Genomics-Based Personalized Healthcare

Presented by:

• Charis Eng, MD, PhD- Chair & Director- Genomic Medicine Institute- Director- Center for Personalized Genetic

Healthcare

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Both Have Asthmatic Attacks B-AdrenergicInhalers

Asthma AttackStopped

Dead

Why the Different Responses to Same Treatment?

Bottom Child Has a Genetic Variant In B-Adrenergic

Receptor Gene

Example Problem at HandExample Problem at Hand

Early StageBreast Cancer

Breast Conserving SurgeryAdjuvant Chemotherapy

Breast Conserving SurgeryAdjuvant Chemotherapy

Cured

Dies of Ovarian Cancer10 Years Later

“Normal” Gene

“Altered” Gene

Why the difference?Why the difference?Why the difference?Why the difference?

Example Problem at HandExample Problem at Hand

Who is at risk for which disease(s)?Who is at risk for which disease(s)?

Based on Objective Genomic or Genetic Data:

• WHO is at risk of developing disease(s)?

• Potentially Entire Population

• Personalized risk assessment

• WHAT can we do about genomic risk?

• Personalized risk management

• Personalized preventive and curative measures?

• WHEN is age (range) of highest risk?

• WHERE: Can surveillance be organ-specific?

• WHY and HOW?

• Patient-Oriented Genomics/Genetics Research

Current DogmaCurrent Dogma

Genetic Load for Any DiseaseGenetic Load for Any Disease

“Sporadic”“Environmental Exposure”

“Bad Luck”

“Sporadic”“Environmental Exposure”

“Bad Luck”

“Some Genetic Component”“Familial Clustering”

“Some Genetic Component”“Familial Clustering”

High Penetrance Disease Susceptibility Gene(s)High Penetrance Disease Susceptibility Gene(s)

Emerging DogmaEmerging Dogma

Normal Gene: THE BIG RED DOG.Normal Gene: THE BIG RED DOG.

Mutated Genes: THE BIG R.Mutated Genes: THE BIG R. THE BIR EDD OG.THE BIR EDD OG.

Variants:Variants:A BIG RED DOG.A BIG RED DOG.

THE BIG RED GOD.THE BIG RED GOD.

High Penetrance Disease Susceptibility Gene(s)High Penetrance Disease Susceptibility Gene(s)

High Penetrance Breast Cancer Susceptibility GenesBRCA1BRCA2PTENTP53LKB1

High Penetrance Breast Cancer Susceptibility GenesBRCA1BRCA2PTENTP53LKB1

Mutation in Gene > High Likelihood of Developing Breast and Other Component CancersMutation in Gene > High Likelihood of Developing Breast and Other Component Cancers

Variants:Variants:A BIG RED DOG.A BIG RED DOG.

THE BIG RED GOD.THE BIG RED GOD.

Genome-Wide Association StudiesGenome-Wide Association Studies

Common Low Penetrance Variants Associated with Breast CancerCommon Low Penetrance Variants Associated with Breast Cancer

A BIG RED DOG.A BIG RED DOG.

THE BIG RED GOD.THE BIG RED GOD.

THE BIG RED DOG.THE BIG RED DOG.

THE BIG RED RIG.THE BIG RED RIG.

WOW BIG RED DOG.WOW BIG RED DOG.

Cases ControlsCases Controls

100 4,000 100 4,000

70 70 70 70

55 70 55 70

1,500 101,500 10

2,500 252,500 25

FGFR2TNRC9

MAP3K1LSP1

CASP8

FGFR2TNRC9

MAP3K1LSP1

CASP8

Easton DF et al Nature 2007Cox A et al Nature Genet 2007Pharoah et al PloS Genet 2007

Easton DF et al Nature 2007Cox A et al Nature Genet 2007Pharoah et al PloS Genet 2007

Low Penetrance Variants in Various Genes Associated with Various Diseases*That Have Replicated (<5% of All Association Studies)*That Give Risks with OR >1.15 (low level risk)

• Subsets of:• Breast Cancer• Prostate Cancer• Diabetes Mellitus Type 2• Obesity• Coronary Heart Disease• Crohn Disease• Others

LOH

N

Ep.

Somatic Genetic Alterations in Sporadic Carcinomas

Epithelial component of carcinomas believed to be the neoplastic component

Pathologists measure invasion by whether the neoplastic epithelial cells invade membrane

Genetic alterations believed in epithelium

Normal Tissue

Ep

TP53 Exon 2 Mutation

Normal

St

TP53 Exon 6 Mutation

Somatic TP53 and Other Gene Mutations in Stroma of Breast CarcinomasSomatic TP53 and Other Gene Mutations in Stroma of Breast Carcinomas

Kurose et al Nature Genet 2002, Fukino et al JAMA 2007Kurose et al Nature Genet 2002, Fukino et al JAMA 2007

Stromal (Not Epithelial) Genomic Alterations Associated with Tumor Aggressiveness and Metastases in Breast and Head and Neck Cancers

St

TP53 Mutation

Weber et al JAMA 2007, Fukino et al JAMA 2007, Patocs et al N Engl J Med (almost in press)Weber et al JAMA 2007, Fukino et al JAMA 2007, Patocs et al N Engl J Med (almost in press)

Personalized Genetic Health Assessment and Management 2007

Is it hereditaryor sporadic?

Epidemiology says10-15% caused by highpenetrance mutant genes,BUT which 10-15%?

Personal & Family HistoryAge at OnsetOther Types of CancerOne or More OrgansPedigree Drawing

High Risk

Pre-Test Genetic CounselingGenetic Testing

Test PositiveRisk ManagementScreeningProphylactic Surgery

Low Risk

Receive Gene Test ResultsPost-Test Counseling Test Negative

ACS GuidelinesGeneral Population

Breast CancerOr Any Disease

Center for Personalized Genetic HealthcareCenter for Personalized Genetic Healthcare

Genomics-Based Personalized Healthcare for Cancer 2008-09

Multidisciplinary CancerConsult Including Genomic Medicine

And Genetic Counseling

Multidisciplinary CancerConsult Including Genomic Medicine

And Genetic Counseling

Multiple Generation PedigreeFor Cancer Genetic Risk Assessment

Multiple Generation PedigreeFor Cancer Genetic Risk Assessment

Somatic Genomic Profiling ofCancer Epithelium & Stroma

Somatic Genomic Profiling ofCancer Epithelium & Stroma

Biopsy of CancerBiopsy of Cancer

HistopathologyHistopathology

Select Multi-Agent TargetedTherapy With >99%

Likelihood of DurableResponse & <1% Likelihood

Of Adverse Effects

Select Multi-Agent TargetedTherapy With >99%

Likelihood of DurableResponse & <1% Likelihood

Of Adverse Effects

Clinical Screening,Preventative Measures,Behavior Modification

Clinical Screening,Preventative Measures,Behavior Modification

Prioritization & Testing ofKnown High Penetrance

Cancer Genes in Setting ofGenetic Counseling

Prioritization & Testing ofKnown High Penetrance

Cancer Genes in Setting ofGenetic Counseling

Germline Variant ProflingGermline Variant Profling