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