1 / 36

Declaration

Genomics, cancer, and medicine: 10 years after the Human Genome Project Edison Liu, M.D. April 13, 2012. Declaration. We are entering one of the most profound periods of advancement in biology and medicine – one that will transform: Health and Medicine

paxton
Download Presentation

Declaration

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Genomics, cancer, and medicine: 10 years after the Human Genome ProjectEdison Liu, M.D.April 13, 2012

  2. Declaration We are entering one of the most profound periods of advancement in biology and medicine – one that will transform: Health and Medicine Driven by technologies in genetics, genomics, and computational biology

  3. Genomics and Genetics Genetics: study of genes and their function Genomics: study of all genes and how they function together “Discover all possible genes involved in a biological process or a human disease” Genomics enables the complete genetic “view” of a disease

  4. Transformative technologies enabling this revolution: • New generation of ultra-fast sequencing • technologies • “Massive Data Generation” • Enabling computational advances • “”Analytical power“ • Genetic engineeringto model organisms of disease • “Surrogates of disease”

  5. T* T* G* A* T* C* AAGT A* AGT CTAGCTGATTCAG CTAGCTGATTCAG Massively Parallel Sequencing: Sequencing by Synthesis ~105-107 kb per run = 0.1-3 X human genome equivalents / run

  6. 7 orders of magnitude increase in throughput MR Stratton et al. Nature458, 719-724 (2009)

  7. Cost of sequencing a human genome 300 million 300 million USD - Cost-effective sequencing = Accessibility of genomic data 30 million USD - 3 million USD - 1 million 300,000 USD - $60,000 30,000 USD - $ 3,000 2001 2003 2005 2007 2009 2011

  8. Low complexity image Data complexity when ordered appropriately gives high resolution picture Genomic scale information provides unique biological insights

  9. Genomics & Personalized Medicine

  10. Towards personalized cancer medicine No benefit Non-selective Conventional chemothrapy Molecular marker & target Severe side effect Responders Personalized cancer medicine Other therapy No treatment Selection by marker High response rate Molecular specific drug

  11. CAT ATE RAT Wild TypeBAT ATE RAT Point MutationRAT ATE CAT RearrangementCathryn PolymorphismKathryn PolymorphismKathrine Polymorphism

  12. Chronic Myelogenous Leukemia: and the 9;22 chromosomal rearrangement

  13. Molecular Mechanisms: How to make a Leukemia • Ph1 chromosome identified 1960 as a marker for CML (Nowell) • bcr-abl cloned and shown to be the molecular mechanism 1984-1990 (Groffen and Lugo) Chronic Myelogenous Leukemia BCR ABL

  14. Chronic Myelogenous Leukemia: Mortality 1969 - 2002 Large scale clinical trials begin with Gleevec Gleevec Approved By FDA STI521:Gleevec BCR ABL

  15. From Concept to Molecular Mechanism to Treatment • Ph1 chromosome identified 1960 as a marker for CML (Nowell) • bcr-abl cloned and shown to be the molecular mechanism 1984-1990 (Groffen and Lugo) • Specific drug (Gleevec) to target gene abnormality 1999 (Druker) • From discovery of a single oncogene to treatment: 39 years

  16. Nature 2007 In 2007, the genomic analysis of one lung cancer from a 62 year-old smoker  EML-ALK fusion in 6% of lung cancer patients Lung Cancer EML ALK

  17. Crizotinib  60% response rate in those 6% of patients with lung cancer with the EML-ALK mutation. On August 26, 2011, the US FDA gave approval of crizotinib by for the treatment of ALK-rearranged lung cancer 4 years from genomic discovery to treatment Ou, Drug Des Devel Ther. 2011; 5: 471–485.

  18. Chronic Myelogenous Leukemia (CML) Optimizing treatment for CML based on genetic makeup of the patient • Clinical Challenge: Drug resistance • Acquired resistance – resistance after long term treatment - due to second ABL mutation • Primary resistance – resistance at the beginning of treatment. • In Asia, complete cytogenetic response rates are lower - 50% vs. 74%. Mechanism unknown

  19. Question: is there a reason why 25% of CML cases do not respond to imatinib? Approach: We compared the genomes of three CML cases with primary resistance to Imatinib with two CML cases sensitive to Imatinib therapy Results: 3/3 resistance cases had the same 2.9kb deletion in the BIM gene not seen in sensitive cases (0/2)

  20. BIM: • BIM is a gene that activates cell death (pro-apoptotic). • Activated BCR-ABL1, suppresses BIM function thus allowing leukemia cells to survive. When CML cells are treated with Imatinib, BIM expression goes up  cell death Death of Leukemia cells Bcr-ABL: CML Intact BIM Imatinib

  21. BIM deletion polymorphism: • This deletion polymorphism is 3-5X more common in CML cases resistant to imatinib that sensitive cases • This 2.9 kb 2 deletion of BIM is not a mutation, but is a polymorphism present in normal genomes (a germline polymorphism): • 12% in Asian individuals • 0% in Africans • 0% in Caucasians

  22. How does it work?: The 2.9kb BIM deletion polymorphism results an abnormal transcript (E3) that a produces a truncated and inactive BIM protein Normal Transcripts E3 Imatinib Death of Leukemia cells Bcr-ABL: CML Intact BIM Imatinib Primary Drug Resistance BIM E3 Bcr-ABL: CML

  23. We used this genomic intelligence to overcome this resistance: Imatinib Primary Drug Resistance BIM 3 Bcr-ABL: CML BH3 mimetics Imatinib Death of Leukemia cells Bcr-ABL: CML BIM

  24. This genomic experiment with 5 patients explains the lower response rate In North Asians to a life saving treatment in CML. Personalizing medicine in Asia Now: New ~50% cytogenetic response CML Patient in Asia Check for bcr-ABL rearrangement YES Check for 2.9kb deletion polymorphism in BIM YES NO Imatinib & BH3-mimetic Imatinib >75% cytogenetic response 75% cytogenetic response

  25. Visualizing the Cancer Genome 17 Copy Number LOH Structural Variations BT55

  26. ‘Conductor’mutation = early event that conducts the direction of further cancer mutations Mutation pattern appears to be generated by separate cuts when mapped to the original physical “map” Chromosomal “origami” simultaneously generates oncogenic “pattern”

  27. Chromosomal origami to generate cancer gene cassette ERBB2 ERBB2 Oncogenes 17q21.3 P53 ERBB2 BRCA1 17q21.3 ERBB2 17q21.3 ERBB2 17q21.3 ERBB2

  28. 17q21.3 amplicon ERBB2/HER2 Oncogene BRCA1 Tumor Suppressor Gene TD207 U-Inv331 TD49 + Del67 There are 16 weak oncogenes here. 4 that are synergistic with ERBB2 oncogenesis U-Inv75 Del51 ERBB2 17q21.3 17q21.3 BT55 (ER+, ERBB2++) Luminal B Amplification

  29. Chr17 ‘evolutionary origami’ has treatment implications for Combination therapy Cancer progression  17p (TP53) loss Chromosomal instability Recurrent Unpaired-Inversion: “Conductor” Mutation Tandem duplication in ERBB2 locus Massive ERBB2 amplification Nutlins 17q21.3 amplification BRCA1 locus loss Oncogenes Lapatinib New Target Tumor Suppressor genes PARP inhibitor

  30. Cancer Genomics Consultation Model Using Mouse Avatars for Human Disease Druggable mutations Tumor DNA sample Automated sequence analysis of tumor and germline Prognostic information Sequence Tumor Germline DNA sample Germline pharmacogenetic analysis Identification of cancer specific rearrangements Generation of serum-based personalized and private cancer biomarker test Monitor for recurrence and clonal variation Visualization formatted report Consultation with patient and physician for treatment plan Devise optimal combination therapy Expand tumor in NSG mice Test specified drugs for response in vivo

  31. Radiologist of the Genome Radiologist Interprets complex data rendered through computational algorithms Is the consultants to doctors

  32. Genomics, cancer, and medicine: 10 years after the Human Genome ProjectEdison Liu, M.D.April 13, 2012

  33. 1990 Age Adjusted Mortality for breast cancer is declining since 1990 D ~ 20%

  34. ER (IHC) positive HER2 (FISH) Positive Ki67: +++ GHI recurrence score: XXX T2N1M0 Age: 56 family history: negative Sequence performance: 9.6 million reads; 75 base pair, paired end on Illumina HiSeq Comparison of germline and cancer genomes This is a visual representation of the cancer genome of your patient as compared to her constitutional (germline) genome. The 23 chromosomes are arrayed in a circle; amplifications are on the outer circle, and the deletions and inversions are in the inner circles. In the innermost circle is a representation of the chromosomal translocations. Each arc represents a translocation, and the intensity of the arcs is an indication of Amplification of that translocation. By clicking onto the figure, you will get a blow up of the schematic and a detailed legend. The mutational load score is a composite score the integrates the mutational load that is seen in the tumor of your patient. It is made up of two components: sequence mutations, structural mutations/rearrangements. Your patient’s mutational score when compared to a panel of XXX tumors of the same type is in the following distribution: Normal Maximal

  35. What if this trend continues? Can death from breast cancer be eliminated? 1990 2020

More Related