Genetic Testing in Genomic Medicine

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Genetic Testing in Genomic Medicine

• Gail H. Vance M.D.
• Professor, Department of Medical Molecular
  Genetics
• Indiana University School of Medicine

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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.

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Personalized Healthcare

• Understanding variability between individuals
  allows for more targeted or personalized
  healthcare based on genetic differences.

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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.

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Medicine of the past could be called
trial-and-error medicine
Observe
Diagnose
Treat
Monitor response
Adjust
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Because we know more specific information, we can
Diagnose more precisely Provide more effective treatment.
Select specific treatment that best fits disease Target the medication to the disorder. Avoid adverse drug reactions. Avoid delay from false starts.
Predict risk before symptoms occur Provide earlier treatment. Take preventive action.
Manage disease more effectively Eliminate unnecessary treatment. Provide better timing. Adjust treatment as disease changes.
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Diagnose more precisely
Genetic tests identify DNA mutations of childhood
leukemia, enabling physicians to choose the
treatment that fits it precisely.
The impact of genetic tests and genome-based
cancer drugs on survival of childhood leukemia

• Acute lymphoblastic leukemia is most common form
  of childhood leukemia
• Genetic tests identify subtypes allow precise
  treatment and timing
• Todays cure-rate exceeds 80 vs. 4 in the 1960s

Source New England Journal of Medicine, 2006,
200l Personalized Medicine Coalition, 2006.
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Comparative Genomic Hybridization
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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.

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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.

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Today, Cancer is experiencing a shift toward
precision medicine
Farber develops 1st chemotherapy for leukemia
Novartis launches Gleevec, the 1st molecular
targeted drug, to treat myeloid leukemia
2 types leukemia lymphoma
1920
1930
1940
1950
1960
1970
1980
1990
2000
2010
Disease of the blood
38 types of leukemia 51 types of lymphoma
3 types of leukemia (acute, chronic, preleukemia)
and 2 types of lymphoma (indolent, aggressive)
Source Mara Aspinall, Genzyme
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Genetic tests identify variations in the BRCA 1
and BRCA 2 genes that increase risks for breast
and ovarian cancer.
Predict Risk of Disease Before Symptoms

• Genetic tests identify greatly increased
  hereditary risk for breast and ovarian cancer
• Knowledge of increased risk allows preventive
  measures, such as closer monitoring, risk
  avoidance, and preventive surgery or chemotherapy

Lifetime risk of developing breast cancer
with BRCA 1 and 2 50 - 85
.without 13
Lifetime risk of developing ovarian cancer
with BRCA 1 and 2 10 - 45
without 1.7
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Hereditary predisposition for cancer

• Autosomal dominant inheritance
• high but incomplete penetrance
• variable expression
• Early-onset diagnosis
• Multiple cases of a cancer
• More than one primary cancer/Bilateral disease

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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
Molecular Diagnostics
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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.

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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

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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 side-effects (ALL, VKORC1/CYP2C9)
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The Promise of Personalized Healthcare

• Tailoring the diagnosis, prognosis, and treatment
  to the individual will improve healthcare
  outcomes and patient safety.