Cytogenetics - technologies, markets and companies

0. Executive Summary  8

1. Introduction ......... 10

Definitions  10

Historical evolution of cytogenetics .. 10

Scope of cytogenetics ...... 11

Molecular cytogenetics..... 11

Basics of molecular biology relevant to cytogenetics ................ 11

Chromosomes12

Telomeres .....12

RNA-induced transcriptional silencing complex............15

Single cell genetics by siRNA ablation .15

RNAi and cancer cytogenetics ............16

Role of miRNAs in cancer cytogenetics 16

Preimplantation genetic haplotyping ...17

FISH probe design software...............17

LS-CAP algorithm ............17

Distance-based clustering of CGH data18

Direct visual in situ hybridization........22

Direct labeled Satellite FISH probes....22

Chromogenic in situ hybridization (CISH) ..22

Primed in situ labeling .....23

Interphase FISH..............23

FISH with telomere-specific probes.....24

High-throughput quantitative FISH.....24

Multicolor FISH ...............25

Fiber FISH.....25

Use of peptide nucleic acid with FISH..25

RNA-FISH27

Use of locked nucleic acids with FISH..27

Automation of FISH .........27

Single copy FISH probes ..28

peT-FISH™....28

In vivo FISH ..29

Companies involved in FISH diagnostics....29

Microarrays/biochips for cytogenetics .32

Combination of FISH and gene chips...33

SignatureChip® ..............33

Array-based comparative genomic hybridization .........35

Comparison of array CGH and multipoint FISH............37

Combined use of tissue microarrays and array CGH.....38

Single-cell array CGH.......38

Regulatory requirements for array CGH ....39

Companies involved in molecular imaging .44

Spectrally resolved fluorescence lifetime imaging microscopy ........45

Single-molecule fluorescence resonance energy transfer ...............46

Confocal laser scanning....46

Real-time PCR systems ....46

Microfluidic assay for protein expression at the single molecule level ....47

Bioinformatic and single molecule detection................47

Application of AFM for biomolecular imaging ...............49

Scanning probe microscopy ...............50

Near-field scanning optical microscopy50

Multiple single-molecule fluorescence microscopy........50

Nanoscale scanning electron microscopy ...50

Nanotechnology-based FISH..............51

Nanobiotechnology for single molecule detection.........52

Nanofluidic/nanoarray devices to detect a single molecule of DNA ..54

Nanopore technology.......54

Portable nanocantilever system for diagnosis..............55

Nanobiosensors ..............55

Definitions....58

Biomarkers and cytogenetics .............58

Technologies for detection of cancer biomarkers .........59

Telomerase as a biomarker of cancer..59

Digital karyotyping for cancer biomarkers .59

Optical systems for in vivo molecular imaging of cancer ................60

Circulating cancer cells in blood as biomarkers of cancer ...............60

Array CGH for biomarker discovery in cancer ..............61

Technologies for diagnosis of genetic disorders ...........62

Cytogenetics in prenatal diagnosis......63

Cytogenetics in preimplantation genetic diagnosis .......65

Conditions detected by preimplantation cytogenetic diagnosis........67

The future of preimplantation genetic diagnosis ..........68

PNA-FISH for diagnosis of infections ...69

Diagnosis of bacterial infections at single molecule level ...............69

Detection of single virus particles .......70

Relation of cytogenetics to personalized medicine .......71

Cytomics as a basis for personalized medicine ............72

Molecular imaging and personalized medicine .............72

Cytogenetics for gender determination73

Applications of array CGH in oncology.77

Loss of heterozygosity .....77

Gene expression profiles predict chromosomal instability in tumors 78

Molecular Combing for cancer diagnosis ....78

Proteomic identification of oncogenic chromosomal translocation partners..............78

Cytogenetics of tumor cells in body fluids..79

Molecular cytogenetics in hematological malignancies..80

Bladder cancer................83

Bone and soft tissue tumors ..............83

Brain tumors .84

Breast cancer 85

Colorectal cancer ............86

Lung cancer...86

Prostate cancer...............87

Renal cancer..87

Thyroid cancer................87

Significance of double minutes...........88

Prognostic and therapeutic significance of gene amplifications .......88

Allele-specific inhibition....89

RNAi-based approach for leukemia .....89

Market for FISH technologies.............93

Sorting the markets of overlapping technologies .........93

Limitations of current technologies .....98

Promising future developments in cytogenetics ...........98

Commercial aspects of genome sequencing technologies...............98

Table 1-1: Historical landmarks in the evolution of cytogenetics...............10

Table 2-1: A classification of technologies used for cytogenetics ..............14

Table 3-1: Classification and scope of FISH and related technologies........21

Table 3-2: A selection of companies with FISH diagnostics .....30

Table 4-1: Companies developing whole genome chips/microarrays .........32

Table 4-2: Microarray/biochip-based technologies for cytogenetics...........32

Table 4-3: Chromosomal structural abnormalities detected by CGH..........36

Table 5-1: Companies involved in developing molecular imaging .............44

Table 5-2: Technologies for single molecule detection............45

Table 6-1: Nanobiotechnologies for single molecule detection.52

Table 7-1: Types of cancer biomarkers relevant to cytogenetics...............59

Table 8-1: Applications of cytogenetics .........62

Table 8-2: Application of preimplantation cytogenetic diagnosis in monogenic disorders ....67

Table 9-1: Fusion genes in in malignant bone and soft tissue tumors........83

Table 9-2: Fusion genes in adenocarcinoma of the thyroid .....88

Table 10-1: Global cytogenetics markets 2007-2017 .............92

Table 10-2: Cytogenetic markets according to technologies from 2007-2017...93

Table 10-3: Market size for cytogenetics according to applications 2007-2017.94

Table 10-4: SWOT of conventional FISH .......96

Table 10-5: SWOT of innovative FISH technologies ...............96

Table 10-6: SWOT of PCR-based assays........96

Table 10-7: SWOT of single molecule imaging .....96

Table 11-1: Major suppliers of reagents/services/equipment for cytogenetics  100

Table 11-2: Major consumers of reagents ... 100

Table 11-3: Companies developing innovative technologies in cytogenetics... 101

Table 11-4: Collaborations in cytogenetics .. 159

Figure 6-1: Scheme of a novel optical mRNA biosensor..........56

Figure 8-1: Relation of various technologies to drug discovery and development...............71

Figure 8-2: Relation of cytogenetics to personalized medicine.71

Figure 8-3: Relation of cytomics to personalized medicine......72

Figure 9-1: Basic scheme of genome-wide screening techniques for cancer.....76

Figure 10-1: Distribution of applications of cytogenetics in the year 2012. 94

Figure 10-2: Distribution of applications of cytogenetics in the year 2017. 95

Figure 10-3: Unfulfilled needs in cytogenetics according to technologies ...97

Figure 10-4: Unfulfilled needs in cytogenetics according to areas of application ................97