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ONCOLOGY GENETICS & GENOMICS

ONCOLOGY GENETICS & GENOMICS. Kristi Wiggins MSN, RN,ANP-BC, AOCNP, CCRC Oncology Adult Nurse Practitioner Duke University Adult Stem Cell Transplant. Objectives. Discuss basic concepts of genetics/genomics in oncology and how these impact personalized healthcare

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ONCOLOGY GENETICS & GENOMICS

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  1. ONCOLOGYGENETICS & GENOMICS Kristi Wiggins MSN, RN,ANP-BC, AOCNP, CCRC Oncology Adult Nurse Practitioner Duke University Adult Stem Cell Transplant

  2. Objectives • Discuss basic concepts of genetics/genomics in oncology and how these impact personalized healthcare • Distinguish between cancer genetic testing and genomic testing and name at least one of each • Identify at least three components of a hereditary cancer risk assessment • Name at least two types of molecular testing used to evaluate cancer genetic/genomic expression that provide diagnostic and prognostic information

  3. All cancer is“genetic” What does this mean?

  4. Genetics:is the study of genes & heredity What is inherited from one’s predecessors • Geneticsfocuses primarily on the likelihood of developing cancer • Genetic tests find mutations, not disease

  5. Cancer Genomics: • The study of tumor biology & how genes interact and are expressed as a whole • Genomics and gene expression profiling tools focus on the cancer itself and can help determine • How aggressive is the cancer (prognosis) • What is the likely benefit from treatment (prediction)

  6. Identifying Patients at Risk Family History &Personal Medical History • Identify diseases that appear to “run in the family” • These can be considered genetic diseases. • Taking a family history can provide important information about a patient’s risk of disease.

  7. Genetic Basis for Cancer • Dysregulated cell signaling pathways • Variations in gene expression • These two characteristics control and influence genes to promote: • Tumor initiation • Tumor growth and spread

  8. Initiation Normal Cell Altered Cell Promotion Tumor Promotion Higher Grade Malignancy progression Promotion Metastasis

  9. Stuck Accelerators & Faulty Brakes • Proto-Oncogenes • (normal role is “accelerator”) Tumor-Suppressors (normal role is “brake”)

  10. Tumor Suppressor Genes: Two “hits” required Normal suppressor gene alleles, brakes function fine One suppressor gene allele mutated, accident waiting to happen Two suppressor gene alleles mutated, disaster

  11. Genetic Testing: Heredity Genetics is the study of what is inherited from one’s predecessors (Germline). One allele, or one copy of genes, from each parent Genetics influence an individual’s genomics, it is responsible for only 5-10%of cancers • Genetics focuses primarily on the likelihood of developing cancer • Genetic tests find mutations, not disease Source: Understanding Cancer Series: Gene Testing, National Cancer Institute

  12. Genetic Test Example • BRCA1 and BRCA2 • The genetic/hereditary make up of patients is tested for BRCA1 and BRCA2 mutations. • Patients with those mutations have higher chances of developingbreast cancer.

  13. Genomic Test Example • Oncotype DX® Breast Cancer Assay • The expression level of 21 genes is measured in tumor tissue from patients that have already been diagnosed with breast cancer. • This assay evaluates if a patient is going to recur (prognostic). • And predicts benefit from chemotherapy and hormonal therapy (predictive).

  14. Genetic Testing vs.Genomic Tumor Profiling • Germline • Heredity • One allele, copy of genes, from each parent • BRCA 1 & 2 • Tumor DNA • Malignant transformation • Over-expression of normal genes • Her2neu • Mutated Suppressor genes • p53

  15. Genomic Testing: Role in Cancer Diagnosis & Treatment The Presence, Absence, or Over-Abundance of Genes Can Infer 1. Prognosis 2.Treatment Outcomes

  16. TUMOR PROFILING • Cancer gene expression • Determine risk • Determine prognosis • Evaluate relationship to chemotherapy responsiveness

  17. Microarray Analysis www.biomedcentral.com

  18. PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 HER2 GRB7 HER2 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC GSTM1 BAG1 INVASION Stromelysin 3 Cathepsin L2 CD68 Cancer Gene ExpressionOncotype DX®21-Gene Recurrence Score™ (RS) Assay 16 Cancer and 5 Reference Genes From 3 Studies Paik et al. N England J Med. 2004;351: 2817-2826

  19. Importance of Gene Expression • Risk • Prognosis • Predict Chemosensitivity • Pharmacogenomics

  20. PharmacogenomicsHow an individual's genetic make-up affects the body's response to drugs • Holds the promise that drugs might one day be tailor-made for individuals, adapted to each person's unique genetic makeup. • GOALS: • Better, safer drugs • More accurate dosing • Better vaccines • Reduced cost • Advanced disease screening Environment, diet, age, lifestyle, and state of health all can influence a person's response to medicines httwww.ornl.gov/sci/techresources/Human_Genome/medicine/pharma.shtml

  21. Definitions • Pharmacokinetics • process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. • What you do to a drug (i.e. your SNPs). • Pharmacodynamics • action of a drug in the body, including absorption, distribution, localization in the tissues, biotransformation, and excretion • What a drug does to you

  22. Pharmacogenomic Targets, Molecular Tests, & Therapies BREAST

  23. Immunohistochemistry (IHC) 1+ IHC 2+ IHC 3+ IHC Breast Cancer – Estrogen Receptor Rohit Bhargava, William L Gerald, Allan R Li, Qiulu Pan, Priti Lal, Marc Ladanyi and Beiyun Chen

  24. Pharmacogenomic Targets, Molecular Tests, & Therapies Chronic Myelogenous Leukemia (CML)

  25. Cytogenetics – Chromosome analysis Example:Philadelphia Chromosome in CML http://en.wikipedia.org/wiki/File:Philadelphia_Chromosom.svg

  26. Fluorescent in situ Hybridization (FISH) CML – Philadelphia Chromosome t 9:22 Translocation FISH probe shows: Signals of BCR gene (green signal) ABL1 gene (red signal) Arrows denote fusion signal on chromosome 9 = BCR/ABL gene that is diagnostic of CML.

  27. Current applications of Genomic Science Gene Testing • Colon Cancer • MSH gene test – at time of surgical resection to stratify risk • UGT1A1 – Screening, positivity predicts toxicity to Irinotecan • Acute Myelogenous Leukemia • FLT3-ITD – worse outcomes, implement more aggressive therapy, and/or stem cell transplant • NPM1 – favorable outcomes (only in the absence of FLT3+), may be cured with chemo alone • Non-Small Cell Lung Cancer (NSCLC) • EGFR & EML4 – increased malignant behavior, implement more aggressive therapy • ALK – worse prognosis, use ALK inhibitors

  28. Current applications of Genomic Science Genomic Testing • Expression Profiles • Breast Cancer • To Direct the Use of Pre-operative Chemotherapy for Early Stage Breast Cancer • Goal – Predict Chemosensitivity

  29. Summary • Consider how genetics/genomics in oncology impact the personalized healthcare you provide • Become more familiar with the ‘red flags’ on a hereditary cancer risk assessment • Understand the difference between: • Genetic testing • Genomic testing • Identify molecular tests used to evaluate cancer genetic/genomic expression: • IHC • FISH • Cytogenetics

  30. The Challenge

  31. Resources American Association for CancerResearch http://clincancerres.aacrjournals.org/content/9/10/3645/F2.expansion?ck=nck Bharhava, R., et al (2011). Modern Pathology. Retrieved 9/18/11, fromhttp://www.nature.com/modpathol/journal/v18/n8/fig_tab/3800438f1.html Eastman, P. (2007, April 25). IOM Report: Much Stronger Leadership Needed to Fuel Biomarker R&D. Oncology Times, XXIX No. 8, p. 11. Genomic Health: Oncotype DX Nursing Education Materials Goetsch, C.M. (2011). Genetic Tumor Profiling and Genetically Targeted Cancer Therapy. Seminars in Oncology Nursing, 27, 34-44. http://www.nature.com/bjc/journal/v100/n1/fig_tab/6604781f1.html#figure-title http://en.wikipedia.org/wiki/File:Philadelphia_Chromosom.svg International Society of Nurses in Genetics www.isong.org/ Lab Med Online (2011). A Case of Concomitant Inv(3)(q21q26) and Cryptic BCR/ABL1 Rearrangement in the Blast Crisis of Chronic Myeloid Leukemia . Retrieved 9/19/11, from http://dx.doi.org/10.3343/lmo.2011.1.3.7 Lee, H., et al., (2011). Lab Med Online. 2011 Jul;1(3):163-167. Published online 2011 July 05.  http://dx.doi.org/10.3343/lmo.2011.1.3.7, Laboratory Medicine Online Nature Reviews Drug Discovery 3, 739-748 (September 2004) National Human Genetics Research Institute: www.nhgri.gov N EnglandJ Med 2009;360:753-764. Oncology Nursing Society: www.ons.org Stenger, E. (2011). Genetic Profiling in Non-Small Lung Cancer. ASCO Post, 5, 6-8. Abstract retrieved 9/09/11, from www.ASCOPost.com. Susman, E. (2007, April 25). Increasing Interest in Stopping Cancer Stem Cells as New Treatment Method. Oncology Times, XXIX No. 8, p. 24. www.cancer.gov/cancertopics/understandingcancer/ www.cancer.gov/cancertopics/understandingcancer/genetesting/AllPages www.cellulargenetix.com/pharmacogenomics.asp www.genomics.gov www.insidecancer.org/ www.medscape.com/viewarticle/487451_4 www.nature.com/cancer/index.html www.nature.com/nrd/journal/v3/n9/images/nrd1497-i1.jpg www.ncbi.nlm.nih.gov/About/primer/microarrays.html www.nci.gov

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