Genomic Issues in Healthcare

Genomic Issues in Healthcare Kathleen Calzone, PhD, RN, APNG, FAAN Center for Cancer Research, Genetics Branch National Cancer Institute

Definitions Genetics study of individual genes and their impact on relatively rare single gene disorders Genomics study of all the genes in the human genome together, including their interactions with each other, the environment, and other psychosocial and cultural factors

Top 10 Leading Causes of Death Heart Disease 24.8% Malignant Neoplasms 23.5% Chronic Respiratory Disease 5.7% Cerebrovascular 5.3% Unintentional Injury 4.8% Alzheimer's Disease 3.3% Diabetes Mellitus 2.9% Influenza & Pneumonia 2.2% Nephritis 2.0% Suicide

Emerging Science/Technology

http://www.genome.gov/27541954

Extent of Genetic and Genomic Testing 9/5/2011, 2430 diseases with available genetic tests 2168 clinical 262 research 8/23/2012, 2735 diseases with available genetic tests 2487 clinical 248 research 3/7/2013, 2941 diseases with available genetic tests 2712 clinical 229 research http://www.ncbi.nlm.nih.gov/sites/genetests/?db=genetests

The Race for the $1000 Genome

Direct to Consumer Marketing and Testing Tests are available direct to the consumer. Most require only a saliva sample. Example: p 23andMe-Evaluating more than 1,000,000 SNP s for >200 health conditions or health related traits $99. http://www.23andme.com

Genomic Healthcare Applications Preconception and Prenatal Testing Monitoring Disease Burden and Recurrence Newborn Screening Genomics Prognosis and Therapeutic Decisions Disease Susceptibility Screening and Diagnosis Calzone, et al. (2013). Relevance of genomics to healthcare and nursing practice. Journal of Nursing Scholarship. [EPub ahead of print].

The Cancer Exemplar Risk Assessment Screening Symptom Management Therapy Selection Diagnosis/Prognosis i i

Risk Assessment More than 55 hereditary cancer syndromes have been identified The most common syndromes are those associated with breast, ovarian, and gastrointestinal cancers Tumor features at diagnosis are now being used as an indication for genetic assessment Germline cancer susceptibility gene testing Relevant to individuals diagnosed with cancer whose cancer management may be altered Individuals unaffected with cancer who could benefit from mutation specific cancer risk management At-risk family members

Screening Genetic information is being used to personalize cancer screening recommendations SNP test results are being studied as a means to increase the specificity it of cancer risk calculation models (i.e. Gail model for breast cancer risk) Screening tests that include DNA analysis are being developed such as the DNA stool test, a less invasive means to screen for colon polyps or cancer

Diagnosis/Prognosis Establish Et blih an accurate diagnosis i Tumor profiling is being used to identify recurrence risk to guide adjuvant therapy Schmitz et al. (2012). Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature, Epub ahead of print. McDermott et al. (2011). Genomics and the continuum of cancer care, NEJM, 364, 350-360.

Therapy Selection The use of therapies targeted to proteins encoded by mutated cancer genes Pre and Post PET Scan using Targeted Treatment for V600E BRAF Mutation in Melanoma McDermott et al. (2011). Genomics and the continuum of cancer care, NEJM, 364, 350-360.

McDermott et al. (2011). Genomics and the continuum of cancer care, NEJM, 364, 350-360.

Symptom Management Priority area of nursing research is the study of the genetic influences of symptom clusters Pharmacogenomics Inhibitors and/or Inducers Implications for: Medications used for other health conditions (i.e. anti-convulsants) Selecting medications to control symptoms such as hot flashes, nausea/vomiting Use of over the counter medications like St. Johns Wort Consumption of certain foods or supplements like grapefruit/grapefruit juice

The Quest for Personalized Health Care Use of an individual's genetic/genomic information In addition to traditional health information to guide health care decision-making Disease prevention, risk reduction, diagnosis, treatment, symptom management and palliative care Pharmacogenomics Medication selection Dose selection Inhibitors Inducers

Implications for Occupational Health and Safety Workplace Wellness Programs Environmental Hazards Health Protection Healthier and Safer Workforce

Genomics and Environmental o e a Hazards a a ds

Epigenetics The study of genetic variation caused by the activation and deactivation of genes without any change in the underlying DNA sequence. The epigenome involves chemical compounds that modify, or mark the genome in a way that tells it what, where, and when to do it. Can be passed on from cell to cell as cells divide, and from one generation to the next.

The International HapMap Project Discovery of common human genetic variation 10 million single nucleotide polymorphisms (SNPs) World-wide population distribution http://hapmap.ncbi.nlm.nih.gov/

Published Genome-Wide Associations through 07/2012 Published GWA at p 5X10-8 for 18 trait categories NHGRI GWA Catalog www.genome.gov/gwastudies www.ebi.ac.uk/fgpt/gwas/

Asbestos Exposure and Cancer Susceptibility Asbestosis results from exposure to asbestos and/or other fibrous minerals (i.e. erionite) Asbestos represents at least 6 fibrous silicate minerals used commercially Exposure increases the risk of lung cancer and mesothelioma Mesolthelioma is an aggressive malignancy of the mesothelial cells of the pleura, peritoneum and pericardium ~5% of workers exposed to asbestos develop mesothelioma Carbone et al. (2012). Molecular pathways: Targeting Mechanisms of asbestos and erionite carcinogenesis in mesothelioma. CCR, 18, 598-604 Wei et al. (2012). Genome-wide gene-environment interaction analysis for asbestos exposure in lung cancer susceptibility. Carcinogenesis, 33:1531-7.

Genetic Influences of Mineral Fiber Carcinogenesis BRCA1 associated protein 1 (BAP1); a tumor suppressor gene on chromosome 3p21 Germline mutations in BAP1 associated with malignant mesothelioma, uveal melanoma, cutaneous melanoma, and melanocytic BAP1- mutated atypical intradermal tumors (MBAITs) Evidence is accumulating that germline BAP1 mutation carriers are more susceptible to the carcinogenic effects of asbestos and erionite Landany et al. (2012). New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment. CCR, 18(17):4485-90 Carbone et al. (2012). BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. JTM, 10. 179

Genomics G i and d Health Protection

Hospital Outbreak of a Drug Resistant Pathogen Snitken et al. (2012). Tracking a hospital outbreak of carbapenem-resistent klebsiella pheumoniae with whole-genome sequencing. Sci Transl Med, 4.

What the Detective Found Gram-negative Klebsiella pneumoniae is a major cause of nosocomial infections Increase in strains resistant to carbapenum antibiotics with limited alternative treatment options Infection containment becomes paramount The CDC has detected this antibiotic resistant strain in 41 states One patient known to be infected was admitted in June 13, 2011 and discharged July 15, 2011 Enhanced isolation procedures were immediately implemented upon admission No spread of the infection was detected while she was in the hospital August 5, 2011, 3 weeks after the first patient was discharged, d a second infected patient t was identified d Snitken et al. (2012). Tracking a hospital outbreak of carbapenem-resistent klebsiella pheumoniae with whole-genome sequencing. Sci Transl Med, 4.

Who Done It? The outbreak progressed despite standard of care infection control procedures As the outbreak progressed even more aggressive measures were employed Nurses caring for infected patients cared for no other patient Monitors were hired to ensure aggressive infection control Traditional infection control epidemiologic assessments did not reveal how the pathogen traveled from one patient t to another 19 patients were infected, 12 died Genome analysis was employed Unexpected manner of transmission All cases appear to be have stemmed from the index case Snitken et al. (2012). Tracking a hospital outbreak of carbapenem-resistent klebsiella pheumoniae with whole-genome sequencing. Sci Transl Med, 4.

Carbapenem-resistant Enterobacteriaceae (CRE) and Infection Control Recognize R i these organisms as epidemiologically important Understand the prevalence in your region Identify colonized and infected patients when present in the facility Implement regional and facility based interventions designed to stop the transmission i of these organisms Byrnes, G., Elkins, M. (2009). Introduction to Infection Control IN:Hazard Byrnes, G., Elkins, M. (2009). Introduction to Infection Control IN:Hazard Recognition and Control in Institutional Settings. CDC. (2012). Guidance for Control of CRE. 12 CRE Toolkit. http://www.cdc.gov/hai/pdfs/cre/cre-guidance-508.pdf

Genomics and Workplace Wellness Programs g

Value of Family History Traditionally focused on identification of mendelian disorders Predicts the risk of common health conditions Demonstrated to be positively associated with risk awareness and risk reducing behaviors Remains the cheapest genomic test available Guttmacher, A., et al. (2004). The family history-more important than ever. NEJM, 351, 2333-2336. Hariri, i S., et al. (2006). Family history of type 2 diabetes: a population-based screening tool for prevention? GIM, 8, 102-8. McCusker, M., et al. (2004). Family history of heart disease and cardiovascular disease riskreducing behaviors. GIM, 6, 153-8.

Prevalence and Relative Risk Estimates due to Family History for Common Diseases Table 1. From: Yoon et al. (2002). Can family history be used as a tool for public health and preventive medicine? Genet Med, 4, 304-310.

Purpose of a Pedigree Facilitates the identification of genetic syndromes. Aides the provider in establishing a presymptomatic diagnosis of a genetic disease Helps identify at risk individuals. Helps to establish patterns of inheritance. Ill i t i l d bi l i l Illuminates social and biological relationships.

Pedigree Red Flags Multiple affected individuals, especially if condition is rare Early age at diagnosis Multiple primary tumors Bilateral disease in paired organs Sudden cardiac death in a healthy individual Individuals i i with 3 or more pregnancy losses di l bl i th ff i Medical problems in the offspring of consanguinous parents

Genomics and the Nursing Workforce Study National Nursing Workforce Study in collaboration with ANA (NNWF) N 619 ANA House of Delegates (HOD) 244 National Coalition of Ethnic Minority Nurses (NCEMNA) 392 Expanding RN Scope of Practice: A 7347 Method for Introducing a New Competency into Nursing Practice (MINC) MINC Admin Only 439

Family History In the prior Took family Took family AGREED OR three months nurses seeing patients who history: Assessed age at dx history: Assessed maternal and STRONGLY AGREED that family history RARELY OR NEVER assessed a family history. NNWFS 67%, (n=288/510) 41% (n=200/483) paternal lineages 66% (n=320/484) taking should be a key component of nursing care 84% (n=369/442) HOD 58% (n=59/102) 51% 75% 91% (n=116/227) (n=168/224) (n=219/242) NCEMNA Not Done 64% (n=231/363) MINC 69% (n=3270/4774) 29% (n=1564/5348) 78% (n=280/361) 53% (n=2850/5336) Not assessed 71% (n=4051/5701) MINC 63% (n=91/294) 34% 64% 80% Admin (n=142/421) (n=267/420) (n=347/436)

Pharmacogenomic Influences Efficacy Toxicity -inducers -inhibitors Pharmacodynamics Target Pharmacokinetics PK = absorption, distribution, metabolism and excretion PD = mechanism of action, drug concentration and effect

Polymorphisms and Phenotype UM-Ultrarapid Metabolizer Unusually high activity of a drug metabolizing enzyme (DME) or drug transport protein (DTP) Limited response to recommended doses EM-Extensive Metabolizer Wild-type (normal activity) it form of a DME or DTP Expected efficacy at recommended doses IM-Intermediate Metabolizer Reduced activity of a DME or DTP Some decreased efficacy at recommended doses PM-Poor P Metabolizer Very low or no activity of a DME or DTP Increased toxicity Decreased efficacy at recommended d doses Katz et al. (2008). Defining drug disposition determinants: A pharmacogenetic pharmacokinetic strategy. Nature Reviews Drug Discovery, 7, 293-305.

Indiana University P450 Drug Interaction Table http://medicine.iupui.edu/clinpharm/ddis/table.aspx

Ethical, Legal and Social Issues

What Is Genetic Discrimination? Social or economic discrimination or stigmatization based on one s genetic information denial of access to or increased cost of insurance loss of employment, educational, or other opportunities Insurance considerations if Health, Life, Long Term Care, Disability **Special consideration for the military

The Burlington Northern Santa Fe Railroad Story Paper published associating variations in PMP22 with peripheral neuropathy disorder-carpal tunnel syndrome Company develops and markets genetic test Burlington Northern incorporates genetic testing into workman s compensation evaluation for carpal tunnel Conducts this genetic test on 35 workers seeking workmen s compensation and/or medical care for carpel tunnel syndrome No consent or knowledge of the test t Termination threatened for failure to submit to the test Unauthorized genetic testing discovered by family February 9, 2001 Complaint filed-eeoc challenging genetic testing under ADA Burlington Northern stops testing and settles suits EEOC Press Releases, Washington DC, February http://www.eeoc.gov/press/2-9-01-c.html and April, 2001 http://www.eeoc.gov/press/4-18-01.html

Genetic Information Nondiscrimination Act (GINA) Forbids genetic discrimination in the workplace and in health Genetic G i information i broadly defined d Genetic test means a test that assess genotypes, mutations, or chromosomal changes. Genetic information means information about: a person s genetic tests genetic tests of a person s family members (up to and including fourth-degree relatives) any manifestation of a disease or disorder in a family member participation of a person or family member in research that includes genetic testing, counseling, or education Specific to group and individual insurance plans Forbids use of genetic information in underwriting Forbids requiring genetic testing by employers and insurers Genetics and Public Policy Center.: Information on the Genetic Information Nondiscrimination Act (GINA). ttp://www.dnapolicy.org/resources/whatginadoesanddoesnotdochart.pdf

Scope of GINA Coverage Coverage Limitations Exclusions Forbids genetic discrimination in the workplace and in health insurance Genetic information broadly defined Specific to group and individual insurance plans Forbids use of genetic information in underwriting Forbids requiring genetic testing by employers and insurers Civil suit is restricted to those that have exhausted all administrative remedies Does not prohibit medical underwriting based on current health status Does not cover life, disability, and long-term care insurance Members of the United States military, veterans obtaining health care through the Veteran s Administration and the Indian Health Service

Resources Journal of Nursing Scholarship Genomic Special Issue Webinar Series with Issue Authors http://www.genome.gov/27552312 Genetics/Genomics Competency Center for Education (G2C2) http://www.g-2-c-2.org 2 CDC Public Health Genomics http://www.cdc.gov/genomics/ Genomic Competency Listserv Leave business card or email: calzonek@mail.nih.gov

Questions/Discussion calzonek@mail.nih.gov 301-435-0538 0538