genetics and genomics research to enable the practice of personalized cancer care

Genetics and Genomics Research to Enable the Practice of Personalized

Cancer Care

Charis Eng, MD, PhD, FACP

Chair, Genomic Medicine Institute

Director, Center for Personalized Genetic Healthcare

Medical Director, Clinical Cancer Genetics Service

Member, Taussig Cancer Institute

Cleveland Clinic

AFMR Transl Med Symposium, April 11, 2011

Genomic Medicine Institute

Contributors to Premature Mortality

Behavior Genetics Social Medical Access Environmental

D.M. Cosgrove, MD, State of the Clinic 2008April, 2009


Elias A. Zerhouni, M.D September 13, 2006Need to Transform Health and Medicine in the 21stCentury

20th Century Medicine 21st Century Medicine

Treat disease when symptoms appear and normal function is lost

Intervene before symptoms appear and preserve normal function for as long as

possible

Did not understand the molecular and cellular events that lead to disease

Understanding preclinical molecular events and ability to detect patients at risk

Expensive in financial and disability costs Order of magnitude more effective

Health & Medicine Transformation Need to Transform Health & Medicine

in the 21st Century


Historical Imperative for Prevention

•Superior doctors prevent the disease.

•Mediocre doctors treat the disease before evident.

Inferior doctors treat the full blown disease.

Nai-Ching (2600 B.C. 1st Chinese Medical Text)


• Medicare and the Drug Plan

• Care and Coverage of the Uninsured

• Rise of the Healthcare Consumer

• Focus on Prevention

• Calls for Patient Safety to Drive HealthCare IT Investments

• Diminishing Drug Pipeline

• Pay for Performance

• Technology Backbone

• Labor Shortages

Top Nine Health Industry Issues in 2010 PricewaterhouseCooper’s Health Research Institute


• Phenomics– Meticulous Documentation of Clinical Features

– Objective Means (Not Self Reports)

• Disease Risk Assessment

• Interpretation– (Must Have Clinical Context[Outcome] and Scientific Content [Research Data])

– To Fellow Professionals

– To Patients / Consumers

• Personalized Risk Management

– Broadest Sense– Prevention

– Treatment

– Behavior Modification

– And so on

• Ethical, Legal, Social Issues and Education

Breath of Personalized Healthcare(ie, Everyone Can Contribute)


Breath of Translational Research

• Myth: Translational Research = Drug Development and Therapeutic Trials – Caution: This is how NIH defines it!

• Truth: Translational Research = All Patient-Oriented Research that Spans the Breath to Refine Diagnostics and Risk Assessment to Genetic Counseling to Preventative Maneuvers and Therapeutics

• “Right Diagnosis – Right Treatment”


Genomics

GeneticsUncommon,

Mendelian, Single-Gene Disorders

(Strong Effect)Eg. Cystic fibrosisLynch syndrome

Hemophilia ASickle-cell anemia

Common Diseases

(multi-gene, smalleffect each)Eg. Obesity

Heart diseaseDiabetesAutism

Alzhemier’s

Genetics and Genomics Important Bases for Personalizing Clinical Care

3,993 number of genes currently known to be associated with disease out of an estimated 35,000 (~12%)

THE BIG RED DOG.THE IGR EDD OG.

THE BIG RED DOG.A BIG RED DOG.


Multidisciplinary CancerConsult Including Genomic Medicine

And Genetic Counseling



Multiple Generation PedigreeFor Cancer Genetic Risk Assessment

Somatic Genomic Profiling ofCancer Epithelium & Stroma

Biopsy of Cancer

Histopathology

Select Multi-Agent TargetedTherapy With >99%

Likelihood of DurableResponse & <1% Likelihood

Of Adverse Effects

Clinical Screening,Preventive Measures,Behavior Modification

Prioritization & Testing ofKnown High Penetrance

Cancer Genes in Setting ofGenetic Counseling

Germline Variant Profiling

Nirvana of Integrated –omics-based Personalized Healthcare for Cancer


Genomic Medicine Institute Mission (Founded Sept, 2005): Genetics and Genomic Medicine are the Bases for Personalized Healthcare

• To be the expert base for the principles and practice of genomic medicine

• Scholarly activity (research), academic clinical practice and education

• Ultimately directed at personalized genetics and genomics-based healthcare


Eng Program in Context of Genomic Medicine Institute (GMI) Research and of Cleveland Clinic

BedsideBench

Very BasicScience Research

Very ClinicalResearch

Already Strong at Lerner Research Institute

GMI Focus

Eng Lab ClinicalActivities

Clinical Cancer Genetics


Sept, 2005 Situational SWOT• Strengths

– Strong Basic Sciences (Ripe for Translation) & Infrastructure

– Strong Clinicians and Clinical Materials

• Weaknesses– Strong Basic Sciences (Lack of Understanding of Translational and Clinical

Genetics and Genomics Investigation and Investigators)

– Strong Clinicians (Clueless what Translational Research is; Revenue-Driven)

– No Clinical Genetics Infrastructure

– No Translational Genetics Research Infrastructure

• Opportunities– Build a “Perfect” Translational Genetics Research Infrastructure

– Initiate Translational Research Multidisciplinary Programs

– Create Comprehensive Clinical Genetics Program

• Threats– Sisiphus Syndrome

– Scientists and Clinicians Fear Change


Nirvana of Integrated Genetics and Omics-Based Personalized Healthcare: 2011 & Beyond






Somatic Molecular Profiling ofCancer Epithelium & Stroma

Biopsy of Cancer

Histopathology



Of Adverse Effects






GMI Faculty Research Programs

MultidisciplinaryConsult Including Genomic Medicine


MultidisciplinaryConsult Including Genomic Medicine



Somatic Molecular Profiling ofEpithelium & Microenvironment

Biopsy of Tissue

Histopathology



Of Adverse Effects



Genes in Setting ofGenetic Counseling

Germline Genome Profiling

Phenotyping by CliniciansEngMoranNatowiczShapiroZurcher11 Genetic Counselors

Genetic Susceptibility to:Hemostasis and Thrombosis (Zhang)Cancer (Eng)Connective Tissue Disorders (Aldred/Moran)Pulm HTN & Wilms Tumor (Aldred)

Genomic Predisposition to Common Diseases:Diabetes/Obesity (Serre)Reverse Cholesterol Transport (Sehayek)Malaria and Populations (Serre)Solid Tumors (Eng)

Somatic Genetics/Epigenetics:Metabiomics (Eng, Sehayek, Serre)Colon CA and Prostate CA Epigenomics (Ting)Microenvironment and Outcome (Eng)Wilms Tumor/HNSCC (Aldred)

Genomics ELSI (Center for Genomic Bioethics)DTC Genomic Testing (Eng, Sharp)Returning Results to Participants who Donated to Biorepository-Based ResearchGenetic Testing in Pediatric Populations (Moran, Sharp)Informed Consent in MFM (Moran, Farrell)


Eng Lab – Translational Cancer Genetics/Genomics






Somatic Genomic Profiling ofCancer Epithelium & Stroma

Biopsy of Cancer

Histopathology



Of Adverse Effects





Germline Predisposition and Cancer Risk PredictionPTEN mutations/variations in Cowden syndrome (breast/thyroid)SDH variants in Cowden syndromeKLLLN germline hypermethylation

Nontraditional Mechanisms of PTEN Loss-of-FunctionNuclear-Cytoplasmic trafficking of PTENEpigenetic modification

FBE Gene Hunt

Complex DisordersGermline homozygosity & predisposition to common solid tumors

Solid Tumor Microenvironment Genomics & OutcomeHNSCC Metabiomics


Cowden Syndrome (CS) as a Model for Cancer Genetics Practice

• The Great Mimic• Difficult to Recognize• Under-Diagnosed• Autosomal Dominant• Multiple Hamartomas• High Risk of:

• Breast CA (50%)• Thyroid CA, especially FTC (10%)

• International Cowden Consortium Diagnostic Criteria• Robust• Complex


Key Features of CS are Difficult to Recognize

Trichilemmoma

Papillomatous Papules (Pathognomonic Feature)


CS Component Neoplasias

• Established– Breast Cancer (28-50%)

– Thyroid Cancer (10%)

–FTC

– Breast FBC/FA (75%)

– Thyroid Follicular Hyperplasia or Adenoma (67%)

– Lhermitte-Duclos Dz (x%)

Suspected Endometrial CA Renal Cell CA Melanoma Basal Cell CA Glioneural Brain CA

Zbuk & Eng. Nature Rev Cancer 2007


Mapping of the CS Gene

• International Cowden Consortium Study

• 12 Extended CS Families

• 40 Affected Individuals

• CS Mapped to 10q22-q23

Nelen et al. Nature Genet 1996

10p - short arm

10q - long arm

10q22-q23


PTEN is the CS Gene

• 5 CS Families, Linkage to 10q22-q23

• Candidate Gene, PTEN, on 10q23.3

• Germline Mutations of PTEN, on 10q23.3, in 4 of 5 Families– Family “without” mutation had highest LOD score on prior linkage

analysis (LOD>1)

Nelen et al. Nature Genet 1996Liaw, Marsh et al. Nature Genet 1997


PTEN

• Phosphatase, Tensin-Homologue, Deleted on Chromosome TEN– 10q23.3

• Tumor Suppressor Gene

• Dual-Specificity Phosphatase– Lipid & Protein Phosphatase

– Ser-Thr as well as Tyr Phosphatase

• Multiple Roles in Cell Cycle Arrest, Apoptosis, Migration, Polarity, Genomic Stability, etc

Reviewed in Waite & Eng. AJHG 2003 & Zbuk & Eng. Nat Rev Cancer 2007


PTEN Hamartoma Tumor Syndrome (PHTS)

• Cowden syndrome (CS)– PTEN Mutation Frequency - 85% (25% in new series)

• Bannayan-Riley-Ruvalcaba syndrome (BRRS)– Mutation Frequency - 65%

– Rare, Autosomal Dominant Disorder: Macrocephaly, Lipomatosis, Haemangiomatosis, Speckled Penis

• Proteus Syndrome (PS)– Mutation Frequency - 20%

– Hemihypertrophy, etc (“Elephant Man”)

• Autism Spectrum Disorder (ASD) with Macrocephaly– Mutation Frequency - 10-20%

Zbuk & Eng. Nature Rev Cancer 2007Tan et al. Am J Hum Genet 2011

Marsh et al. Nature Genet 1997Zhou et al. Lancet 2001


PHTS - What Are the True Associated Clinical Neoplasias?

• Prospective Accrual–Pilot Series: Jan, 1999-July 2005 (N=2205)

–Validation Series: Oct, 2005-Ongoing (N>3000)

• Eligibility: Relaxed from Classic CS Operational Dx Criteria

• Clinical Feature Checklist

• Medical Records & Pathology Review

• Age at Diagnosis for Each Neoplasia

• PTEN Mutation Analysis, Including Promoter & Large Deletion/Rearrangement Analyses

Tan et al. Am J Hum Genet 2011Eng et al. Unpublished 2011


Over-Representation of Malignancies in PTEN Mutation Positive Individuals

Increased over Gen

Pop?

P-Value(Chi-Square)

Breast (Female) Yes <0.001

Endometrium Yes <0.001

Epith Thyroid Yes <0.001

Eng et al. Unpublished 2011 Mester and Eng. ASHG 2009


PTEN Testing for Diagnosis

• (Pretty) Accurate Molecular Diagnostic Adjunct– Must Include Intragenic PTEN (Exons 1-9), Promoter and Large

Deletion Analysis

• Helps with Cancer Risk Assessment and Management

• Predictive Testing is Possible– Always Start with a Known Affected (Living)

–Family-Specific Mutation

– Test for Family-Specific Mutation in as Yet Unaffected First Degree Relative(s)


Genetics-Enabled Molecular Diagnosis, Predictive Testing & Medical Management

PTEN Testing, Affected Person, with Cancer Genetics Consultation

Mutn Negative PTEN Mutn Positive

All First Degree Relatives ofMutation Positive Individuals

Offered Gene Testing forFamily-Specific Mutation

STOPSTOP

Breast, Thyroid, Endometrial Surveillance, Etc (NCCN)

If Mutn Negative

If Mutn Positive

Promoter Analysis in CSDeletion Analysis in BRRS

To Research

If Mutn Negative If Mutn Positive

Reviewed in Zbuk & Eng. Nature Rev Cancer 2007


What About Those Germline PTEN Mutation Negative Patients?

• CS: 15% (75% - 2011) PTEN Mutation Negative

• CS-Like: 85% PTEN Mutation Negative

• BRRS: 35% PTEN Mutation Negative

• BRRS-Like: Who Knows?

• Proteus Syndrome: 80% PTEN Mutation Negative

• PS-Like: 40% PTEN Mutation Negative


Why is it Important to Find Genes and Mutations to Account for a High Frequency of a Heritable Cancer?

Clinical Function Known Gene and Mutation(s)

Gene Unknown

Clinical Diagnosis Yes Yes if Clinically Classic

Molecular Diagnosis Yes No

Genetic Counseling Yes Yes but Cookie-Cutter

Gene-Informed Cancer Risk Assessment

Yes Can be Done but not Gene-Informed

Predictive Testing Yes No

Gene-Informed Management

Yes No (Can Do Cookie-Cutter Management)


Genes Encoding Succinate Dehydrogenase (SDH) as Predisposition Genes in PTEN Mutation Negative CS/CSL Individuals?

• Germline Heterozygous Mutations in SDHB, SDHC, SDHD Cause Heritable Pheochromocytoma/Paraganglioma (PC/PGL) Syndrome

• European-American PC-PGL Registry

• PC/PGL Individuals with SDHB Mutations – 1-5% Had Renal Cell Carcinoma

– A Few Had Papillary Thyroid Carcinoma (PTC)

– Reminiscent of Component Neoplasias of CS

• Hypothesis: SDH Genes May be Novel Predisposition Genes for PTEN Mutation Negative CS/CSL

Neumann et al. N Engl J Med 2002, JAMA 2004,Vanharanta et al. Am J Hum Genet 2004, Ni et al. Am J Hum Genet 2008


Mitochondrial Complex II = SDH

Eng et al, Nat Rev Cancer 2003


SDHB-D Germline Mutation Analysis of PTEN Mutation Negative CS/CSL Individuals

Ni et al. Am J Hum Genet 2008


MnSOD Expression Screen > SDHB-D Mutation Analysis

Increased ROSNi et al. Am J Hum Genet 2008


Variably Increased P-AKT and P-MAPK Resulting from Germline PTEN Mutation Positive CS/CSL


Variably Increased P-AKT and P-MAPK Resulting from Germline SDHB/SDHD Mutation/Variant Positive CS/CSL Individuals without PTEN Mutations



Proposed Cross-Talk Between PTEN and SDH Pathways


Cancer Risks in SDH Mutation/Variant Positive versus Cancer Risks in PTEN Mutation Positive CS/CSL

Cancer SDH Mut%

95% CIPTEN Mut

%

95% CIP-Value*

Renal 2/1020%

5-52%4/230

1.2%

0.5-4.5%0.03

Thyroid 5/1050%

25-76%15/206

7.2%

4-12%<0.001

Breast 6/966.7%

36-88%30/107

28%

22-34%<0.001

Uterine 1/911%

0-45%15/107

14%

8-22%0.64

Colon 0/100

0-32%4/210

6.7%

0.6-5%>0.99

*Fisher 2-Tailed Exact TestNi et al. Am J Hum Genet 2008, Eng et al, unpublished


Proposed Clinical Algorithm for Gene Testing in CS and CSL Probands



Example of Work Flow for a Translational Genetics Research (PTEN) Protocol & the Team Ensuring the Flow

Mut + ResultsChecked in CLIALab -> to Patients

Mut+/Var+ Patients Choice ofEnrollment in Annual Questionnaire

Study

PI Conceives of Hypotheses & Study Design & is Responsible for the Study Protocol.PI can & does Delegate Various Responsibilities to Protocol Members

PI: C Eng; GC Coordinator: Jessi Mester; General Research Coordinator: Dawn Caraballo

CPGH Physicians and GC’sCC/National/International Clinicians


Dawn, GC Assts, GCsDawn, GC Assts, GCs

Dawn, Jessi x 2, GC Assts,Student Interns, OthersDawn, Jessi x 2, GC Assts,Student Interns, Others

LabMatrix Entry: Kim and TomLabMatrix Entry: Kim and Tom

Gloria, GC Assts, Student Interns, Others

Gloria, Others Send Out Blood KitGloria, Others Send Out Blood Kit

Genomic Medicine BiorepositoryGenomic Medicine Biorepository

Eng Lab MembersEng Lab Members

Genomics Core FacilityGenomics Core Facility



Jessi Me (Mut+)Dawn via email (Mut-)Jessi Me (Mut+)Dawn via email (Mut-)

Dawn Offers Questionnaire Study;A Whole New Protocol RollsDawn Offers Questionnaire Study;A Whole New Protocol Rolls


Genetics-Enabled Cancer Risk-Assessment and Management: Paradigm for Personalized Genetic Health Assessment and Management

Is it hereditaryIs it hereditaryor sporadic?or sporadic?

Epidemiology saysEpidemiology says10-15% caused by 10-15% caused by High penetrance genes, High penetrance genes, BUT which10-15%?BUT which10-15%?

Personal & Family HistoryPersonal & Family HistoryAge at OnsetAge at OnsetFamilial ClusteringFamilial ClusteringOne or More OrgansOne or More OrgansPedigree DrawingPedigree Drawing

Pre-Test Genetic CounselingPre-Test Genetic CounselingGenetic TestingGenetic Testing

Test PositiveTest PositiveRisk ManagementRisk ManagementScreeningScreeningProphylactic SurgeryProphylactic Surgery

High RiskHigh Risk

Low RiskLow Risk

Receive Gene Test ResultsReceive Gene Test ResultsPost-Test CounselingPost-Test Counseling Test NegativeTest Negative

Standard GuidelinesStandard GuidelinesGeneral PopulationGeneral Population

CancerCancer


Patients at Genetic Risk for Cancer Are Under-Served by Not Being Systematically Recognized

• Cleveland Clinic Health System sees ~1.8 Million New Patients/Yr– 2009: 38 Million Total Visits

• ~10% of All with Disease Due to High Penetrance Genetic Predisposition

• Should Have Referred >380,000 to Genetic Care in 2009

• In Reality, 2,900 were Referred in 2009

Eng et al., Unpublished


National Trends -- No Different

• >35,000 Healthy Patients

• ~350 Had Family Histories Consistent with Hereditary Breast-Ovarian Cancer Syndrome Due to Germline BRCA1/2 Mutations

• 35 of 350 Discussed Concerning Family History with Any Healthcare Provider

• 4 of 35 Underwent BRCA1/2 Mutation Analysis

Levy D et al. 2009


Important Reasons that Individuals at Genetic Risk of Disease are Under-Served

• Lack of systematic and comprehensive ascertainment of individuals at genetic risk of disease;

• Traditional practice model for genetics in the context of small workforce;

• Because of the exponential increase in genetics knowledge in the last 10 years, there is a lag in knowledge acquisition by both healthcare providers and the public.– Fear of Genetic Discrimination (GINA passed in 2009)

• Genetics is a 21st century subspecialty on a 19th century organizational structure


Potential Solutions that will Revolutionize Genetics-Informed Delivery of Healthcare

• To develop a process to ensure systematic and comprehensive ascertainment of individuals at genetic risk of disease– Beta Test with Cancer Genetics

• To increase access by changing the traditional practice model of genetics – Beta Testing with Cancer Genetics (Very Successful)

– Same Day Service

– Quintupled Patient Volumes

• To engrain a multi-modality cancer genetics education campaign throughout CCHS– Point of Care Education

– Genetics Champions (Non-Genetics Healthcare Provider) in Each Institute

• Working with CC leadership to bring organizational structure and practice models into the 21st century– Integration of genetics into all of healthcare

– Standardization of practice


Who is Patient Population for Future Genomic Medicine?

With Disease

Subclinical Disease(s)

Healthy

Now

But: There are Only 500 Physicians who Practise Any Genetics, and There are Perhaps 3000+/- Genetic Counselors in this Country!

Challenge to Researchers: Innovative Discoveries that FacilitateGenetics-Informed Healthcare in Setting of Caregiver Shortage

genetics and genomics research to enable the practice of personalized cancer care

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