Precision medicine: How to exploit the growing knowledge on the evolving genomes of cells to improve cancer prevention and therapy Joe Costello, PhD Department of Neurological Surgery
A more accurate and precise classification of disease (i.e., a New Taxonomy ), which in turn will enable better medicine Start of Germ Theory: Girolamo Fracastoro (c. 1476 1478 1553) Republic of Venice University of Padova
Surpassing single-layer health care Nascent curve Incumbent curve Genomes, Microbiome, Exposures, Behavior, Clinical Tests, Patient-contibuted data Sam Hawgood et al., 2015;7:300ps17
Presentation Outline The Human Genome The Human Epigenome Tumor evolution Precision Medicine in Oncology
This is the human genome sequence The alphabet has only four letters A C G T
A paragraph of the human genome 3,000,000,000 bases in total
DNA GENE GENE RNA Transcription RNA RNA The central dogma of biology RNA PROTEIN Translation ALTERED PROTEIN NO PROTEIN
Enhancers interact with promoters and transcription factors to regulate gene expression Enhancer RNA Pol II Enhancer Promoter GENE Gene Expression Requires: Open chromatin of gene and cres Proper transcription factors
Each cell type expresses a different combination of genes Nerve Cells Muscle Cells Blood Cells GENE A GENE B GENE C
A cell nucleus is about 6 microns, but DNA is 2 meters!
Epigenetic Mechanisms DNA methylation Hydroxymethylation gene expression; chromosome stability 8 Different types, 15 different locations on each histone = the histone code Histones --Chromatin remodeler --Transcription --Histone tails Chromosome Nature, 2008
Large scale analyses of the epigenome: ENCODE NIH Roadmap Epigenome Project International Human Epigenome Project
Roadmap Epigenome Consortium, Nature, February 2015
Epigenomics in Cancer
DNA Methylation DNMT3A DNA Hydroxymethylation TET1, TET2 IDH1 Histones H3F3A Chromatin Regulators SMARCA, SMARCB1, ARID1A Histone Methylation MLL (H3K4) MMSET/NSD2 (H3K36me2) EZH2 (H3K27) Histone Demethylation KDM4 (H3K9) KDM5 (H3K4) KDM6A (H3K27)
Relationship of genetic and epigenetic defects in cancer Cause Genetics Epigenetic regulator Mechanism Epigenetics Malignant Cancer Progression MGMT + TMZ
Sequencing of DNA from normal and tumour tissue to detect mutations normal tumour Patient tumor has a C T mutation in the IDH1 gene
Classification of mutations Driver Vs Passenger
Clonal evolution of tumor cell populations Normal cells Mutation Preclinical Overt tumor
Intratumoral heterogeneity
Reconstructing clonal evolution of tumors Initial A Initial B Recurrence Nowell, 1976; Gerlinger and Swanton, 2012
Low-grade glioma (LGG) Common treatment o Surgery o Radiation? Chemotherapy with TMZ? o Watchful waiting Risk of malignant progression Mayo Clinic, 2012
Malignant transformation is unpredictable Precursor cells 8q24.21 rs55705857 Astrocytoma Anaplastic astrocytoma Malignant Progression Frequency: 17-73% Median Interval: 2.1 to 10.1 years Secondary glioblastoma Adapted from Huse JT, et al. Glia 2011
Two Patterns of Tumor Evolution Primary Recurrence Patient 17 17 1 38 Patient 18 49 26 2585
Early Origin of the Recurrent Tumor Patient 17 IDH1 (R132H) Initial C Initial A, B TP53 (C44F) ATRX (K1035fs) TP53 (S127F) ATRX (K96fs) PIK3CA (H1047R)
Model of low grade brain tumor evolution Life before symptoms and diagnosis 8q SNP Diagnosis of LGG LGG recurrence First IDH1, then Early p53 origin and ATRX, of recurrence CNA GBM Recurrence chemotherapy-induced mutations inactivate cell cycle checkpoint and activated growth promoting pathways Johnson & Mazor, Science, 2014; van Thuijl, Acta Neuro, 2015
Exceptions: Benign clonal expansion of cells with mutations 1. Moles on skin. BRAF mutation in melanocytes 2. Normal eyelid. Similar driver mutations as cscc Martincorena et al, Science, 2015
A basic form of precision medicine in cancer Biomarker Targeted Drug BRC-ABL HER2 EGFR mtor BRAF MGMT Gleevec Herceptin Erlotinib Everolimus Sorafenib Alkylating agent?? Immunotherapy
The Immune system protects against non-self
Immune checkpoint inhibitors unleash a patient's own T cells to kill tumors Inhibited anti-tumor immunity Enhanced anti-tumor immunity Wolchok and Chan, Nature Immunology, 2015
Improved Survival in patients with metastatic melanoma after immunotherapy
Why do some cancer patients respond to immunotherapies while others do not?
Patients with tumors that have more mutations do better after immunotherapy Higher number of mutations Lower number of mutations
Integration of vast knowledge from the natural sciences, Aristotelian logic and religion Albertus Magnus (before 1200 1280), aka Albert the Great, University of Padova 1941, canonized as the Patron Saint of Natural Scientists Arsenic?