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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

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Genetics and Genomics Research to Enable the Practice of Personalized Cancer Care

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  1. 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

  2. Behavior Genetics Social Medical Access Environmental Contributors to Premature Mortality D.M. Cosgrove, MD, State of the Clinic 2008 April, 2009

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

  4. 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)

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

  6. Breath of Personalized Healthcare (ie, Everyone Can Contribute) • 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

  7. 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”

  8. Uncommon, Mendelian, Single-Gene Disorders (Strong Effect) Eg. Cystic fibrosis Lynch syndrome Hemophilia A Sickle-cell anemia Common Diseases (multi-gene, small effect each) Eg. Obesity Heart disease Diabetes Autism Alzhemier’s Genetics and Genomics Important Bases for Personalizing Clinical Care Genomics THE BIG RED DOG. THE IGR EDD OG. Genetics THE BIG RED DOG. A BIG RED DOG. 3,993 number of genes currently known to be associated with disease out of an estimated 35,000 (~12%)

  9. Prioritization & Testing of Known High Penetrance Cancer Genes in Setting of Genetic Counseling Multiple Generation Pedigree For Cancer Genetic Risk Assessment Clinical Screening, Preventive Measures, Behavior Modification Select Multi-Agent Targeted Therapy With >99% Likelihood of Durable Response & <1% Likelihood Of Adverse Effects Germline Variant Profiling Biopsy of Cancer Histopathology Somatic Genomic Profiling of Cancer Epithelium & Stroma Nirvana of Integrated –omics-based Personalized Healthcare for Cancer Multidisciplinary Cancer Consult Including Genomic Medicine And Genetic Counseling

  10. 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

  11. GMI Focus Clinical Activities Eng Lab Clinical Cancer Genetics Already Strong at Lerner Research Institute Eng Program in Context of Genomic Medicine Institute (GMI) Research and of Cleveland Clinic Bedside Bench Very Basic Science Research Very Clinical Research

  12. 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

  13. Prioritization & Testing of Known High Penetrance Cancer Genes in Setting of Genetic Counseling Multiple Generation Pedigree For Cancer Genetic Risk Assessment Clinical Screening, Preventive Measures, Behavior Modification Select Multi-Agent Targeted Therapy With >99% Likelihood of Durable Response & <1% Likelihood Of Adverse Effects Germline Variant Profiling Biopsy of Cancer Histopathology Somatic Molecular Profiling of Cancer Epithelium & Stroma Nirvana of Integrated Genetics and Omics-Based Personalized Healthcare: 2011 & Beyond Multidisciplinary Cancer Consult Including Genomic Medicine And Genetic Counseling

  14. GMI Faculty Research Programs Prioritization & Testing of Known High Penetrance Genes in Setting of Genetic Counseling Multiple Generation Pedigree For Cancer Genetic Risk Assessment Clinical Screening, Preventive Measures, Behavior Modification Multidisciplinary Consult Including Genomic Medicine And Genetic Counseling Select Multi-Agent Targeted Therapy With >99% Likelihood of Durable Response & <1% Likelihood Of Adverse Effects Germline Genome Profiling Biopsy of Tissue Histopathology Somatic Molecular Profiling of Epithelium & Microenvironment Genetic Susceptibility to: Hemostasis and Thrombosis (Zhang) Cancer (Eng) Connective Tissue Disorders (Aldred/Moran) Pulm HTN & Wilms Tumor (Aldred) Phenotyping by Clinicians Eng Moran Natowicz Shapiro Zurcher 11 Genetic Counselors Genomic Predisposition to Common Diseases: Diabetes/Obesity (Serre) Reverse Cholesterol Transport (Sehayek) Malaria and Populations (Serre) Solid Tumors (Eng) Genomics ELSI (Center for Genomic Bioethics) DTC Genomic Testing (Eng, Sharp) Returning Results to Participants who Donated to Biorepository-Based Research Genetic Testing in Pediatric Populations (Moran, Sharp) Informed Consent in MFM (Moran, Farrell) Somatic Genetics/Epigenetics: Metabiomics (Eng, Sehayek, Serre) Colon CA and Prostate CA Epigenomics (Ting) Microenvironment and Outcome (Eng) Wilms Tumor/HNSCC (Aldred)

  15. Eng Lab – Translational Cancer Genetics/Genomics Prioritization & Testing of Known High Penetrance Cancer Genes in Setting of Genetic Counseling Multiple Generation Pedigree For Cancer Genetic Risk Assessment Clinical Screening, Preventive Measures, Behavior Modification Multidisciplinary Cancer Consult Including Genomic Medicine And Genetic Counseling Select Multi-Agent Targeted Therapy With >99% Likelihood of Durable Response & <1% Likelihood Of Adverse Effects Germline Variant Profiling Biopsy of Cancer Histopathology Somatic Genomic Profiling of Cancer Epithelium & Stroma Germline Predisposition and Cancer Risk Prediction PTEN mutations/variations in Cowden syndrome (breast/thyroid) SDH variants in Cowden syndrome KLLLN germline hypermethylation Nontraditional Mechanisms of PTEN Loss-of-Function Nuclear-Cytoplasmic trafficking of PTEN Epigenetic modification FBE Gene Hunt Complex Disorders Germline homozygosity & predisposition to common solid tumors Solid Tumor Microenvironment Genomics & Outcome HNSCC Metabiomics

  16. 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

  17. Trichilemmoma Papillomatous Papules Key Features of CS are Difficult to Recognize (Pathognomonic Feature)

  18. 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 CS Component Neoplasias Zbuk & Eng. Nature Rev Cancer 2007

  19. 10p - short arm 10q - long arm 10q22-q23 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

  20. 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 1996 Liaw, Marsh et al. Nature Genet 1997

  21. 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

  22. 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% Marsh et al. Nature Genet 1997 Zhou et al. Lancet 2001 Zbuk & Eng. Nature Rev Cancer 2007 Tan et al. Am J Hum Genet 2011

  23. 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 2011 Eng et al. Unpublished 2011

  24. Over-Representation of Malignancies in PTEN Mutation Positive Individuals Eng et al. Unpublished 2011 Mester and Eng. ASHG 2009

  25. 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)

  26. Mutn Negative STOP If Mutn Negative If Mutn Positive To Research Genetics-Enabled Molecular Diagnosis, Predictive Testing & Medical Management PTEN Testing, Affected Person, with Cancer Genetics Consultation PTEN Mutn Positive Promoter Analysis in CS Deletion Analysis in BRRS Breast, Thyroid, Endometrial Surveillance, Etc (NCCN) If Mutn Positive All First Degree Relatives of Mutation Positive Individuals Offered Gene Testing for Family-Specific Mutation If Mutn Negative Reviewed in Zbuk & Eng. Nature Rev Cancer 2007

  27. 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

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

  29. 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

  30. Eng et al, Nat Rev Cancer 2003 Mitochondrial Complex II = SDH

  31. SDHB-D Germline Mutation Analysis of PTEN Mutation Negative CS/CSL Individuals Ni et al. Am J Hum Genet 2008

  32. Increased ROS MnSOD Expression Screen > SDHB-D Mutation Analysis Ni et al. Am J Hum Genet 2008

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

  34. Variably Increased P-AKT and P-MAPK Resulting from Germline SDHB/SDHD Mutation/Variant Positive CS/CSL Individuals without PTEN Mutations Ni et al. Am J Hum Genet 2008

  35. Proposed Cross-Talk Between PTEN and SDH Pathways

  36. Cancer Risks in SDH Mutation/Variant Positive versus Cancer Risks in PTEN Mutation Positive CS/CSL Ni et al. Am J Hum Genet 2008, Eng et al, unpublished *Fisher 2-Tailed Exact Test

  37. Proposed Clinical Algorithm for Gene Testing in CS and CSL Probands Ni et al. Am J Hum Genet 2008

  38. Mut + Results Checked in CLIA Lab -> to Patients PI Conceives of Hypotheses & Study Design & is Responsible for the Study Protocol. PI can & does Delegate Various Responsibilities to Protocol Members Example of Work Flow for a Translational Genetics Research (PTEN) Protocol & the Team Ensuring the Flow PI: C Eng; GC Coordinator: Jessi Mester; General Research Coordinator: Dawn Caraballo CPGH Physicians and GC’s CC/National/International Clinicians Dawn, GC Assts, GCs Gloria, Others Send Out Blood Kit Dawn, Jessix 2, GC Assts, Student Interns, Others Genomic Medicine Biorepository Eng Lab Members LabMatrix Entry: Kim and Tom Genomics Core Facility Mut+/Var+ Patients Choice of Enrollment in Annual Questionnaire Study Gloria, GC Assts, Student Interns, Others Dawn Offers Questionnaire Study; A Whole New Protocol Rolls CPGH Physicians and GC’s CC/National/International Clinicians Jessi Me (Mut+) Dawn via email (Mut-)

  39. Genetics-Enabled Cancer Risk-Assessment and Management: Paradigm for Personalized Genetic Health Assessment and Management Is it hereditary or sporadic? Personal & Family History Age at Onset Familial Clustering One or More Organs Pedigree Drawing Low Risk Epidemiology says 10-15% caused by High penetrance genes, BUT which10-15%? Cancer Standard Guidelines General Population High Risk Pre-Test Genetic Counseling Genetic Testing Risk Management Screening Prophylactic Surgery Receive Gene Test Results Post-Test Counseling Test Positive Test Negative

  40. 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

  41. 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

  42. 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

  43. 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

  44. With Disease Subclinical Disease(s) Healthy Who is Patient Population for Future Genomic Medicine? 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 Facilitate Genetics-Informed Healthcare in Setting of Caregiver Shortage

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