Genotyping and Disease Research in Taiwan

1
Genotyping and Disease Research in Taiwan

• Y.T. Chen, MD, PhD
• Director
• Institute of Biomedical Sciences
• Academia Sinica, Taiwan

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NATURE VOL 421 6 FEBRUARY 2003
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National Core Facilities (Funded by National
Science Council)

• Cores Supporting Genomic Medicine Program
• Clinical core
• High-throughput genotyping core
• Microarray core
• Mouse ENU mutagenesis core
• Proteomics core
• High-field NMR
• Functional and micro-MRI
• Bioinformatics core
• Research innovation and technology development

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National Genotyping Center Academia Sinica

• Gene mapping strategy, technology platform and
  through-put
• Candidate gene approach
• SNP using MALDI-TOF mass spectrometry
  30,000/day
• Genome-wide scan
• SNP using Affymetrix gene chips
  millions/day

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Genotyping Platform ( I )
SpectroPREP
Hamilton MPH-96

• SNP (Single Nucleotide Polymorphism) Genotyping
  Platform
• Sequenom MassARRAY 7K System
• Open system, high flexibility
• Relatively low throughput, 7,000 genotypings/day

Major Instruments (SNP, Sequenom)
SpectroPOINT
SpectroREADER
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Affymetrix GeneChip Platform

• SNP (Single Nucleotide Polymorphism) Genotyping
  Platform
• Affymetrix GeneChip System
• closed system, ultra-high throughput,
  half-million genotypings/day
• Sequenoms MassARRAY and Affymetrix GeneChip
  complement each other functionally as platforms
  for SNP genotyping

Major Instruments (SNP, Affymetrix)
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National Genotyping Center Layout
SNP detection

Bio-IT Data management LIMS
ABI system
Sequenom Mass
Array
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National Genotyping Center IT Infrastructure for
Clinical Genetic Research
Documents
Subject Recruitment
Storage
Blood for DNA Preparation
Cell Pellets
Blood for Clinical Test
CRF
Blood for Cell Line Creation
DNA Extraction
Lab Data
Phenotype Data
Genotyping
Genotype Data
Data Cleaning
Data Cleaning
PhenotypeDatabase
GenotypeDatabase
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Bioinformatics Tools and Applications

• Novel Human Gene and cSNP Discovery
• CGI a comparative gene identification
  bioinformatics tool (Genome Res. 2000 BBA 2001
  J. Genet. Mol. Biol. 2002)
• Gene-specific probes for human and mouse genes
  (Bioinformatics, 2003)
• Genome Annotation
• CRASA a complexity reduction algorithm for
  analysis and annotation of large genomic
  sequences (Genome Res. 2003)
• Long continuous stretches of homozygosity (Human
  Mutation, 2006)
• SNP and Synteny mapping
• mGPS/UM a marker-based genome positioning system
  for fast and PC-doable genome-scale SNP mapping
  (Genome Res. 2002) and synteny mapping of large
  genomes (Bioinformatics,2004)
• SNP functional analysis (Nucleic Acid Res, 2006)
• DNA pooling (Nucleic Acid Res, 2006, BMC,
  Bioinformatics, 2006, Ann Human Genet 2006)

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Genotyping Applications

• Human disease gene mapping
• Linkage and Association study
• Mouse genetics
• Disease gene mapping, QTLs
• Speed generation of congenic strains
• (from traditional 10 generations to 4-5)
• Cancer genomics

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Academia Sinica Genomic Medicine Multi-center
Study (Cross-sectional disease genes study)

• Highly Hereditable diseases
• Single gene disorders
• Complex diseases young hypertension, hand
  osteoarthritis, bipolar disorder, morbid
  obesity, type II diabetes, psoriasis, etc
• Pharmacogenetics of drug efficacy and
  adverse reactions
• Cancer
• Breast cancer, lung cancer
• gt 15,000 samples collected

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Establishment of Taiwan Han Chinese Cell and
Genome bank (Taiwan Super control study)
Objectives

• To establish a representative control pool that
  has a large enough sample size (3,312
  individuals) to serve as multiple controls for a
  range of diseases
• To establish cell lines for long-term DNA supply
  and function study, serum/plasma and DNA are all
  banked
• To document genetic variation

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Super Control Study Design(Total 3,312)
Age (y) Male Female 20-29 276 276 30-39 2
76 276 40-49 276 276 50-59 276 276 60-69 276
276 70 276 276 Total 1656 1656
Random sampling Probabilities Proportional to
Sizes Age and Sex Stratification
Human Hereditary,2006
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Taiwan Biobank A Prospective Cohort Study
Gene
Environment
Life Style
Medical factor
Diet
Multi-factorial process
Cohort of Healthy Individual Population-at-risk
200,000
Seeking for Causes of Diseases
Diseased
Long term follow-up
To promote the health of next generations
Approaches of preventing disease or Protocols of
early diagnosis/effective treatment
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Disease susceptibility genes/targets/Biomarkers
mapped/identified

• Monogenic diseases
• Familial psoriasis Hwu WL et al, J Med
  Genet, 2005.
• Familial cardiac arrhythmia Hwang et al, J
  Med Genet, 2005
• Familial osteonecrosis (Liu YF, Tsai Peter)
  N Engl J Med, 2005
• Common diseases Young hypertension (Wen-Harn
  Pan) J biomed Sci, 2005, Diabetes Diabetelogia,
  2006
• Cancer Breast cancer risk genes (Shen CY)
  Cancer Research 2003, 2004, Int J Cancer, 2005
• Lung cancer markers (Peck
  Yang) JNCI 2004, 2006 Clin Cancer Res 2003,
  2005, NEJM 2007
• Pharmacogenetics of adverse drug reactions
• Stevens-Johnson syndrome/ toxic epidermal
  necrolysis
• Chung et al Nature, 2004 Hung et al PNAS,
  2005 Personalized Med, 2005 Pharmacogenetics
  Genomics 2006
• Warfarin sensitivity Human Mol Genet, 2005

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Genotyping Applications in Disease Research

• Adverse drug reactions pharmacogenetic study
• Mapping genes for mouse models of human diseases
• Cancer genomics

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Predicting Risk is Key to Genomic Medicine

• Adverse Drug Reactions Pharmacogenetic study
• Predicting drug toxicity with a gene test

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Types of Adverse Drug Reactions

• Type A dose dependent, usually predictable,
  common, monogenic or oligogenic model
• (example excessive bleeding with warfarin
• Inter-individual difference in warfarin
  sensitivity)
• Type B dose independent, unpredictable??, rare,
  polygenic model ??
• (example penicillin anaphylaxis,
  Stevens-Johnson syndrome)

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Prospective study of warfarin dosage requirements
based on CYP2C9 and VKORC1 genotypes
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Warfarin, an anti-coagulant is widely used to
prevent and treat blood clots.
Pulmonary Embolism (PE)
Heart Valve Replacement
Atrial Fibrillation with embolism, eg. Stroke
Deep Vein Thrombosis (DVT)

• Warfarin treatment is problematic
• Narrow therapeutic index.
• Wide inter-individual and inter-ethnic in dose
  response.
• INR needs to be monitored closely.

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Promoter SNP in VKORC1(-1639 GgtA) is associated
with warfarin dosage
Human Molecular Genetics, 14 1745-1751, 2005.

• The polymorphism abolished an E-box and was found
  to regulate VKORC1 expression. Promoter analysis
  demonstrated that the G allele has approximately
  50 higher activity than the A allele
• This functional polymorphism underscores the
  inter-ethnic and inter-individual differences in
  warfarin dosage

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Purpose of prospective Study

• To determine whether an individuals VKORC1 and
  CYP2C9 genotypes can be used to predict warfarin
  dosage
• To reduce/prevent adverse bleeding complications
  for warfarin sensitive patients
• To shorten the time to stable dosing thus
  reducing the burden of constant INR monitoring

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Suggested Starting dose based on genotypes
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Correlation between predicted dose and
maintenance dose
Dose Matched
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INR VS genotype
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Conclusions Warfarin Prospective Study

• Dosage prediction based on genotypes alone can
  achieve high sensitivity (67)
• This sensitivity may increase when other factors
  are used in the prediction
• Time to stable INR is also shorten (1-2 weeks vs
  3-4 weeks)

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Types of Adverse Drug Reactions

• Type A dose dependent, usually predictable,
  common, monogenic or oligogenic model
• (example excessive bleeding with warfarin)
• Type B dose independent, unpredictable??, rare,
  polygenic model ??
• (example penicillin anaphylaxis,
  Stevens-Johnson syndrome)

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Stevens-Johnson Syndrome (SJS), a
life-threatening cutaneous adverse drug reactions
caused by medication
Patient No. 69, 22F, Drug Tegretol
Phenotype severe mucosal erosions and widespread
cutaneous erythematous macules with blisters
(bullous cADRs)
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• Drugs associated with Stevens-Johnson
• Syndrome (Data from 230 pts admitted to
  Chang-Gung
• Hospital during 1996-2003)
• Potential causes No. of patients
  of total patients
•  
• Anticonvulsants 91
  39.57
• Carbamazepine ???? 60
  26.1
• Phenytoin 19
  8.26
• Phenobarbital 8
  3.48
• Other 4
  1.74
• Antibiotics 23
  10
• NSAIDs 17
  7.39
• Allopurinol ???? 14
  6.09
• Other
  85 36.96
  
  
• Overall incidence 8 cases per million-person
  year in Taiwan
• Carbamazepine users 2,500 cases per
  million-users
• (50 new
  cases per year)

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Carbamazepine (Tegretol) is an aromatic
anti-convulsant widely used for seizure,
trigeminal neuralgia, bipolar disorder, etc.
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Carbamazepine-SJS/TEN Study design and methods

• Subjects Han Chinese residing in Taiwan
• Case 44 pts with carbamazepine-induced
  SJS/TEN
• Controls 101 pts tolerant to carbamazepine
• 93 normal subjects
• Methods
• Screening for association with candidate gene
  single nucleotide polymorphisms (SNPs) using high
  throughput MALDI-TOF mass spectrometry, followed
  by sequence based allele typing and short tandem
  repeat polymorphism (STRP) studies

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Candidate genes for adverse drug reactions SNP
association study
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Comparison of allele frequencies in the MHC region
44 CBZ-SJS/TEN patients vs. 101 tolerant
control 46 SNPs plt0.01 MHC class I, II
and III 6 SNPs plt10-10 between HLA-C
and DRA rs3130690 plt10-30 near HLA-B locus
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SJS patients vs. tolerant group
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-log(p value)
20
10
0
A
C B
DRA
29.8
30.8
31.8
32.8
33.8
Position of SNP on Chr6 (Mb)
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Medical genetics A marker for Stevens-Johnson
syndrome (HLA-B1502)
Nature 428
486, 2004
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Allele frequencies of HLA-B1502 among different
ethnic populations
Carbamazepine as the leading culprit drug
Ref http//www.allelefrequencies.net/
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HLA-B1502 a genetic marker for
CBZ-SJS/TEN in Southeast Asians
United States
China
Taiwan
Hong-Kong
Vietnam Cambodia
Chung et al Nature, 2004, Hung et al,
Pharmacogenetics Genomics, 2006
Reunion Island
Lonjou et al Pharmacogenomics J, 2006
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Is genetic marker drug-specific? Allopurinol

• A structural analog of hypoxanthine
  (4-hydroxypyrazole(3,4-d)pyrimidine)
  inhibit xanthine oxidase to produce uric acid
• A widely prescribed medication to prevent gout in
  patients with hyperuricemia

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Allopurinol induced severe cutaneous adverse
reaction (SCAR)
Stevens-Johnson syndrome (SJS) extensive
mucocutaneous
eruptions with
epidermal necrosis Toxic epidermal necrolysis
(TEN) gt30 detachment Hypersensitivity
syndrome (HSS) fever, rash, LAP, leukocytosis
internal organs involvement (acute nephritis,
hepatitis)
HSS
SJS
TEN
TEN
SJS
HSS
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Initial SNPs screen 30 cases vs. 60 tolerant
controls
(plt0.01) 29 SNPs in the MHC region (Plt10-7) rs31
17583 of BAT3 (encoding HLA-B associated
transcript 3), rs1150793 of MSH5 (mutS homolog
5), rs2855804 of MICB (MHC class I
polypeptide-related sequence B)
Chr 6
40

• Conclusions
• Allopurinol-SCAR (21 SJS/TEN, 30 HSS) is strongly
  associated with a genetic predisposition in Han
  Chinese.
• HLA-B5801 allele is an important genetic risk
  factor for this life-threatening condition.

(PNAS 102 4134, 2005)
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Allele frequencies of HLA-B5801 among different
ethnic population
Ref http//www.allelefrequencies.net/
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Pharmacogenetic Study Summary

• Carbamazepine-induced Stevens-Johnson
  syndrome/Toxic Epidermal Necrolysis is associated
  with HLA-B1502 allele ( OR 2,500), however, MPE
  is associated with HLA-A3101(OR 17.5) and HSS
  with promoter SNP in the motilin gene(OR7.1)
• Allopurinol-induced severe cutaneous adverse drug
  reactions is associated with HLA-B5801(OR 580)
• Question Are these specific alleles directly
  involved in the pathogenesis of the disease? or
  just a simple association?

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Genome-wide Scan 100K GeneChip
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Affy CBZ-SJS(40) vs tolerant (40)
Whole genome scanAffymetrix 100k
chip (Carbamazepine-Stevens Johnson Syndrome)
SNPs with p values less than 0.001
HLA-B
-log (p values)
the cutoff for Pc 0.05 after Bonferroni
correction
14
16
6
8
SNPs on the specific Chromosome
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Susceptible region for CBZ-induced SJS/TEN on
the extended HLA-B1502 haplotype
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Working model of the pathogenesis of SJS/TEN
Danger molecules

• HLA-B1502 presents CBZ/peptides to T cell
  receptor
• Infiltration of CBZ-specific T cells
• Activation of cytotoxic T cells
• Initiation of the apoptotic pathway
• Full-thickness necrosis of the epidermis with
  separation of epidermis and dermis by fluid

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Scientist as Fortune Teller

• Predicting risk is key to Genomic Medicine
• (Predicting drug toxicity with a gene test)

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HLA-B1502 as a test for carbamazepine-induced
Stevens-Johnson syndrome
Sensitivity 100 Specificity 97Positive
predictive value 7.7 Negative predictive
value 100
Odds ratio 3180, Pc 1.04x10-31
Assuming
0.25 prevalence rate Personalized Medicine
2225, 2005
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Conclusions - Severe Cutaneous ADR

• HLA-B alleles underlie the genetic susceptibility
  to severe cADRs
• The genetic susceptibility to drug-induced severe
  cADRs is both drug-specific and
  phenotype-specific (in the case of carbamazepine)
• The genetic susceptibility to drug-induced severe
  cADRs is likely ethnic-specific

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Potential new ways to manage health and disease

• Prescribe safe and appropriate warfarin dosage
  based on the genotypes ----- personalized
  medicine
• Severe ADRs the genetic markers can be used to
  identify individuals at risk for these
  drug-related life-threatening conditions
• Preventing ADRs by screening people at risk
  before prescription of a drug---- preventive
  medicine

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Genotyping Applications in Disease Research

• Adverse drug reactions pharmacogenetic study
• Mapping genes for mouse models of human diseases
• Cancer genomics

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ENU mouse library construction and screen
for disease phenotypes
Dominant screen
Recessive screen
ENU
ENU
X
Go
Go

X
G1
G1
X
G2


Random matings
G3
Map clone the disease gene
Screen for desired phenotypes
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Mouse Models of Human Diseases Identified
Through ENU Mutagenesis Program

• Neurological necrotizing encephalopathy,
  hydrocephalus, brain atrophy, pain insensitivity
  (YiJuang Chern Chen Chang)
• Cardiovascular arrhythmia, aortic stenosis ( CF
  Cheng JJ Chen)
• Renal hydronephrosis (Lee-Young Chau)
• Hematology lymphopenia (Jeff Yen)
• Pharmacogenetics phenobarbital resistance (David
  Tu)
• Metabolic branched chain amino acids elevation
  (YT Chen JY Wu)
• Metabolomics approach identified a mouse
  model of a genetic metabolic disease (J Clin
  Invest 2004 with accompanying commentary)
• fatty acid oxidation
  defects

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Mapping gene for lymphopenia phenotype
Genome-wide SNP scan
Mapped to chromosome 3 within 3Mbp IL-7 as the
responsible gene
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Mapping gene for mouse with cardiac fibrosis and
fatty liver (whole genome SNPs assay)

• 8 outcrossed N1F1 affected mice
• Homozygosity for B6 genotype

Human Molecular Genetics 15 3569, 2006
SNP ID
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Genotyping Applications in Disease Research

• Adverse drug reactions pharmacogenetic study
• Mapping genes for mouse models of human diseases
• Cancer genomics

57
Genome-wide SNP scan detects submicroscopic
chromosomal aberrations in acute lymphoblastic
leukemia

• You-Chin Lin, Ling-Hui Li, Alice Lin-Tsing Yu,
  Mitchell Diccianni, Chun-Yu Wei, Chien-Hsiun
  Chen, Sheng-Feng Ho, Kuo-Ching Jiang, Jer-Yuarn
  Wu, Yuan-Tsong Chen

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Why choosing T-Acute Lymphoblastic Leukemia
(T-ALL) for Affy 100K study?

• Cytogenetic analysis of ALL, esp. T-lineage, is
  difficult due to the low mitotic index and poor
  quality of the metaphases.
• There are still considerable portion of T-ALL
  demonstrating normal karyotypes.
• Unidentified submicroscopic chromosomal
  abnormalities and/or mutations may be responsible
  for leukaemogenesis or treatment failure of
  subtype T-ALL.
• Affymetrix GeneChip Mapping 100K set is a
  feasible tool to detect submicroscopic
  chromosomal abnormalities (lt 4Mb) as well as
  allelic alterations.

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Comparison of DNA Copy Number Change Detected by
Affymetrix and qPCR
60
Allelic imbalance detects complicated and
preferential amplification
3A1B
0.75
0.66
2A1B
0.34
1A2B
0.25
1A3B
61
Preferential amplification of the MYCN gene in
case 14
CN
LOH
Chr2
Existence of allelic imbalanced SNPs indicates
differential amplification of one allele. eg.
AF0.75 150A50B when there are 200 copies
of MYCN
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Cancer Genomics

• How the genome technologies help the area?
• Genotyping An example of using high density
  oligonecleotide arrays for genome-wide scan to
  detect subtle chromosomal changes in T-ALL
• Microarray expression profiles Toward
  personalized medicine

63
(No Transcript)
64
AGTCACCAGTTGTTATCTTGAAAGCCTCAGGAACTTCAGACGCAATTCAT
CCTGGCTACCCAGTGGGTCC AGAAAGGACCCAAGTGCACAAAGGGGCCG
GCATCGGCCAATCCTAGGGTGGGGAAAAGTTAGGTATCCAT
GCCCCTGTGCCCACTTCTTCCAGGCACAGCCCTTGGTTCTTGCTCTAGCT
CCCCTAAAGACACAGAAAAT ATTTAGAAGTTCACTTAACAAAAATATTA
CAGCTGGAAAGGACCTCAGAGATAACAATGGTAGTCCATCC
ACTTCATTTTATAGATGAGGAAAGTGAGGCCCAAACAAGTAAAGGAGCCG
ACTGAAGCGCCCGTGGTGAA TTAATGGCACAGTCGGAACTAGAGCCCAG
GCCTCTCTCCTCTCTAAAGTCTAAAACATTCTTGGATTTCA
GTTTCCTCTTCTGTAAAACGGGGTGAAAATTAGCCTCTCAGGACAGTGGT
GAGGAGCAAATGAGATAATG AATGTAAAAGAAATTACTATATTAGCAAC
AGAAATCAGAGCGGAGCGAGATGGTGTAGAGGAATCTAAGG
GGTGTCCGGAGACATGTGTTCCAGTCATGTCATCTCTGTGAACCTCAGTC
TCCTCATCTGCAAATGCAGG ACCTGGCCCGGCTGACCGCCGAGACCCTT
CCAGCTCTGCCGACCCAGGCCCTGAGGCCCTTCCCGGAGGG
CCGGACCCTGAGGGAAAAAAACGAAGGAGCCCGTGGGGACCCTCGAGTTA
CCGTCCTGCAGCAGCGCAGT CTTCTGGGCTGTCCGCAGACTCTCCAACC
AGCCCGTCACCGCCATCTTTCCCCTGCTAAGCAGCACGCCC
AGCCGCTGCCATGGCAACCGTTCCAGAGGGTCACTTCCGGCTGACTCGGA
AGCTATTCTGGCCATTTGCC CTCCTTCCCCCCTTCGTCCGCTCTCATTG
GCTCTGCTGGTAAGTGGTCTATTCCTGCCCACCCCCGGGTG
ACTAGCTTGGCCAGTAGTCGACCCCACCCGGGGACCGACTCTGGGGGTTG
GAGAGACTCTTGGGGCCGGG GTCGGGCACTCCAGCTTTCTTCTAGCCCC
GAGCTGGGATTCCCTGGCCTGCGCCAGCTGCGTACACGGCG
AGTACACCGCACCTGCCCGGGACTTCACCCGCAGCTGCGAGACTCCTCCA
TTCCCGGAGGGCTCCCCACA CCTGCTGCGGCCGTGCCCCATCTCCCCGC
AGCTGCGGCGCTGAGCACCCCCATGTCGAGAGGCTGAGACC
AGGACAGGTGCAGGGCGTTCCCACTCACCCCCGAAAGTCCTCCTCCTTCC
TCTGCGAGTCTGTGTTGGAG GTAGAGAAATAGTATGTGGGGTTTATGTG
CAGGTCCTCCCCAGGCTCCGCTCCATCCCCTAAAGCTCCAT
TTCCTAGCCCAGCATCCCATTTGGTAAAGCCCTTCGAAGTGGGCCGCAGC
AGGGCTGTGCTGAATCTTTA GCGCAACCCCTCTGAGGAATGGTGTCGTT
TCCTACTCCTCAAAAGTACCCCCGATGGCACCAGCCTTCCC
CTCATTTCCCGTAATACTCCAACTTCGAAAGGCTGGGGAGTGTGAAGCTA
GGCTAAACCACTGAAGTTTA ACCGGGTTTGAAGAGACCCCCTCCCCCGA
CCCGCTTCCCCAAACTGGGCTGCTACCCCCAAAGCCTGGTC
AGGAAAGACCCTACCTCCATAGGCAAAGGGGTTGGAGGGCCTCAATTCTG
GATTTCCACGTGCAGCAGCC CTGACCAACGCTCCAATAGGCCGGGATCC
AGCCATACTTCAATGGATCCCAGGGGTATCTTGAAGGCATT
TCCCAAGCGGCAGAAAATTCATGCTGATGCATCATCAAAAGTACTTGCAA
AGATTCCTAGGAGGGAAGAG
65
Progress of Lung Cancer Genomics

• Lung cancer network and patient cohorts
• 2,400 Pts and controls, serum, DNA, tissue
  bank
• Identify specific genetic and epigenetic changes
• (Wang YC JCI 2003, JCO 2005, CCR 2005)
• Aptamer for specific protein markers
• Mechanisms of EGFR mutation and EGFR-TKI response
  (Chen YR Oncogene 2006)
• Novel tumor suppressor and invasion suppressor
  CRMP-1, HLJ1 (JNCI 2001, 2004, 2006)
• Gene signature for personalized therapy (NEJM
  2007)
• MicroRNA signature to predict lung cancer outcome

Yang PC and Peck K
66
Affymetrix GeneChip Mapping 100K set

• Covering 116,204 (100K) SNPs
• DNA hybridization-based genotyping platform
• Generating genotypes and DNA copy number
• Applied to cancer genetics for detecting
  submicroscopic chromosomal aberrations and
  allelic alterations

67
On-going Cancer Research Projects
68
Allelic imbalance detects copy-number neutral LOH
Assume CN 2 for each SNP
(A)f 2/2 1 if AA (A)f 1/2 0.5 if AB (A)f
0/2 0 if BB
69
Taiwan Biobank A Prospective Cohort Study
Gene
Environment
Life Style
Medical factor
Diet
Multi-factorial process
Cohort of Healthy Individual Population-at-risk
200,000
Seeking for Causes of Diseases
Diseased
Long term follow-up
To promote the health of next generations
Approaches of preventing disease or Protocols of
early diagnosis/effective treatment
70
Academia Sinica Genomic Medicine Research Theme
Human Genetics Genomics
ENU Mouse
Bioinformatics
Structural Biology
Proteomics
Disease Genes/Targets/Markers
Diagnostics Pharmacogenetics
Preventive Medicine
Pathways, Biology Drugable Targets
Predictive Medicine
Drug Therapy
Gene Therapy
(Ethnic differences in genes associated with
complex diseases and pharmacogenetics)
71
Copy number change of a T-ALL pt
gain
3
Copy number P-Value
2
2
loss
1.3
72
GeneChip Platform (III)

• Established in 2005 as Affymetrix 100K GeneChip
  System Center of Excellence
• Enables Human Whole Genome Scan

73
SJS is not just a skin disorder A patient
suffered from SJS caused by Motrin received lung
transplant
74
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75
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76
Genotyping Platform (II)
Major Instruments (STRP)

• STRP (Short Tandem Repeat Polymorphism, or
  Microsatellite) Genotyping Platform
• Applied Biosystems 3730 DNA Analyzer
• Highly automated capillary electrophoresis
  technology

Hamilton MPH-96
SpectroREADER
ABI 3730
Hamilton MPH-96