Cytogenetics

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Summary

This report deals with cytogenetics in a broader sense rather than the classical use mainly to describe the chromosome structure and identify abnormalities related to disease. In the age of molecular biology, it is also referred to as molecular cytogenetics. Historical landmarks in the evolution of cytogenetics are reviewed since the first images of chromosomes were made in 1879. The scope of cytogenetics includes several technologies besides fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), and multicolor FISH. Molecular cytogenetics includes application of nanobiotechnology, microarrays, real-time polymerase chain reaction (PCR), in vivo imaging, and single molecule detection. Bioinformatics is described briefly as it plays an important role in analyzing data from many of these technologies.

FISH remains the single most important technology in cytogenetics. Several innovations are described of which the most important are single copy FISH, in vivo FISH (imaging of nucleic acids in living cells) and nanotechnology-based FISH. The unique character of peptide nucleic acid (PNA) allows these probes to hybridize to target nucleic acid molecules more rapidly and with higher affinity and specificity compared with DNA probes. PNA-FISH is more suited for rapid diagnosis of infections. RNA-FISH and locked nucleic acids (LNAs), are also described.

Microarray/biochip-based technologies for cytogenetics promise to speed up detection of chromosome aberrations now examined by FISH. Other important genomic technologies are whole genome expression array and direct molecular analysis without amplification. Analysis of single-cell gene expression promises a more precise understanding of human disease pathogenesis and has important diagnostic applications. Optical Mapping can survey entire human genomes for insertions/deletions, which account for a significantly greater proportion of genetic variation between closely-related genomes as compared to single nucleotide polymorphisms (SNPs), and are a major cause of gene defects.

Technologies encompassed within molecular imaging include optical imaging, magnetic resonance imaging (MRI) and nuclear medicine techniques. Positron emission tomography (PET) is the most sensitive and specific technique for imaging molecular pathways in vivo in humans. Cytogenetics can be refined by application of cytogenetics at single molecule level. Nanotechnology has facilitated the development of technology for single molecule imaging. Atomic force microscope (AFM) has become a well-established technique for imaging single biomolecules under physiological conditions. The scanning probe microscope (SPM) system is emerging as an increasingly important tool for non-intrusive interrogation of biomolecular systems in vitro and have been applied to improve FISH. Another example of application of nanobiotechnology is QD (quantum dot)-FISH probes, which can detect down to the single molecule level.

There are connections between cytogenetics and biomarkers of genetic disorders as well as cancer. Biomarkers are very important for molecular diagnostics. Not only are molecular diagnostic technologies used for discovery of biomarkers, biomarkers are the basis of several diagnostics. As a means to understand pathomechanism of disease and as links between diagnostics and therapeutics, biomarkers are playing a role in development of personalized medicine. Application of cytogenetics extend beyond genetic disorder and cancer to diagnosis of several other diseases. Other important applications are drug discovery, and development of personalized medicine.

The chapter on markets provides a global perspective of the cytogenetics business in the major markets: US, Western Europe (including France, Germany, Italy, Spain, and the UK), and Japan. The total figures for the market are also broken out according to the technologies and major disease areas in which they are applied. Markets figure are given for the year 2009 and estimates are made for the years 2014 and 2019. Advantages and limitations of various technologies have been pointed out throughout the report but this chapter includes SWOT (Strengths, Weaknesses, Opportunities and Threats) analysis of some of the competing technologies including the following: conventional FISH, innovative FISH technologies, PCR-based assays, and single molecule imaging. Unfulfilled needs in cytogenetics market are depicted graphically. Among various technologies, FISH is most advanced and less opportunities for further development than single molecule detection, which is in infancy and has more future potential.
The report includes summary profiles of 67 companies relevant to cytogenetics along with their 56 collaborations. Companies developing innovative technologies as well as those supplying equipment/services/reagents are identified.The report text is supplemented with 27 Tables and 9 figures. Selected 180 references are included in the bibliography.

Contents

• 0. Executive Summary
• 1. Introduction
  • Definitions
  • Historical evolution of cytogenetics
  • Scope of cytogenetics
  • Molecular cytogenetics
  • Basics of molecular biology relevant to cytogenetics
  • DNA
  • RNA
  • DNA transcription
  • Chromosomes
  • Mitochondrial DNA
  • Genes
  • The genetic code
  • Gene expression
  • The human genome
  • Variations in the human genome
  • Variations in DNA sequences
  • Single nucleotide polymorphisms
  • Genotype and haplotypes
  • Complex chromosomal rearrangements
  • Insertions and deletions in the human genome
  • Large scale variation in human genome
  • Variation in copy number in the human genome
  • Structural variations in the human genome
  • Mapping and sequencing of structural variation from human genomes
  • Replication of the DNA helix
• 2. Technologies used for cytogenetics
  • Introduction
  • Quantitative fluorescent polymerase chain reaction
  • RNA interference and cytogenetics
  • RNA-induced transcriptional silencing complex
  • Single cell genetics by siRNA ablation
  • RNAi and cancer cytogenetics
  • Role of miRNAs in cancer cytogenetics
  • Preimplantation genetic diagnosis
  • Preimplantation genetic haplotyping
  • Bioinformatics and cytogenetics
  • FISH probe design software
  • LS-CAP algorithm
  • Distance-based clustering of CGH data
• 3. Fluorescent In Situ Hybridization
  • Introduction
  • Innovative FISH technologies
  • Direct visual in situ hybridization
  • Direct labeled Satellite FISH probes
  • Chromogenic in situ hybridization (CISH)
  • Primed in situ labeling
  • Interphase FISH
  • FISH with telomere-specific probes
  • High-throughput quantitative FISH
  • Multicolor FISH
  • Multicolor chromosome banding
  • Fiber FISH
  • Use of peptide nucleic acid with FISH
  • RNA-FISH
  • Use of locked nucleic acids with FISH
  • Automation of FISH
  • Single copy FISH probes
  • peT-FISH™
  • In vivo FISH
  • Applications of FISH
  • Companies involved in FISH diagnostics
• 4. Genomic Technologies relevant to Cytogenetics
  • Introduction
  • Microarrays/biochips for cytogenetics
  • Tissue microarrays
  • Chromosome copy number analysis
  • Combination of FISH and gene chips
  • SignatureChip®
  • Molecular Combing
  • High density oligonucleotide arrays
  • Next Generation Screening®
  • Comparative genomic hybridization
  • Array-based comparative genomic hybridization
  • Comparison of array CGH and multipoint FISH
  • Combined use of tissue microarrays and array CGH
  • Single-cell array CGH
  • Regulatory requirements for array CGH
  • Whole genome expression microarrays
  • Life Technologies Expression Array System
  • Arrayit's® H25K
  • Optical Mapping
  • Single cell cytogenetics
  • Single cell PCR
  • LATE-PCR
  • AmpliGrid-System
  • Digital Counting
  • Analysis of single-cell gene expression
  • Application of single cell cytogenetics in preimplantation genetic testing
  • Direct molecular analysis without amplification
• 5. Molecular Imaging & Single Molecular Detection
  • Molecular imaging
  • Companies involved in molecular imaging
  • Single molecule detection
  • Spectrally resolved fluorescence lifetime imaging microscopy
  • Single-molecule fluorescence resonance energy transfer
  • Confocal laser scanning
  • PCR systems for single molecule detection
  • Real-time PCR
  • Digital PCR
  • Emulsion PCR
  • Rolling circle amplification technology
  • Microfluidic assay for protein expression at the single molecule level
  • Bioinformatic and single molecule detection
• 6. Role of Nanobiotechnology in Cytogenetics
  • Introduction
  • Nanobiology and the cell
  • Visualization on nanoscale
  • Application of AFM for biomolecular imaging
  • Future insights into biomolecular processes by AFM
  • Scanning probe microscopy
  • Near-field scanning optical microscopy
  • Multiple single-molecule fluorescence microscopy
  • Nanoscale scanning electron microscopy
  • Nanotechnology-based FISH
  • Study of chromosomes by atomic force microscopy
  • Quantum dot FISH
  • Nanobiotechnology for single molecule detection
  • Nanolaser spectroscopy for detection of cancer in single cells
  • Carbon nanotube transistors for genetic screening
  • Quantum-dots-FRET nanosensors for single molecule detection
  • 3D single-molecular imaging by nanotechnology
  • Manipulation of DNA sequence by use of nanoparticles
  • Nanofluidic/nanoarray devices to detect a single molecule of DNA
  • Nanopore technology
  • Portable nanocantilever system for diagnosis
  • Nanobiosensors
• 7. Biomarkers and Cytogenetics
  • Introduction
  • Definitions
  • Biomarkers and cytogenetics
  • Cancer biomarkers
  • Technologies for detection of cancer biomarkers
  • Telomerase as a biomarker of cancer
  • Digital karyotyping for cancer biomarkers
  • Optical systems for in vivo molecular imaging of cancer
  • Circulating cancer cells in blood as biomarkers of cancer
  • Array CGH for biomarker discovery in cancer
  • Genetic biomarkers
• 8. Applications of Cytogenetics
  • Introduction
  • Applications of cytogenetics in research
  • Cytogenetics of embryonic stem cells
  • Genetic disorders
  • Technologies for diagnosis of genetic disorders
  • Cytogenetic microarrays for diagnosis of mental retardation
  • Detection of copy number variations in genetic disorders
  • Detection of non-recurrent DNA rearrangements by aCGH
  • Quantitative fluorescent PCR
  • Representational oligonucleotide microarray analysis
  • SignatureChip®-based diagnostics for cytogenetic abnormalities
  • Cytogenetics in prenatal diagnosis
  • aCGH for prenatal diagnosis
  • BAC HD Scan test
  • FISH for prenatal diagnosis
  • PCR for prenatal diagnosis of trisomy 21
  • Plasma DNA sequencing to detect fetal chromosomal aneuploidies
  • Concluding remarks and future prospects of prenatal diagnosis
  • Cytogenetics in preimplantation genetic diagnosis
  • Array CGH for PGD
  • Fluorescent PCR for PGD
  • FISH for PGD
  • PGD using whole genome amplification
  • Conditions detected by preimplantation cytogenetic diagnosis
  • The future of preimplantation genetic diagnosis
  • Disorders of the nervous system
  • Cardiovascular disorders
  • Infections
  • PNA-FISH for diagnosis of infections
  • Diagnosis of bacterial infections at single molecule level
  • Detection of single virus particles
  • Role of cytogenetics in drug discovery and development
  • Role of cytogenetics in the development of personalized medicine
  • Relation of cytogenetics to personalized medicine
  • Cytomics as a basis for personalized medicine
  • Molecular imaging and personalized medicine
  • Cytogenetics for gender determination
  • Gender determination in competitive sport
  • Gender determination in forensic cases
  • Regulatory aspects of FISH
• 9. Cancer Cytogenetics
  • Cancer genetics
  • Cytogenetic abnormalities in cancer
  • Cytogenetic technologies for molecular diagnosis of cancer
  • Applications of array CGH in oncology
  • Cytogenetics of tumor cells in body fluids
  • Gene expression profiles predict chromosomal instability in tumors
  • Loss of heterozygosity
  • Molecular Combing for cancer diagnosis
  • Mutation detection at molecular level
  • Proteomic identification of oncogenic chromosomal translocation partners
  • Tissue microarrays for cancer diagnosis
  • Applications of cytogenetics in molecular diagnosis of cancer
  • Molecular cytogenetics in hematological malignancies
  • Chromosome translocations in leukemias
  • Cytogenetics diagnostics for leukemia
  • Detection of p53 deletions in chronic lymphocytic leukemia
  • Cytogenetics of lymphomas
  • Cytogenetics of myelodysplastic syndrome
  • Cytogenetics of plasma cell myeloma
  • Bladder cancer
  • Bone and soft tissue tumors
  • Brain tumors
  • Breast cancer
  • Chromosomal aberrations in breast carcinomas
  • FISH vs CISH and SISH for determining of HER-2/neu amplification
  • Genomic profiles of breast cancer
  • Colorectal cancer
  • Lung cancer
  • Ovarian cancer
  • aCGH analyses of cisplatin-resistant ovarian cancer cells
  • Prostate cancer
  • Renal cancer
  • Thyroid cancer
  • Cytogenetics-based anticancer strategies
  • Significance of double minutes
  • Prognostic and therapeutic significance of gene amplifications
  • Allele-specific inhibition
  • RNAi-based approach for leukemia
  • Online resources for cancer cytogenetics
  • The Cancer Genome Atlas
• 10. Cytogenetics Markets
  • Introduction
  • Methods for study of cytogenetic markets
  • The overall market for cytogenetics
  • Cytogenetic markets according to technologies
  • Market for FISH technologies
  • Sorting the markets of overlapping technologies
  • Markets for cytogenetics according to therapeutic areas
  • SWOT of competing technologies
  • Unfulfilled needs
  • Limitations of current technologies
  • Promising future developments in cytogenetics
  • Commercial aspects of genome sequencing technologies
  • Cost of genotyping
• 11. Companies
  • Profiles of companies
  • Collaborations
• 12. References
• Tables
  • Table 1-1: Historical landmarks in the evolution of cytogenetics
  • Table 2-1: A classification of technologies used for cytogenetics
  • Table 3-1: Classification and scope of FISH and related technologies
  • Table 3-2: A selection of companies with FISH diagnostics
  • Table 4-1: Microarray/biochip-based technologies for cytogenetics
  • Table 4-2: Chromosomal structural abnormalities detected by CGH
  • Table 4-3: Companies developing whole genome chips/microarrays
  • Table 5-1: Companies involved in developing molecular imaging
  • Table 5-2: Technologies for single molecule detection
  • Table 6-1: Nanobiotechnologies for single molecule detection
  • Table 7-1: Types of cancer biomarkers relevant to cytogenetics
  • Table 8-1: Applications of cytogenetics
  • Table 8-2: Application of preimplantation cytogenetic diagnosis in monogenic disorders
  • Table 9-1: WHO classification of myelodysplastic syndromes
  • Table 9-2: Fusion genes in in malignant bone and soft tissue tumors
  • Table 9-3: Fusion genes in adenocarcinoma of the thyroid
  • Table 10-1: Global cytogenetics markets 2009-2019
  • Table 10-2: Cytogenetic markets according to technologies from 2009-2019
  • Table 10-3: Market size for cytogenetics according to applications 2009-2019
  • Table 10-4: SWOT of conventional FISH
  • Table 10-5: SWOT of innovative FISH technologies
  • Table 10-6: SWOT of PCR-based assays
  • Table 10-7: SWOT of aCGH
  • Table 10-8: SWOT of single molecule imaging
  • Table 11-1: Major suppliers of reagents/services/equipment for cytogenetics
  • Table 11-2: Major consumers of reagents
  • Table 11-3: Companies developing innovative technologies in cytogenetics
  • Table 11-4: Collaborations in cytogenetics
• Figures
  • Figure 6-1: Scheme of a novel optical mRNA biosensor
  • Figure 8-1: Relation of various technologies to drug discovery and development
  • Figure 8-2: Relation of cytogenetics to personalized medicine
  • Figure 8-3: Relation of cytomics to personalized medicine
  • Figure 9-1: Basic scheme of genome-wide screening techniques for cancer
  • Figure 10-1: Distribution of applications of cytogenetics in the year 2014
  • Figure 10-2: Distribution of applications of cytogenetics in the year 2019
  • Figure 10-3: Unfulfilled needs in cytogenetics according to technologies
  • Figure 10-4: Unfulfilled needs in cytogenetics according to areas of application

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