentation of cognitive decline. Therefore, there is an essential need for reliable biomarkers to aid in the early detection of disease in order to implement preventative strategies. microRNAs (miRNA) are small non-coding RNA species that are involved in post-transcriptional gene regulation. Expression levels of miRNAs have potential as diagnostic biomarkers as they are known to circulate and tissue specific profiles can be identified in a number of bodily fluids such as plasma, CSF and urine. Recent developments in deep sequencing technology present a viable approach to develop biomarker discovery pipelines in order to profile miRNA signatures in bodily fluids specific to neurodegenerative diseases. Here we review the potential use of miRNA deep sequencing in biomarker identification from biological fluids and its translation into clinical practice.
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Affiliation(s)
- Lesley Cheng
- Department of Biochemistry and Molecular Biology, The University of Melbourne Melbourne, VIC, Australia ; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne Melbourne, VIC, Australia
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16
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Bath C. Human corneal epithelial subpopulations: oxygen dependent ex vivo expansion and transcriptional profiling. Acta Ophthalmol 2013; 91 Thesis 4:1-34. [PMID: 23732018 DOI: 10.1111/aos.12157] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Corneal epithelium is being regenerated throughout life by limbal epithelial stem cells (LESCs) believed to be located in histologically defined stem cell niches in corneal limbus. Defective or dysfunctional LESCs result in limbal stem cell deficiency (LSCD) causing pain and decreased visual acuity. Since the first successful treatment of LSCD by transplantation of ex vivo expanded LESCs in 1997, many attempts have been carried out to optimize culture conditions to improve the outcome of surgery. To date, progress in this field of bioengineering is substantially hindered by both the lack of specific biomarkers of LESCs and the lack of a precise molecular characterization of in situ epithelial subpopulations. The aim of this dissertation was to optimize culture systems with regard to the environmental oxygen concentration for selective ex vivo expansion of LESCs and to analyse in situ subpopulations in human corneal epithelium using a combination of laser capture microdissection and RNA sequencing for global transcriptomic profiling. We compared dissociation cultures, using either expansion on γ-irradiated NIH/3T3 feeder cells in serum-rich medium or expansion directly on plastic in serum-free EpiLife medium, using a range of physiologically relevant oxygen concentrations (2%, 5%, 10%, 15% and 20%). Using immunocytochemistry and advanced fluorescence microscopy, cells were characterized regarding growth, cell cycle distribution, colony-forming efficiency (CFE), phenotypes and cytomorphometry. Limbal epithelial cells expanded in 2% O2 exhibited slow growth, low fraction of cells in S/G2 , high CFE, high expression of stem cell markers ABCG2 and p63α, and low fraction of differentiation marker CK3 resembling a LESC phenotype. The effect of hypoxia to maintain LESCs in culture was not dependent on the system used for propagation (Bath et al. 2013a). Laser capture microdissection was used to isolate cellular subpopulations in situ from the spatially defined differentiation pathway in human corneal epithelium according to an optimized protocol for maintenance of expression profiles. Isolated total RNA from basal limbal crypts (BLCs), superficial limbal crypts (SLCs), paracentral/central cornea and limbal stroma was amplified and converted to fragmented cDNA libraries for use in deep paired-end next-generation sequencing. Global transcriptional profiling was carried out using bioinformatics. The location of primitive cells in BLCs, migratory and activated cells in SLCs and differentiated cells in paracentral/central cornea was evident from mapping of significantly upregulated genes in each compartment to the gene ontology (GO). Interestingly, many GO terms in BLCs were also involved in neurogenic processes, whereas many GO terms in SLCs were related to vasculature. Mapping upregulated genes in BLCs to pathway annotations in Kyoto Encyclopedia of Genes and Genomes described many active pathways as signalling and cancer-associated pathways. We supply extensive information on possible novel biomarkers, reveal insight into both active pathways and novel regulators of LESCs such as Lrig1 and SOX9 and provide an immense amount of data for future exploration (Bath et al. 2013b). Selective ex vivo expansion of LESCs in hypoxia and the comprehensive molecular characterization of corneal epithelial subpopulations in situ are expected to be beneficial for the future treatment of LSCD by cultured limbal epithelial transplantation.
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Affiliation(s)
- Chris Bath
- Department of Ophthalmology, Aalborg University Hospital, Aalborg, Denmark
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17
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Liang F, Liu YZ, Zhang P. Universal base analogues and their applications in DNA sequencing technology. RSC Adv 2013. [DOI: 10.1039/c3ra41492b] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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18
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Wilkerson PM, Reis-Filho JS. the 11q13-q14 amplicon: Clinicopathological correlations and potential drivers. Genes Chromosomes Cancer 2012; 52:333-55. [DOI: 10.1002/gcc.22037] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2012] [Accepted: 11/01/2012] [Indexed: 01/04/2023] Open
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19
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Bissonnette L, Bergeron MG. Multiparametric technologies for the diagnosis of syndromic infections. ACTA ACUST UNITED AC 2012. [DOI: 10.1016/j.clinmicnews.2012.09.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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20
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Abstract
This article reviews the conceptual and practical implications of the intrinsic subtype classification of breast cancers and the limitations of this approach. It presents the most extensively validated gene expression assays proposed as predictors of clinical outcome and discusses their potential clinical utility and limitations.
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21
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Jantus-Lewintre E, Usó M, Sanmartín E, Camps C. Update on biomarkers for the detection of lung cancer. LUNG CANCER-TARGETS AND THERAPY 2012; 3:21-29. [PMID: 28210122 DOI: 10.2147/lctt.s23424] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Patients at risk for lung cancer may have subclinical disease for years before presentation. The diagnosis of this disease is primarily based on symptoms, and detection often occurs after curative intervention is no longer possible. At present, no lung cancer early-detection biomarker is clinically available. This study reviews the most recent advances in early detection and molecular diagnostic biomarkers for the detection of lung cancer. This review includes an overview of the various biological specimens and matrices in which these biomarkers could be analyzed, as well as the diverse strategies and approaches for identifying new biomarkers that are currently being explored. Several novel and attractive biomarker candidates for the early detection of lung cancer exist. A remarkable shift is taking place from research based on single markers to analyzing signatures that are more complex in order to take advantage of new high-throughput technologies. However, it is still necessary to validate the most promising markers and the standardization of procedures that will lead to specific clinical applications.
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Affiliation(s)
- Eloisa Jantus-Lewintre
- Molecular Oncology Laboratory, Fundación para la Investigación del Hospital General Universitario, Valencia, Spain
| | - Marta Usó
- Molecular Oncology Laboratory, Fundación para la Investigación del Hospital General Universitario, Valencia, Spain
| | - Elena Sanmartín
- Molecular Oncology Laboratory, Fundación para la Investigación del Hospital General Universitario, Valencia, Spain
| | - Carlos Camps
- Molecular Oncology Laboratory, Fundación para la Investigación del Hospital General Universitario, Valencia, Spain; Deparment of Medical Oncology, Consorcio Hospital General Universitario, Valencia, Spain; Department of Medicine, Universitat de València, Valencia, Spain
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22
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Rizzo JM, Buck MJ. Key principles and clinical applications of "next-generation" DNA sequencing. Cancer Prev Res (Phila) 2012; 5:887-900. [PMID: 22617168 DOI: 10.1158/1940-6207.capr-11-0432] [Citation(s) in RCA: 128] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Demand for fast, inexpensive, and accurate DNA sequencing data has led to the birth and dominance of a new generation of sequencing technologies. So-called "next-generation" sequencing technologies enable rapid generation of data by sequencing massive amounts of DNA in parallel using diverse methodologies which overcome the limitations of Sanger sequencing methods used to sequence the first human genome. Despite opening new frontiers of genomics research, the fundamental shift away from the Sanger sequencing that next-generation technologies has created has also left many unaware of the capabilities and applications of these new technologies, especially those in the clinical realm. Moreover, the brisk evolution of sequencing technologies has flooded the market with commercially available sequencing platforms, whose unique chemistries and diverse applications stand as another obstacle restricting the potential of next-generation sequencing. This review serves to provide a primer on next-generation sequencing technologies for clinical researchers and physician scientists. We provide an overview of the capabilities and clinical applications of DNA sequencing technologies to raise awareness among researchers about the power of these novel genomic tools. In addition, we discuss that key sequencing principles provide a comparison between existing and near-term technologies and outline key advantages and disadvantages between different sequencing platforms to help researchers choose an appropriate platform for their research interests.
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Affiliation(s)
- Jason M Rizzo
- Department of Biochemistry and Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, 701 Elicott St., Buffalo, NY 14203, USA.
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23
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Geyer FC, Lacroix-Triki M, Colombo PE, Patani N, Gauthier A, Natrajan R, Lambros MBK, Khalifeh I, Albarracin C, Orru S, Marchiò C, Sapino A, Mackay A, Weigelt B, Schmitt FC, Wesseling J, Sneige N, Reis-Filho JS. Molecular evidence in support of the neoplastic and precursor nature of microglandular adenosis. Histopathology 2012; 60:E115-30. [PMID: 22486256 DOI: 10.1111/j.1365-2559.2012.04207.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AIMS Microglandular adenosis (MGA) is a proliferative breast lesion, which has been proposed to be a potential precursor of triple-negative breast cancers. The aims of this study were to determine whether MGAs harbour genetic alterations and if any such genetic aberrations found in MGAs are similar to those found in matched invasive carcinomas. METHODS AND RESULTS Twelve cases of MGA and/or atypical MGA (AMGA), 10 of which were associated with invasive carcinoma, were evaluated. Immunohistochemical profiling revealed that all invasive carcinomas were of triple-negative phenotype and expressed S100, cytokeratins 8/18 and 'basal' markers. The morphologically distinct components of each case (MGA, AMGA and/or invasive carcinoma) were microdissected and subjected to microarray comparative genomic hybridization. Apart from three typical MGAs, all samples harboured genetic alterations. The percentage of the genome affected by copy number aberrations in MGA/AMGA ranged from 0.5 to 61.9%, indicating varying levels of genetic instability. In three cases, MGA/AMGA displayed copy number aberrations similar to those found in matched invasive components, providing strong circumstantial evidence that MGA may constitute the substrate for the invasive carcinoma development. CONCLUSIONS Our results support the contention that MGA can be a clonal lesion and non-obligate precursor of triple-negative breast cancer.
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Affiliation(s)
- Felipe C Geyer
- Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
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24
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Baudhuin LM, Donato LJ, Uphoff TS. How novel molecular diagnostic technologies and biomarkers are revolutionizing genetic testing and patient care. Expert Rev Mol Diagn 2012; 12:25-37. [PMID: 22133117 DOI: 10.1586/erm.11.85] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Technological applications and novel biomarkers in the field of molecular diagnostics have never been evolving at a more rapid pace. These novel applications have the promise to change the face of clinical care as we move into the era of personalized medicine. While some of these technologies and biomarkers have been adopted by some clinical laboratories, most laboratories face a steep learning curve in bringing these dramatically new and different molecular diagnostic applications on board. Furthermore, interpreting the vast amounts and new types of data produced by these novel applications brings forth challenges for laboratorians and clinicians alike. In this article, we discuss how some of these emerging novel molecular diagnostic technologies and analytes, such as next-generation sequencing, chromosomal microarray, microRNAs and circulating fetal nucleic acids are revolutionizing patient care and personalized medicine.
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Affiliation(s)
- Linnea M Baudhuin
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
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25
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Dancey JE, Bedard PL, Onetto N, Hudson TJ. The genetic basis for cancer treatment decisions. Cell 2012; 148:409-20. [PMID: 22304912 DOI: 10.1016/j.cell.2012.01.014] [Citation(s) in RCA: 212] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2011] [Indexed: 02/06/2023]
Abstract
Personalized cancer medicine is based on increased knowledge of the cancer mutation repertoire and availability of agents that target altered genes or pathways. Given advances in cancer genetics, technology, and therapeutics development, the timing is right to develop a clinical trial and research framework to move future clinical decisions from heuristic to evidence-based decisions. Although the challenges of integrating genomic testing into cancer treatment decision making are wide-ranging and complex, there is a scientific and ethical imperative to realize the benefits of personalized cancer medicine, given the overwhelming burden of cancer and the unprecedented opportunities for advancements in outcomes for patients.
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Affiliation(s)
- Janet E Dancey
- Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada
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26
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Ozretić L, Heukamp LC, Odenthal M, Buettner R. The Role of Molecular Diagnostics in Cancer Diagnosis and Treatment. ACTA ACUST UNITED AC 2012; 35 Suppl 1:8-12. [DOI: 10.1159/000334823] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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