Special Topic II Genomics and Personalized Medicine

Genomics and Personalized Medicine Videos http://www.youtube.com/watch?v=dUL5f8nB-8w&list=PL8B8F905B1B09259C Genomics and Personalized Medicine Videos © 2012 Pearson Education, Inc.

How do drugs work? © 2012 Pearson Education, Inc.

Personalized Medicine and Pharmacogenomics: Optimizing Drug Therapies What do you think pharmacogenomics is? Pharmacogenomics is the study of how an individual's entire genetic makeup determines the body's response to drugs Why is this an important area of research? Because there are so many interactions that occur between a drug and proteins within the patient, many genes and many different genetic polymorphisms can affect a person's response to a drug © 2012 Pearson Education, Inc.

Optimizing Drug Therapies On average, a drug will be effective in only about 50% of patients who take it (ST Figure 2.1) Trial and error is used till the correct drug is found for a patient This is a waste of time and can be dangerous © 2012 Pearson Education, Inc.

ST Figure 2.1 © 2012 Pearson Education, Inc.

Optimizing Drug Therapies Pharmacogenomics increases the efficacy of drugs by matching those drugs to subpopulations of patients who will benefit widely practiced in the diagnosis and treatment of cancers © 2012 Pearson Education, Inc.

Optimizing Drug Therapies: HER-2 gene & Herceptin Personalized medicine was successfully used in the HER-2 gene and the use of the drug Herceptin in breast cancer The human epidermal growth factor receptor 2 (HER-2) gene is located on chromosome 17 and codes for transmembrane tyrosine kinase receptor protein called HER-2 © 2012 Pearson Education, Inc.

Human epidermal growth factor receptor 2 © 2012 Pearson Education, Inc.

Optimizing Drug Therapies In about 25 percent of invasive cancers, the HER-2 gene is amplified and the protein is overexpressed on the cell surface In some breast cancers, the HER-2 gene may have as many as 100 copies per cell This amplification is associated with increased tumor invasiveness, metastasis, and cell proliferation as well as poorer patient prognosis © 2012 Pearson Education, Inc.

Optimizing Drug Therapies Using recombinant DNA technology, Genentech Corporation in California developed a monoclonal antibody known as trastuzumab (or Herceptin®) In cancer cells that overexpress HER-2, Herceptin treatment causes cell-cycle arrests and, in some cases, death of cancer cells © 2012 Pearson Education, Inc.

© 2012 Pearson Education, Inc.

© 2012 Pearson Education, Inc.

© 2012 Pearson Education, Inc.

Optimizing Drug Therapies Herceptin only acts on breast cancer cells that have amplified HER-2 genes; therefore, it is important to know the HER-2 phenotype of each cancer Herceptin has potentially serious side-effects; therefore, its use must be limited to those who could benefit from the treatment © 2012 Pearson Education, Inc.

Optimizing Drug Therapies Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are molecular assays that can be used to determine the gene and protein status of breast cancer cells (ST Figure 2.2) Herceptin used in combination with chemotherapy increases survival by 25 to 50 percent versus chemotherapy alone © 2012 Pearson Education, Inc.

© 2012 Pearson Education, Inc.

ST Figure 2.2 © 2012 Pearson Education, Inc.

Optimizing Drug Therapies There are dozens of drugs whose prescription and use depend on the genetic status of the target cells Approximately 10 percent of FDA-approved drugs have labels that include pharmacogenomic information (ST Table 2.1) © 2012 Pearson Education, Inc.

ST Table 2.1 © 2012 Pearson Education, Inc.

© 2012 Pearson Education, Inc.

Reducing Adverse Drug Reactions Every year, about 2 million people in the United States have serious side-effects from pharmaceutical drugs, and approximately 100,000 people die The costs associated with these adverse drug reactions (ADRs) are estimated to be $136 billion annually © 2012 Pearson Education, Inc.

Reducing Adverse Drug Reactions Sequence variations in a large number of genes can affect drug responsiveness (ST Table 2.2) Cytochrome P450 family of proteins is particularly significant and is encoded by 57 different genes The products of the CYP2A6, CYP2B6, CYP2C9, CYPC19, CYP2D6, CYP2E1, and CYP3A4 genes are responsible for metabolizing most important pharmaceutical drugs. © 2012 Pearson Education, Inc.

ST Table 2.2 © 2012 Pearson Education, Inc.

Reducing Adverse Drug Reactions People with some gene variants metabolize and eliminate drugs slowly, which can lead to accumulations of the drug and overdose side-effects In contrast, other people have variants that cause drugs to be eliminated quickly, leading to reduced effectiveness © 2012 Pearson Education, Inc.

Reducing Adverse Drug Reactions There are more than 70 variant alleles of the gene CYP2D6, which encodes debrisoquine hydroxylase enzyme, which is involved in the metabolism of approximately 25 percent of all pharmaceutical drugs, including diazepam, acetaminophen, clozapine, beta blockers, tamoxifen, and codeine Some mutations reduce the activity of the enzyme, whereas others increase it (ST Figure 2.3). © 2012 Pearson Education, Inc.

ST Figure 2.3 © 2012 Pearson Education, Inc.

Reducing Adverse Drug Reactions The TPMT gene encodes the enzyme thiopurine S-methyltransferase (TPMT), which metabolizes a large number of drugs, including many psychoactive drugs and thiopurine drugs used to treat cancers There are more than 28 variant alleles of this gene, most of which are single-nucleotide polymorphisms (SNPs). Create amino acid substitutions and reduce enzyme activity. © 2012 Pearson Education, Inc.

Reducing Adverse Drug Reactions The FDA approved (2005) the use of a microarray gene test (AmpliChip®) that detects 29 genetic variants of CYP2D6 and CYP2C19 (ST Figure 2.4) Detects SNPs, deletions, and duplications. © 2012 Pearson Education, Inc.

ST Figure 2.4 © 2012 Pearson Education, Inc.

Reducing Adverse Drug Reactions Another example of pharmacogenomics in personalized medicine is the CYP2C9 and VKORC1 genes and the drug warfarin Warfarin (Coumadin) is an anticoagulant drug prescribed to prevent blood clots after surgery and aid people with cardiovascular disease who are prone to blood clots © 2012 Pearson Education, Inc.

Reducing Adverse Drug Reactions Warfarin inhibits vitamin K-dependent synthesis of several clotting factors If the dosage of warfarin is too high, the patient may experience serious hemorrhaging; if it is too low, the patient may develop life-threatening blood clots © 2012 Pearson Education, Inc.

Reducing Adverse Drug Reactions Variations in warfarin activity are affected by polymorphisms of several genes, particularly CYP2C9 and VKORC1 Two single-nucleotide mutations in CYP2C9 lead to reduced elimination of warfarin and increased risk of hemorrhage Patients who are heterozygous or homozygous for some alleles of CYP2C9 require a 10–90 percent lower dose of warfarin. © 2012 Pearson Education, Inc.

Reducing Adverse Drug Reactions The VKORC1 gene encodes vitamin K epoxide reductase complex subunit 1b, a vitamin K-activating enzyme that is required for the formation of clotting factors The activity of this enzyme is inhibited by warfarin A mutation in the promoter region of this gene leads to lower levels of VKORC1 and clotting factors, which leads to increased sensitivity to warfarin, requiring lower doses of the drug. © 2012 Pearson Education, Inc.

Reducing Adverse Drug Reactions The FDA has recommended the use of CYP2C9 and VKORC1 genetic tests to predict the likelihood that a patient may have adverse effects to warfarin It is estimated that the use of warfarin genetic tests could prevent 17,000 strokes and 85,000 serious hemorrhages per year The savings in health care could reach $1.1 billion per year © 2012 Pearson Education, Inc.

Personal Medicine and Disease Diagnosis As of 2009, there were genetic tests for approximately 2000 different diseases (ST Figure 2.6) © 2012 Pearson Education, Inc.

ST Figure 2.6 © 2012 Pearson Education, Inc.

Personal Medicine and Disease Diagnosis Diagnostic Tests Detect the presence or absence of gene variants linked to suspected genetic disorder in a symptomatic patient Predictive Tests Detect a gene mutation in patients with a family history of having a known disorder (e.g. Huntington Disease or BRCA-linked breast cancer). © 2012 Pearson Education, Inc.

Personal Medicine and Disease Diagnosis Carrier Tests Help identify patients carrying a mutation linked to a disorder that may be passed to offspring (e.g. Tay–Sachs or cystic fibrosis). Prenatal Tests Detect potential genetic disease in a fetus (e.g. Down syndrome). Preimplantation Tests Performed early on embryos in order to select embryos that do not carry a suspected disease. © 2012 Pearson Education, Inc.

Personal Medicine and Disease Diagnosis Most of these genetic tests detect the presence of known mutations in single genes that are linked to a disease (ST Table 2.3) However, most diseases are multifactorial and complex These diseases tend to be chronic and have a significant burden on the health-care system © 2012 Pearson Education, Inc.

Insert ST Table 2.3 from page 512 here. © 2012 Pearson Education, Inc.

Personal Medicine and Disease Diagnosis Genomic sequencing, SNP identification, and genome-wide association studies (GWAS) are beginning to reveal some of the DNA variants that may contribute to the risk of developing multifactorial diseases such as cancer, heart disease, and diabetes © 2012 Pearson Education, Inc.

Personal Medicine and Disease Diagnosis As whole-genome sequencing becomes faster and more economical, scientists predict that genomics and personal genome sequencing will become a significant part of personalized diagnosis and treatment by 2015 © 2012 Pearson Education, Inc.

Analyzing One Personal Genome A personal genome of a 40-year-old male who had a family history of arthritis, aortic aneurysm, coronary heart disease, and sudden cardiac death was done using a rapid single-molecule sequencing method The patient's sequence was compared with other human genome sequences in databases, and a total of 2.6 million SNPs and 752 copy number variations were discovered © 2012 Pearson Education, Inc.

Analyzing One Personal Genome The researchers sorted through genome sequence data to determine which of these variants might have an effect on phenotype The analysis required the combined efforts of more than two dozen scientists and clinicians over a period of a year and information gleaned from more than a dozen sequence databases, new and exiting sequence analysis tools, and hundreds of individually assessed research papers © 2012 Pearson Education, Inc.

Analyzing One Personal Genome The analysis of the patient's genome sequence for predicting development of multifactorial disease was even more challenging Once all the genetic risks were made available, the patient was offered the services of clinical geneticists, counselors, and clinical directors in order to help interpret the information generated from the genome sequence © 2012 Pearson Education, Inc.

Analyzing One Personal Genome Genetic counseling covered areas such as psychological and reproductive implications of genetic disease risk, the possibilities of discrimination based on genetic test results, and the uncertainties of assessments © 2012 Pearson Education, Inc.

Technical, Social, and Ethical Challenges The technologies of genome sequencing and alignment, microarray analysis, and SNP detection need to be faster, more accurate, and cheaper Personalized genome analysis needs to be used with caution until the technology becomes highly accurate and reliable © 2012 Pearson Education, Inc.

Technical, Social, and Ethical Challenges A greater challenge lies in the ability to store and interpret the vast amount of emerging sequence data Each personal genome generates the letter equivalent of 200 large phone books, which must be stored in databases, be mined for relevant sequence variants, and have meaning assigned to each SNP © 2012 Pearson Education, Inc.

Technical, Social, and Ethical Challenges Experts suggest that such studies will take the coordinated efforts of public and private research teams, and more than a decade to complete Personalized medicine will also need to integrate information about environmental, personal lifestyle, and epigenetic factors © 2012 Pearson Education, Inc.

Technical, Social, and Ethical Challenges Health-care providers will need to use electronic health records to store, retrieve, and analyze each patient's genomic profile, as well as to compare this information with constantly advancing knowledge about genes and disease To make personalized medicine available to everyone, the cost of genetic tests and genetic counseling that accompanies them needs to be reimbursed by insurance © 2012 Pearson Education, Inc.

Technical, Social, and Ethical Challenges Regulations need to insure the accuracy of such tests and the reliability of the stored databases to ensure privacy Less than 1 percent of genetic tests are FDA regulated Personalized medicine will also require additional education and training by physicians © 2012 Pearson Education, Inc.

Technical, Social, and Ethical Challenges The costs involved in the development of genomics and personalized medicine may be taking away from larger problems such as the distribution of food and clean water Personalized medicine will touch almost every aspect of medical care, and we can guide its use for the maximum benefit to the greatest number of people © 2012 Pearson Education, Inc.