Transcript Genetic Testing in Genomic Medicine

Genetic Testing
in Genomic Medicine
Gail H. Vance M.D.
Professor, Department of Medical & Molecular Genetics
Indiana University School of Medicine
Genomic Medicine
• The Human Genome Project completed in 2003
provided access to the entire human gene sequence
or genome…..
• In effect, the genome is a set of tools enabling
physicians to understand the biological and disease
variability of their patients.
Personalized Healthcare
• Understanding variability between individuals allows
for more targeted or personalized healthcare based
on genetic differences.
Genetic Tests
• Genetic tests are powerful as they:
– Diagnose the disease more precisely.
– Allow for selection of a specific medication to best
treat the disease.
– Predict the risk of disease before symptoms occur.
– Manage the disease more effectively.
Medicine of the past could be called “trial-and-error” medicine
Observe
Diagnose
Treat
Monitor
response
Adjust
Because we know more specific information, we can…
Diagnose more precisely
AND…
• Provide more effective treatment.
Select specific treatment that best AND…
fits disease
• Target the medication to the disorder.
• Avoid adverse drug reactions.
• Avoid delay from false starts.
Predict risk before symptoms occur AND…
• Provide earlier treatment.
• Take preventive action.
Manage disease more effectively
AND…
• Eliminate unnecessary treatment.
• Provide better timing.
• Adjust treatment as disease changes.
Diagnose more precisely
Genetic tests identify DNA mutations of childhood leukemia, enabling
physicians to choose the treatment that fits it precisely.
•
Acute lymphoblastic
leukemia is most common
form of childhood leukemia
The impact of genetic tests and genome-based
cancer drugs on survival of childhood leukemia
90
80
70
•
Genetic tests identify
subtypes; allow precise
treatment and timing
60
50
40
30
•
Today’s cure-rate exceeds
80% vs. 4% in the 1960s
20
10
0
1962
2007
Source: New England Journal of Medicine, 2006, 200l; Personalized Medicine Coalition, 2006 .
Comparative Genomic Hybridization
Courtesy of Signature
Genomics
Select specific treatment
• A translocation between chromosomes 9 and 22
results in a fusion gene formed from the BCR and
ABL1 genes. The fusion on chromosome 22 is known
as the Philadelphia chromosome and is
characteristic of chronic myeloid leukemia.
Chronic Myeloid Leukemia
• The BCR/ABL1 fusion results in increased
cellular signaling causing white blood cell
proliferation.
• Imatinib (Gleevec) is an oral medication that
targets the translocation and arrests the
disorder.
Today, Cancer is experiencing a shift
toward precision medicine
2 types: leukemia
& lymphoma
1920
1930
1940
Disease of
the blood
Source: Mara Aspinall, Genzyme
Farber develops
1st chemotherapy
for leukemia
1950
1960
Novartis launches Gleevec, the
1st molecular targeted drug, to
treat myeloid leukemia
1970
1980
3 types of leukemia (acute,
chronic, preleukemia) and 2
types of lymphoma (indolent,
aggressive)
1990
2000
38 types of
leukemia; 51 types
of lymphoma
2010
Predict Risk of Disease Before Symptoms
Genetic tests identify variations in the BRCA 1 and BRCA 2 genes that
increase risks for breast and ovarian cancer.
• Genetic tests identify
greatly increased
hereditary risk for breast
and ovarian cancer
Lifetime risk of developing breast cancer…
…with BRCA 1 and 2 = 50% - 85%
….without = 13%
• Knowledge of increased
risk allows preventive
measures, such as closer
monitoring, risk
avoidance, and preventive
surgery or chemotherapy
Lifetime risk of developing ovarian cancer…
…with BRCA 1 and 2 = 10% - 45%
…without = 1.7%
Hereditary predisposition for cancer
Br ca, dx 50
Br ca, dx 42
Pr ca, dx 60
Ov ca, dx 58
Br ca, dx 35
1) Autosomal dominant inheritance
• high but incomplete penetrance
• variable expression
2) Early-onset diagnosis
3) Multiple cases of a cancer
4) More than one primary cancer/Bilateral disease
Br ca, dx 45
Molecular diagnostics is at the core of
the personalized medicine vision
Diseases will be diagnosed
long before the patient
begins to manifest any
evidence using traditional
tools
Signs & Symptoms
Molecular
Diagnostics
In vitro
Laboratory
Tests
In vivo
Imaging
Techniques
Managing Disease More Effectively
• Warfarin is an anticoagulant used to
decrease the incidence of
thromboembolisms (blood clots).
• Highly variable responses to the drug.
• Tight range of therapeutic response.
• Variants of two genes, CYP2C9 and VKORC1
account for 30-50% of the variability.
Genomic medicine implies
personalization and all its benefits
• Diagnosis/ predicting risk of disease
• Determining whether a treatment
is working
• Monitoring healthy people to
detect early signs of disease
• Producing safer drugs by predicting
potential for adverse effects earlier
• Producing better medical products
• Ready access to information
• Decreasing health care costs
Genetic testing enables new way of thinking about health
reform
Concerns underlying health
reform
Impact of genetic testing
Overutilization
Utilization only by those who
can benefit- (Imatinib)
Inappropriate care
More tailored care that precisely
fits the disease (ALL)
High Costs
Less spent on unnecessary care
Patient Safety
Precise treatments reduce sideeffects (ALL, VKORC1/CYP2C9)
The Promise of Personalized
Healthcare
• Tailoring the diagnosis, prognosis, and
treatment to the individual will improve
healthcare outcomes and patient safety.