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 Adjust ObserveDiagnoseTreat Monitor response

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. AND…

Acute lymphoblastic leukemia is most common form of childhood leukemia Genetic tests identify subtypes; allow precise treatment and timing Today’s cure-rate exceeds 80% vs. 4% in the 1960s The impact of genetic tests and genome-based cancer drugs on survival of childhood leukemia Source: New England Journal of Medicine, 2006, 200l; Personalized Medicine Coalition, Diagnose more precisely Genetic tests identify DNA mutations of childhood leukemia, enabling physicians to choose the treatment that fits it precisely.

Courtesy of Signature Genomics Comparative Genomic Hybridization

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 Disease of the blood 2 types: leukemia & lymphoma Farber develops 1 st chemotherapy for leukemia 3 types of leukemia (acute, chronic, preleukemia) and 2 types of lymphoma (indolent, aggressive) Novartis launches Gleevec, the 1 st molecular targeted drug, to treat myeloid leukemia 38 types of leukemia; 51 types of lymphoma Source: Mara Aspinall, Genzyme

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 Knowledge of increased risk allows preventive measures, such as closer monitoring, risk avoidance, and preventive surgery or chemotherapy Predict Risk of Disease Before Symptoms … with BRCA 1 and 2 = 50% - 85% ….without = 13% Lifetime risk of developing breast cancer… Lifetime risk of developing ovarian cancer… …with BRCA 1 and 2 = 10% - 45% … without = 1.7%

Hereditary predisposition for cancer 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 50 Br ca, dx 42Pr ca, dx 60Ov ca, dx 58 Br ca, dx 45Br ca, dx 35

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 In vitro Laboratory Tests In vivo Imaging Techniques Signs & Symptoms Molecular Diagnostics

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 CostsLess spent on unnecessary care Patient Safety Precise treatments reduce side- effects (ALL, VKORC1/CYP2C9)

The Promise of Personalized Healthcare Tailoring the diagnosis, prognosis, and treatment to the individual will improve healthcare outcomes and patient safety.