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Genomics, cancer, and medicine: 10 years after the
Human Genome Project
Edison Liu, M.D.April 13, 2012
We are entering one of the most profound periods of advancement in biology and medicine – one that will
transform:
Health and Medicine
Driven by technologies in genetics, genomics, and computational biology
Declaration
Genomics and Genetics
Genetics: study of genes and their function
Genomics: study of all genes and how they function together
“Discover all possible genes involved in a biological process or a human disease”
Genomics enables the
complete genetic “view” of a disease
Transformative technologies enabling this revolution:
•New generation of ultra-fast sequencing
technologies
“Massive Data Generation”
• Enabling computational advances
“”Analytical power“•Genetic engineering to model organisms of disease
“Surrogates of disease”
CTAGCTGATTCAG
CTAGCTGATTCAG
AAGT
T*
A*C*
G*
T*
T*
AGT
A*
Massively Parallel Sequencing:
Sequencing by Synthesis
~105-107 kb per run = 0.1-3 X human genome equivalents / run
MR Stratton et al. Nature 458, 719-724 (2009)
7 orders of magnitudeincrease in throughput
Cost of sequencing a human genome
300,000 USD -
30 million USD -
300 million USD -
2003
2005
2007
2009
2001
300 million
1 million
$60,000
$ 3,000
2011
3 million USD -
30,000 USD -
Cost-effective sequencing =Accessibility of genomic data
Low complexityimage
Data complexity when ordered
appropriately giveshigh resolution
picture
Genomic scale information providesunique biological insights
Genomics & Personalized Medicine
Conventional chemothrapy
Towards personalized cancer medicine
Non-selective
No benefit
RespondersSevere side effect
Personalized cancer medicine
Molecular marker&
target
Selection
by marker
Other therapyNo treatment
Molecular specific
drug
High response rate
CAT ATE RAT Wild Type
BAT ATE RAT Point Mutation
RAT ATE CAT Rearrangement
Cathryn Polymorphism
Kathryn Polymorphism
Kathrine Polymorphism
Chronic Myelogenous Leukemia:and the 9;22 chromosomal rearrangement
• Ph1 chromosome identified 1960 as a marker for CML (Nowell)• bcr-abl cloned and shown to be the molecular mechanism 1984-1990 (Groffen and Lugo)
Molecular Mechanisms: How to make a Leukemia
BCR
ABL
ChronicMyelogenous
Leukemia
Chronic Myelogenous Leukemia: Mortality 1969 - 2002
Gleevec Approved By FDA
Large scale clinical
trials begin with Gleevec
BCR ABL
STI521:Gleevec
• Ph1 chromosome identified 1960 as a marker for CML (Nowell)• bcr-abl cloned and shown to be the molecular mechanism 1984-1990 (Groffen and Lugo)• Specific drug (Gleevec) to target gene abnormality 1999 (Druker)
From discovery of a single oncogene to treatment: 39 years
From Concept to Molecular Mechanism to Treatment
EML
ALK
LungCancer
Nature 2007
In 2007, the genomic analysis of one lung cancer from a 62 year-old smoker EML-ALK fusion in 6% of lung cancer patients
Crizotinib 60% response rate in those 6% of patients with lung cancer with the EML-ALK mutation. On August 26, 2011, the US FDA gave approval of crizotinib by for the treatment of ALK-rearranged lung cancer
Ou, Drug Des Devel Ther. 2011; 5: 471–485.
4 years from genomic discovery to treatment
Chronic Myelogenous Leukemia (CML)
Optimizing treatment for CML based on genetic makeup of the patient
Clinical Challenge: Drug resistance•Acquired resistance – resistance after long term treatment - due to second ABL mutation•Primary resistance – resistance at the beginning of treatment. •In Asia, complete cytogenetic response rates are lower - 50% vs. 74%. Mechanism unknown
Question: is there a reason why 25% of CML cases do notrespond to imatinib?
Approach: We compared the genomes of three CML cases with primary resistance to Imatinib with two CML cases sensitive to Imatinib therapy
Results:
3/3 resistance cases had the same 2.9kb deletion in the BIM gene not seen in sensitive cases (0/2)
BIM:
•BIM is a gene that activates cell death (pro-apoptotic). •Activated BCR-ABL1, suppresses BIM function thus allowing leukemia cells to survive. When CML cells are treated with Imatinib, BIM expression goes up cell death
Bcr-ABL: CML Intact BIMDeath of
Leukemia cells
Imatinib
BIM deletion polymorphism:
•This deletion polymorphism is 3-5X more common in CML cases resistant to imatinib that sensitive cases
•This 2.9 kb 2 deletion of BIM is not a mutation, but is a polymorphism present in normal genomes (a germline polymorphism):
12% in Asian individuals 0% in Africans
0% in Caucasians
How does it work?: The 2.9kb BIM deletion polymorphism results an abnormal transcript (E3) that a produces a truncated and inactive BIM protein
Bcr-ABL: CML Intact BIMDeath of
Leukemia cells
Imatinib
Bcr-ABL: CML BIM E3
Primary Drug Resistance
Imatinib
NormalTranscripts
E3
We used this genomic intelligence to overcome this resistance:
Bcr-ABL: CML BIM 3 Primary Drug
Resistance
Imatinib
Imatinib
Bcr-ABL: CML BIM
BH3 mimetics
Death of Leukemia
cells
This genomic experiment with 5 patients explains the lower response rate In North Asians to a life saving treatment in CML. Personalizing medicine in Asia
Now: New
CML Patientin Asia Check for bcr-ABL
rearrangementCheck for 2.9kb
deletion polymorphism in BIM
YES
~50% cytogenetic response
YESNO
Imatinib
Imatinib&
BH3-mimetic
75% cytogenetic response
>75% cytogenetic response
LOHCopyNumber
StructuralVariations
BT55
17
Visualizing the Cancer Genome
‘Conductor’ mutation = early event that conducts the direction of further cancer mutations
Mutation patternappears to be generated by separate cuts when mapped to the original physical “map”
Chromosomal “origami” simultaneously generates oncogenic “pattern”
Chromosomal origami to generate cancer gene cassette
ERBB2P53 BRCA1
ERBB2
ERBB2
ERBB2
ERBB2ERBB2
17q21.3
17q21.3
17q21.3
Oncogenes 17q21.3
BT55 (ER+, ERBB2++)Luminal B
ERBB2/HER217q21.3 amplicon
BRCA1
TD207
U-Inv331
U-Inv75Del51TD49 + Del67
Amplification
ERBB217q21.3 17q21.3
Oncogene
There are 16 weak oncogenes here.4 that are synergisticwith ERBB2 oncogenesis
Tumor Suppressor
Gene
Chr17 ‘evolutionary origami’ has treatment implications for Combination therapy
17p (TP53) loss17p (TP53) loss
BRCA1 locus lossBRCA1 locus loss
Tandem duplication in ERBB2 locus
Tandem duplication in ERBB2 locus
Recurrent Unpaired-Inversion:
“Conductor” Mutation
Recurrent Unpaired-Inversion:
“Conductor” Mutation
Chromosomal instabilityChromosomal instability
Cancer progression
17q21.3 amplification
17q21.3 amplification
Tumor Suppressor
genes
Tumor Suppressor
genes
OncogenesOncogenes
Massive ERBB2 amplification
Massive ERBB2 amplification
Lapatinib
PARP inhibitor
New Target
Nutlins
Cancer Genomics Consultation Model Using Mouse Avatars for Human Disease
Tumor DNA sample
Germline DNA sample
Generation of serum-based
personalized and private cancer biomarker test
Monitor for recurrence and clonal variation
Visualization formatted report
Sequence Tumor
Expand tumor inNSG mice
Automated sequence
analysis of tumorand germline
Druggable mutations
Prognostic information
Germline pharmacogenetic
analysis
Identification of cancer specific
rearrangements
Test specified drugs for
response in vivo
Devise optimal combination
therapy
Consultation with patient and
physicianfor treatment
plan
RadiologistRadiologist of the Genome
Interprets complex datarendered through
computational algorithms
Is the consultants to doctors
Genomics, cancer, and medicine: 10 years after the
Human Genome Project
Edison Liu, M.D.April 13, 2012
1990
Age Adjusted Mortality for breast cancer is declining since 1990
T2N1M0
ER (IHC) positiveHER2 (FISH) PositiveKi67: +++ GHI recurrence score: XXX Age: 56 family history: negative
Sequence performance: 9.6 million reads; 75 base pair, paired end on Illumina HiSeq
Comparison of germline and cancer genomesThis is a visual representation of the cancer genome of your patient as compared to her constitutional (germline) genome.The 23 chromosomes are arrayed in a circle; amplifications are on the outer circle, and the deletions and inversions are in the inner circles. In the innermost circle is a representation of the chromosomal translocations. Each arc represents a translocation, and the intensity of the arcs is an indication ofAmplification of that translocation. By clicking onto the figure, you will get a blow up of the schematic and a detailed legend.
The mutational load score is a composite score the integrates the mutational load that is seen in the tumor of your patient. It is made up of two components: sequence mutations, structuralmutations/rearrangements. Your patient’s mutational score when compared to a panel of XXX tumors of the same type is in the following distribution:
Nor
mal
Max
imal
1990
2020
Can death from breast cancer be eliminated?
What if this trend continues?