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Bringing Next-Generation Sequencing (NGS) to the Clinic
Mark Stevenson
President and COO
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Applied Markets
Diagnostics
Investing in Enabling TechnologiesInnovation is our focus and is a core competency at LIFE
Cell Biology
Flow Cytometry
PCR
Sequencing
Targeting GrowthMarkets
Creating the Technologies to Understand Biology Driving Innovation intoDiagnostics and Applied Markets
Investing over$300M in R&D
User CenteredInnovation
LeveragingScale & Scope
3
SOLiDTM System: Increasing Throughput and Lowering Cost
<2 weeks~$3,000
0.01
0.10
1.00
10.00
100.00
1,000.00
10,000.00
100,000.00
$MThroughput(Gb)
Cost per Human GenomeInnovation of SOLiDTM throughput
3Gb 6Gb
20Gb
0
20
40
60
80
100
120
300
2007 2008 2009 2010
SOLiD 5500
SOLiD Platform
1990 2001 20112007 20090.001
Moore’s Law
13 years~$3,000,000,000
SOLiD 4(June 2010)
2010
Lower costs make sequencing more accessibleNote: Any products discussed in this presentation are for research use only. Not for use in human or animal diagnostics or therapeutics. Please ensure compliance to all applicable laws and regulation
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Whole Genomic Sequencing Is Becoming Cost Effective to Existing Tests
Cost per Human Genome
20102009 2011
$ R
eage
nt c
ost
Cost range
Charcot Marie Tooth test, $8,500
Oncotype Dx test, $3,900
AlloMap test, $2,900
Duchenne muscular dystrophy test, $3,000
Existing Genetic Tests
Note: Any products discussed in this presentation are for research use only. Not for use in human or animal diagnostics or therapeutics. Please ensure compliance to all applicable laws and regulation
5
Growing List of Genetic TestsGene Rearrangement Molecular Detection | Acute Myeloid Leukemia: Molecular Detection of the AML1/ETO Chimeric Transcript | ADmark ApoE Genotype Analysis & Interpretation (Symptomatic) | Alpha-1-Antitrypsin and Alpha-1-Antitrypsin Genotype with Reflex to Alpha-1- Antitrypsin Phenotype | Amyloidosis Evaluation | Anaplastic Large Cell Lymphoma: Molecular Detection of the NPMA/ALK Chimeric Transcript APRTAT Aprataxin DNA Sequencing TEST | Ashkenazi Jewish Carrier Testing | Autoimmune Polyglandular Syndrome (AIRE) Evaluation | Autosomal Dominant Ataxia Evaluation | bcl-1 Gene Rearrangement, Molecular Detection | bcl-2 Gene Rearangement, Molecular Detection | BCR-ABL: Molecular Detection of Major Breakpoint Region, CML Type, Quantitative | BCR-ABL: Molecular Detection of Minor Breakpoint Region, ALL Type, Qualitative | BRAC Analysis, BRCA1 and BRCA2 Gene | BRAC Analysis, Multiple Mutation | BRAC Analysis, Single Mutation | BRAF V600E Mutation | Caveolin 3 DNA Sequencing Test | Charcot-Marie-Tooth 1A CMTX1 Charcot-Marie-Tooth X-Linked COMCMT Charcot-Marie-Tooth, Complete | Collagen Genes 1 & 2 LSMISC COMP Gene Analysis in Multiple Epiphyseal Dysplasia and Pseudoachondroplasia (PSACH) CATAXT Complete Ataxia Evaluation | Complete CADASIL Evaluation COMSPG Complete Hereditary Spastic Paraplegia Evaluation MYOTON Complete Myotonia Evaluation | Complete Myotonic Dystrophy Evaluation CON26 Connexin 26 | Sequencing Test | Cystathionine B-Synthase, Genotype (833 & 919) | Cystic Fibrosis Mutation Analysis | Cystic Fibrosis Screening | Dentatorubrapallidotuysian Atrophy DNA Test DM2DNT DM2 DNA Test | DNA Marker Engraftment, Graft vs Host | DNA Marker, Post BMT Engraftment | DNA Marker, Pre BMT Engraftment DOMCMT Dominant Charcot-Marie-Tooth Evaluation DYTI Dystonia (DYT1) DNA | Emery-Dreifuss Muscular Dystrophy: emerin and/or lamin A/C Mutation Detection by Sequencing MD Ewing's Sarcoma: Molecular Detection of the EWS/FLI-1 Chimeric Transcript Factor 2 (Prothrombin) by PCR F5MA Factor 5 by PCR | Familial Amyotrophic Lateral Sclerosis (SOD1) DNA Test | Familial Hemiplegic Migraine Type 1 DNA Test | Familial Hypocalciuric Hypercalcemia (CASR) Evaluation | Fibrillin-1 Gene | FKRP DNA Sequencing Test | FLT3 Mutation Assays for AML FRAGX Fragile X Molecular Analysis FDXT Friedreich's Ataxia DNA Test | FSHD DNA Test | GCK (MODY2) DNA Sequencing Test | GDAP1 DNA Sequencing Test | Gene Rearrangement, B-Cell, Immunoglobulin Heavy Chain, PCR | Gene Rearrangement, T-Cell Receptor, PCR | GM1 Triad Autoantibody Test | Hemochromatosis Mutation Analysis (S65C, C282Y and H63D) | Hereditary Pressure Palsey Neuropathy IMM HLA-A, B and C Typing, HLA Class I (Allele Resolution) | HLA-A, B, and C Typing, HLA Class I (Low Resolution) IMM HLA-DR and DQ Typing, HLA Class II (Allele Resolution) | HLA-DR and DQ Typing, HLA Class II (Low Resolution) | HR2 Haplotype (Factor VHR2), A4070G Polymorphism | Huntington Disease Molecular Analysis Contact Genetics Counselor at 612-624-8948 prior to collection. LSMISC Hurlers Mucolipidosis Type II Gene Sequencing | JAK2 V617F Mutation | KCNJ11 (CH) DNA Sequencing Test | Kennedy's Disease DNA Test | Leber Optic LITAF LITAF/SIMPLE DNA Sequencing Test | LRRK2 DNA Test | Medium Chain Acyl-Co-A Dehydrogenase (Mutation Analysis) | MFN2 DNA Sequencing Test | Microsatellite Instability Testing for Hereditary Nonpolyposis Colorectal Cancer Screen (HNPCC) | Mitochondrial DNA Disorder, Genetic Analysis | Mitochondrial Myopathy Screen, Muscle | MTHFR Genotype MPZ Myelin Protein Zero (MPZ) DNA Sequencing MD Myotonic Dystrophy Molecular Analysis MD Myotonic Dystrophy Molecular Southern Analysis PANTP Neonatal Alloimmune Thrombocytopenia Investigation AVPR2 Nephrogenic Diabetes Insipidus Evaluation LSMISC Neurofibromatosis T1 NFT2 Neurofibromatosis Type 2 DNA Test NFL Neurofilament Light DNA Sequencing Test SPG6 NIPA (SPG6) DNA Sequencing Test NPH1 NPH1 (FJN) Molecular Analysis NPHS2 NPHS2 (Podocin) Sequencing Analysis MD Nucleophosmin (NPM1) Analysis MD OCA1, Oculocutaneous Albinism Type 1, Mutation Detection by DNA Sequencing Ornithine Transcarbamylase Mutation Carrier Analysis MD p53 Mutation Detection by DNA Sequencing PARKIN Parkin DNA Test CMTAXO Partial CMT - Axonal Only PCMTDM Partial CMT Evaluation - Demyelinating Only MD PAX2 Gene Mutation CMT4F Periaxin DNA Sequencing Test | PINK1 DNA Sequencing Test | PKU Mutation Detection by DNA Sequencing LSMISC Platelet Antigen Genotyping, Level 1 | PML/RAR: Molecular Detection of Acute Promyelocytic Leukemia | PMP22 DNA Sequencing Test | Prader Willi/Angelman Syndrome Analysis | Prader-Willi/Angelman Syndrome Molecular Detection | SCA1 DNA Test | SCA10 DNA Test | SCA14 DNA Test SCA17 SCA17 DNA Test SCA2B SCA2B DNA Test | SCA3 DNA Test | SCA5 DNA Test | SCA6 DNA Test | SCA7 DNA Test | SCA8 DNA Test | SETX DNA Sequencing Test SMACT Spinal Atrophy LSMISC Spinal Muscular Atrophy DNA Test | Spinal Muscular Atrophy Test | TPMT Genetics (genotype) | Warfarin Sensitivity by CYP2C9 and VKORC1 Genotyping
A $6k genome means doctors could do all the tests at once
A $6k genome means doctors could do all the tests at once
Note: Any products discussed in this presentation are for research use only. Not for use in human or animal diagnostics or therapeutics. Please ensure compliance to all applicable laws and regulation
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Medicine Today: An Imperfect ArtSe
lect
The
rape
utic
s
Response Rates (%)
Source: Spear et al. TRENDS in Molecular Medicine Vol.7 No.5 May 2001; PMC Nov 2006
Given toolbox of drugs, clinicians are
forced to practice trial-and-error
medicine (statistical medicine)
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Bisgrove Trial (April 2009)
Molecular Profiling: Proven Benefits
• Patients unresponsive to standard therapies
• Key mutations identified using: gene expression arrays and IHC
• Drugs personalized to patient’s cancer based on mutations
• 27% of patients showed response as defined as improvement in progression free survival
Phoenix, AZ
Source: Bisgrove trial, April 2009
Overall survival (months)
Cum
ulat
ive
Surv
ival
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Relationship between what clinician selected as what she/he would use to treat the patient before knowing what Molecular Profiling (IHC/Microarray) results suggested (n=66)
Clinician Selected
Mol
ecul
ar P
rofil
ing
Sele
cted
No Correlation
How Does Molecular Profiling Compare To What Doctors Would Have Chosen?
R2 = 0.0164
Source: Bisgrove trial, April 2009
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First Life Tech Collaboration Project: TGen’s Triple Negative Breast Cancer Research
• Triple Negative Breast Cancers – about 20% of breast cancers –focused on patients who have failed standard chemo
• Applying Genomic Knowledge: 14 patients have tumor and normal sequencing analysis. US Oncology running trial.
• Outcome measurement: Time To Progression improvement by >30%
• 1st patient getting sequenced now
Spyro Mousses, PhD
Dan Von Hoff, MDDavid Craig, PhD
John Carpten, PhD
Joyce O‘Shaughnessy, MD Linh Hoang, MD PhD
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Targets Identified
Future of Oncology Care
+
Monitoring
Drug XDrug XDrug YDrug YDrug ZDrug Z
Treatment &MonitoringPatient
presentsTests
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How It May Play Out:Next Generation Sequencing Casts Broader Net
Whole GenomeWhole exome(~25,000 genes)
Gene panel
2011
• Bioinformatics to look at whole genome
• Bioinformatics focus on actionable genes
• Bank rest for research
• Reimbursable, actionable genes
(1) Can structure as Technical Component (CPT stacking) and Professional Component (pathologist read)
Today, cost to do a 500-gene test by Next Generation Sequencing is equal to a 3 gene test on capillary electrophoresis sequencing
2013 2014+
Test
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Everything In The Beginning Is Hard…
P1P1 P2P2IAIATag 1Tag 1 Tag 2Tag 2
IAIA
X
X
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• Targeted (amplicon. medical) resequencing
• Bacterial, fungal, and viral identification
• Multiple fragment analysis apps (microsatellite and
multiplexed SNP detection)
• Whole humangenome sequencing
• Whole human exome sequencing
• Whole transcriptome analysis
One to Hundreds oflong reads per sample,Mbp of data per day
Millions to Billions ofshort reads per sample,
Gbp of data per day
CE SOLiDPGM
• Microbial genome sequencing
• Preliminary library assessment and QC
• Targeted resequencing(larger scale)
Thousands to Millions ofmoderate reads per sample,
Hundreds of Mbp of data per day
LIFE’s Sequencing Portfolio
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GenomicMedicine
Clinical utility becomes the focus
Technology Only Part Of Solution
EthicalEthical
PrivacyPrivacy
RegulatoryRegulatory
EconomicsEconomics
TechnologyTechnology
MedicalMedical
✓✓
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Need for a “Genomic Physician” Subspecialty
Interpretation of data
• Likely a specialist “molecular physician”
• Requires extensive software and IT infrastructure
• Requires a specialist: radiologist, cardiologist, neurologist
• For MRI, CT, requires PACS system to function efficiently
Laying the groundwork for the Genomic Physician
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LIFE is creating the necessary bridges between research and clinical application
Life
StanfordMax Planck
Harvard
Univ. of Paris
Univ of Tokyo
U Minn
Baylor
Beijing
MD Anderson
• 100+ sponsored research
• 300+ direct research relationships
• 50+ technology companies
Academic centers / labsTechnology companies / associations
NOTE: Any products discussed in this presentation are for research use only. Not for use in human or animal diagnostics or therapeutics. Please ensure compliance to all applicable laws and regulation