Diving Into the Gene Pool: Genetics, Genomics and Primary Care Medical Practice

1. Diving Into the Gene Pool:Genetics, Genomics and Primary Care Medical Practice H. Eugene Hoyme, MD Chief Academic Officer, Sanford Health President, Sanford Research USD Professor of Pediatrics (Medical Genetics) Sanford School of Medicine University of South Dakota

3. Learning Objectives • Define:genetics, genomics and genomic medicine. • Understand the importance of the role of primary care physicians in the provision of genetic/genomic information to their patients. • List four applications of genomic medicine currently in use in clinical practice. • Apply principles of genetics and genomics in provision of health maintenance for some of the common disorders of adult life. • Discuss the need to exercise caution in provision of genetic and genomic information to patients in light of its potential ethical, legal and social implications.

4. Definitions • Genetics:The study of specific, individual genes and their role in inheritance. (In medicine, genetics has historically applied to the study of rare single gene disorders). • Genomics:The study of an organism's entire genetic makeup (genome)and its interaction with environmental or non-genetic factors, including lifestyle. • Applied to the study of complex diseases such as cancer, diabetes, heart disease, hypertension and asthma.

5. Definitions • Genomic Medicine:The medical discipline that involves using genomic information about an individual as part of his/her comprehensive health care supervision (e.g., for diagnostic or therapeutic decision-making). • Genomic medicine is becoming an integral part of primary care for adults.

6. Why Must Primary Care Physicians Understand Genetics and Genomics? • To answer requests for information • Practitioners need to be able to respond to patients' questions about the possibility of a genetic disease in the family. • A survey conducted by the American Medical Association in March 1998 found that 71% of patients who questioned whether there was a genetic disease in their family would contact their primary care physician first. American Medical Association. Genetic testing: a study of consumer attitudes. March 1998: AMA survey results. www.amaassn.org/ama/pub/article/2304-2937.html Accessed September 23, 2007.

7. Why Must Primary Care Physicians Understand Genetics and Genomics? • To assist in case recognition • By increasing their awareness of the manifestations of common genetic diseases, practitioners can expand the differential diagnoses of some patients' symptoms to include common genetic diseases. • Whereas all diseases have both a genetic and an environmental component, in some, the genetic effect predominates, and these are commonly referred to as “genetic diseases.”

8. Why Must Primary Care Physicians Understand Genetics and Genomics? • To provide effective health supervision for patients with genetic disorders • Practitioners need to know how patients' primary genetic diseases may affect their health, what secondary diseases they are likely to develop, and the unusual ways that common diseases may present in these patients. • Children and adolescents with genetic disorders must transition to knowledgeable adult medicine primary care physicians who can provide comprehensive health supervision.

9. Why Must Primary Care Physicians Understand Genetics and Genomics? • To decrease over-utilization of limited genetics resources • Primary care physicians play a crucial role in the integration of genetics into clinical practice, since there are currently few MD clinical geneticists and genetic counsleors. • In a study of referrals for genetics services in the United Kingdom, most referrals were found to be low-risk persons who could have received reassurance from their primary care physicians. Harris R, Harris HJ. Primary care for patients at genetic risk [editorial]. BMJ 1995;311: 579-580.

10. Why Must Primary Care Physicians Understand Genetics and Genomics? • To screen for potential genetic disorders in patients in their practices • Genetic screening measures historically have focused on reproductive issues, such as preconception screening for those at risk of being carriers of autosomal recessive diseases (Tay-Sachs disease, CF) or prenatal diagnosis (Down syndrome). • Newborn screening is generally mandated by state or federal government health policies and occurs outside the physician's purview (newborn screening).

11. Why Must Primary Care Physicians Understand Genetics and Genomics? • The role of genetics and genomics in routine health care maintenance for adults as a means to assess the genetic risk of disease is becoming increasingly important. • An understanding of the genomic components of the common chronic diseases of adult life will lead to a personalized approach to health supervision, i.e, personalized or genomic medicine.

12. Genomic Medicine Future State • In addition to the usual tools physicians use in health assessment, the tools of genomics will allow for personalizing: • Screening protocols for heart disease, cancer and other chronic disorders • Informed dietary and lifestyle choices • Individualized presymptomatic medical therapies, e.g., antihypertensive agents before hypertension develops, anti-schizophrenia agents before schizophrenia develops • Prescribing medications based on pharmacogenetics/pharmacogenomics

13. A Fun Fact: How Many Human Genes Do All Current Drugs Target? • ~500 (5% of the genome) • ~1,000 (10%) • ~5,000 (25%) • ~10,000 (50%) • ~ 15,000 (75%) • ~20,000 (100%)

14. A Fun Fact: How Many Human Genes Do All Current Drugs Target? • ~500 (5% of the genome) • ~1,000 (10%) • ~5,000 (25%) • ~10,000 (50%) • ~ 15,000 (75%) • ~20,000 (100%)

15. The Benefits of Genomic Medicine • Detect disease at an earlier stage, when it is easier to treat effectively; • Enable the selection of optimal therapy and reduce trial-and-error prescribing; • Reduce adverse drug reactions; • Increase patient compliance with therapy; • Improve the selection of targets for drug discovery and reduce the time, cost, and failure rate of clinical trials; • Shift the emphasis in medicine from reaction to prevention; • Reduce the overall cost of healthcare.

16. Personalized Medicine: A Shift from Reactive to Preventive

17. Health Care Savings • Personalized medicine may help control costs by decreasing the number of unnecessary screening and diagnostic tests ordered. • Personalized medicine may identify individuals genetically at high risk for the common diseases of adulthood (hypertension, heart disease, cancer and diabetes), allowing for extensive environmental intervention.

18. Health Care Savings • Personalized medicine may lead to more rapid recovery since the correct medication and dosing for the individual patient will lead to the end of “trial and error” prescribing. • Drugs may become less expensive since pharmaceutical companies will use genetic and molecular data to develop more effective “targeted” therapies.

19. Current Applications of Genomic Medicine in the Clinic

20. Tumor-based Screening • Current oncology practice has moved toward tumor genotyping of cancers such as melanoma, breast, colon and lung for targeting of therapy. • Sanford’s SSKT trial • Genetic screening of patients with a family history of breast or colon cancer may be indicated based on the nature of the tumor(s) and the number and degree of relatedness of affected relatives.

21. BRCA1/BRCA2 and Breast Cancer • The likelihood of a harmful mutation in BRCA1 or BRCA2 is increased with certain familial patterns of cancer. These patterns include the following: • Multiple breast and/or ovarian cancers within a family (often diagnosed at an early age) • Two or more primary cancers in a single family member (more than one breast cancer, or breast and ovarian cancer) • Cases of male breast cancer

22. Genetics and Colon Cancer

23. Family History Directed Decision Support • Electronic family history data collection tools allowing patients to input their family history have been validated, allowing for individual genetic risk assessment. • Surgeon General’s My Family Health Portrait • Integrating this information into the EHR has proven to be formidable. • Duke University has designed a web-based tool that collects family history and provides decision support information on four conditions (breast, ovarian and colon cancer and venous thrombosis).

24. https://familyhistory.hhs.gov/

25. eMERGE • The eMERGE (Electronic Medical Records and Genomics) Network is a national consortium formed to develop, disseminate, and apply approaches to research that combine DNA biorepositories with electronic medical record (EMR) systems for large-scale, high-throughput genetic research. • Goal is to provide user-friendly decision support algorithms for health care providers

26. Pharmacogenomics • Nearly every pathway of drug metabolism, transport and action is influenced by genetic variation. • The FDA lists 131 prescription medications with genomic biomarkers that affect: clinical response variability, risk for adverse events, genotype specific dosing, mechanisms of drug action and polymorphic drug target and disposition genes. http://www.fda.gov/drugs/scienceresearchareas/pharmacogenetics/

27. Pharmacogenomics • 20-90% of individual variability of response to prescribed medications is genetically based. • 59% of the 27 most frequently cited medications in adverse drug reactions have gene variants that code for reduced functioning or non-functioning proteins. NEJM 348; 529-538, 2003 / JAMA 286; 2270, 2001)

28. Pharmacogenomics • Pharmacogenetic testing has the potential to minimize side effects and decrease the frequency of adverse drug events by allowing for individualized rather than “one size fits all” prescribing. • Among drugs for which pharmacogenetic testing is currently available are: • SSRI and TCA antidepressants • Opioid pain medications • Beta blockers • Type I antiarrhythmics • Anticoagulants (coumadin and plavix)

29. Pharmacogenomics • Example of pharmacogenetic testing: Plavix (clopidogrel) • One cytochrome gene variant (CYP2C19) appears to account for most of the variability in bioactivation and efficacy among patients. • 2% of whites, 4% of African Americans and 14% of Asians are slow metabolizers and at higher risk of cardiovascular events and stroke. This group may benefit from an alternative medication or a larger dose of the medication. • The number of medications for which pharmacogenetic testing is indicated is expected to grow at a rapid pace.

30. “Pre-emptive” Genotyping in Pharmacogenomics • Pharmacogenomic testing for multiple drugs becomes clinically practical if appropriate decision support tools present relevant data to physicians only when needed. • Reactive genotyping is slow and the uptake by physicians has been low.

31. “Pre-emptive” Genotyping in Pharmacogenomics • However, programs for “pre-emptive” genotyping are being developed whereby patients have extensive array based pharmacogenomic genotyping as part of their health supervision, the data being presented to the physician only when a related drug is being prescribed. • At St. Jude’s, array based testing for 225 genes is performed, and results for those genes with the strongest clinical evidence are placed in the EHR.

32. Diagnostic Genome Sequencing • Whole exome (the protein coding exons) and whole genome sequencing are now clinically available through CLIA certified laboratories. • Whole exomesequencing has revealed the etiology of many rare single gene disorders • Whole genome and RNA (transcriptome) sequencing are necessary in oncology, since genetic material other than exomes (e.g., regulatory genes) often drive cancer.

33. Next Generation sequencing Technology: the Engine of “Genomic Medicine”

34. The Cost of Genome Sequencing is Decreasing Rapidly

35. Evolution of Genomic Sequencing in Clinical Laboratory Testing

36. Bioinformatics and Next Generation Sequencing • Bioinformatics is the science of collecting and analyzing complex biological data. • In 2013, the sequencing of the genome has become relatively routine. • The difficult part of its clinical application is sorting out normal genetic variation from the DNA changes that are clinically actionable. • Any CLIA certified whole exome or genome sequencing laboratory must have access to such bioinformatics skill.

37. The 1000 Genomes Project • The goal of the 1000 Genomes Project is to provide a comprehensive resource on human genetic variation to aid with genomics research and clinical interpretation of sequencing data for genomic medicine. • The first phase is complete, with 1092 individual genomes sequenced with low coverage. • Subsequent work will provide deep coverage and more clinically applicable data.

38. The 1000 Genomes Project • The project catalogs human DNA variants present at >1% frequency, or within genes, at >0.5% frequency. • Include not only SNPs, but also rearrangements, deletions, and duplications. • In its initial production phase, produced about 8.2 billion bases/day (> two genomes/day). • Samples from: Europeans: British, Finnish, Italian, Spanish, European Americans (Utah); Asians: Japanese, Chinese (Beijing and Denver); Africans: Yoruba, Maasai, African American (Los Angeles); Gujarata Indian; Mexican American (Los Angeles). Integrated map of genetic variation from 1,092 human genomes. Nature 2012; 491:56-65

39. The Multiplex Initiative • Investigates the interest of 1,000 healthy, young adults in genetic testing for eight common conditions: type 2 diabetes, coronary disease, hypercholesterolemia, hypertension, lung cancer, osteoporosis, colorectal cancer, and malignant melanoma. • Evaluates responses to offer of free genetic testing to learn about influences on deciding whether to be tested and how individuals who are tested interact with the health care system. • Research team combines scientists in NHGRI’s intramural program and at Henry Ford Health System in Detroit and the Group Health Cooperative in Seattle.

40. Two Case Illustrative Case Studies

41. Case #1: Sara’s Story in 2020 • Sara completes the Surgeon General’s family history tool at age 14, learns of uncles with early heart disease • She consults her health care provider who suggests complete genome sequencing at age 18 for $500 • She inquires about the risk of genetic discrimination, but her pediatrician tells her that federal legislation has outlawed this

42. Case #1: Sara’s Story in 2020 • At 18, she is found to have four genetic variants that well validated studies have conclusively shown increase risk of early heart attack five-fold • She and her health care team design a program of prevention based on diet, exercise, and medication, at age 35, precisely targeted to her genetic makeup

43. Case #1: Sara’s Story in 2020 • Sara does well until age 75 • She develops left arm pain that she assumes is due to gardening, but her primary care provider knows her higher risk and diagnoses an acute MI • Referring to her genome sequence, the drugs that will work best to treat her are chosen • She survives and is alive and well in the 22nd century

44. Case #1: Sara’s Story…An Alternative Reality • The Surgeon General’s Family History Initiative never really takes off and her pediatrician is too busy filling out insurance forms to ask about family history, so Sara never learns about her family history • Sara is offered genome sequencing, but after seeing her brother lose his disability insurance from this information, she declines

45. Case #1: Sara’s Story…An Alternative Reality • Sara eats an unhealthy diet, gains weight, and develops hypertension • While tests to predict which drug would be most effective for Sara have been proposed, they have never been validated, and are not reimbursed • Sara’s hypertension is treated with a drug that causes a hypersensitivity reaction, so she stops treatment

46. Case #1: Sara’s Story…An Alternative Reality • After 10 years of uncontrolled hypertension, Sara develops left arm pain at age 45 • Since she has no primary care physician, she presents to urgent care, where the physician, unaware of her high risk, assumes her pain to be musculoskeletal and prescribes rest • Sara returns to the ER the next day in cardiogenic shock

47. Case #1: Sara’s Story…An Alternative Reality • The absence of her genome sequence information prevents optimal choice of therapy • Sara dies in the ER

48. Case #2: Genomic Medicine in Oncology • A true case study from a few years ago: • A young leukemia researcher is diagnosed with the cancer he had devoted his life to studying. • With no other treatment available, his colleagues decide to sequence his entire genome and his RNA, to see if they can find the gene(s) that are driving his cancer, adult acute lymphoblastic leukemia (ALL). • The sequencing takes a month to complete and reveals multiple pathologic changes in several genes, none of which are in pathways responsive to existing medications.

49. Case #2: Genomic Medicine in Oncology • However, RNA analysis points to a single gene which is driving overproduction of a protein that spurs growth of cancer cells. • A new drug, Sutent, blocks the effects of the gene. However, the cost ($330 per day) is prohibitive. His insurance company will not pay for it, and despite two appeals, the manufacturer, will not grant him a supply through its compassionate use program. • After scraping up some money to buy a week’s worth, he begins taking Sutent. His colleagues also pitch in to buy a month’s supply for him. • Two weeks later, bone marrow biopsy reveals a full remission.

50. Conclusions • Primary care physicians must be familiar with the principles of genetics in order to: • Recognize genetic disease in their patients. • Provide effective health supervision for their patients with genetic disorders. • Answer patients’ questions about genetic vs. environmental factors in common diseases. • Appropriately refer cases to clinical geneticists and genetic counselors for additional diagnostic evaluation.