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ONCOLOGYGENETICS & GENOMICS
Kristi WigginsMSN, RN,ANP-BC, AOCNP, CCRC
Oncology Adult Nurse PractitionerDuke University Adult Stem Cell Transplant
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
All cancer is“genetic”
What does this mean?
• Genetics focuses primarily on the likelihood of developing cancer
• Genetic tests find mutations, not disease
Genetics: is the study of genes & heredity
What is inherited from one’s predecessors
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)
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.
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
NormalCell
Altered Cell
Tumor
Higher GradeMalignancy
Metastasis
Initiation
Promotion
Promotion
Promotion
progression
Stuck Accelerators & Faulty Brakes
Proto-Oncogenes (normal role is “accelerator”)
Tumor-Suppressors (normal role is “brake”)
Tumor Suppressor Genes: Two “hits” required
Normal suppressorgene alleles, brakesfunction fine
One suppressor geneallele mutated, accidentwaiting to happen
Two suppressor genealleles mutated, disaster
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
Genetic Testing: Heredity
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 developing breast cancer.
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).
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
Genomic Testing: Role in Cancer Diagnosis & Treatment
The Presence, Absence, or Over-Abundance of Genes Can Infer 1. Prognosis 2. Treatment Outcomes
TUMOR PROFILING
• Cancer gene expression• Determine risk • Determine prognosis• Evaluate relationship to
chemotherapy responsiveness
www.biomedcentral.com
Microarray Analysis
Cancer Gene ExpressionOncotype DX®
21-Gene Recurrence Score™ (RS) Assay
PROLIFERATIONKi-67STK15
SurvivinCyclin B1MYBL2
ESTROGENERPR
Bcl2SCUBE2
INVASIONStromelysin 3Cathepsin L2
HER2GRB7HER2
BAG1GSTM1
REFERENCEBeta-actin
GAPDHRPLPO
GUSTFRC
CD68
16 Cancer and 5 Reference Genes From 3 Studies
Paik et al. N England J Med. 2004;351: 2817-2826
Importance of Gene Expression
• Risk• Prognosis• Predict Chemosensitivity
• Pharmacogenomics
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 medicineshttwww.ornl.gov/sci/techresources/Human_Genome/medicine/pharma.shtml
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
Pharmacogenomic Targets, Molecular Tests, & Therapies
BREASTGene Expression Tested:
Tests Used: Treatments Indicated by Positive Results:
Examples:
Her2neu Immunohisto-chemistry(IHC) & FISH
Her2neu antagonists
Herceptin & Tykerb
ER/PR Immunohisto-chemistry(IHC)
Endocrine Therapy Tamoxifen, aromatase inhibitors
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
Immunohistochemistry (IHC)
Pharmacogenomic Targets, Molecular Tests, & Therapies
Chronic Myelogenous Leukemia (CML)Gene Expression Tested:
Tests Used: Treatments Indicated by Positive Results:
Examples:
Tyrosine Kinase Cytogenetics &Fluorescent In Situ Hybridization (FISH)
Tyrosine Kinase Inhibitors (TKI)
Imatinib (Gleevec), Dasatinib, Nilotinib
Tyrosine Kinase with T315i mutation
FISH Posatinib
Example:
Philadelphia Chromosome in CML
http://en.wikipedia.org/wiki/File:Philadelphia_Chromosom.svg
Cytogenetics – Chromosome analysis
CML – Philadelphia Chromosome t 9:22
Translocation FISH probe shows:1) Signals of BCR gene (green
signal)2) ABL1 gene (red signal)3) Arrows denote fusion signal on
chromosome 9 = BCR/ABL gene that is diagnostic of CML.
Fluorescent in situ Hybridization (FISH)
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
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
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
The Challenge
ResourcesAmerican Association for Cancer Research
http://clincancerres.aacrjournals.org/content/9/10/3645/F2.expansion?ck=nckBharhava, R., et al (2011). Modern Pathology. Retrieved 9/18/11, fromhttp://www.nature.com/modpathol/journal/v18/n8/fig_tab/3800438f1.htmlEastman, 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 MaterialsGoetsch, 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-titlehttp://en.wikipedia.org/wiki/File:Philadelphia_Chromosom.svgInternational 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 OnlineNature Reviews Drug Discovery 3, 739-748 (September 2004)National Human Genetics Research Institute: www.nhgri.govN EnglandJ Med 2009;360:753-764.Oncology Nursing Society: www.ons.orgStenger, 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/AllPageswww.cellulargenetix.com/pharmacogenomics.aspwww.genomics.govwww.insidecancer.org/www.medscape.com/viewarticle/487451_4www.nature.com/cancer/index.htmlwww.nature.com/nrd/journal/v3/n9/images/nrd1497-i1.jpgwww.ncbi.nlm.nih.gov/About/primer/microarrays.htmlwww.nci.gov