Precision Medicine PDF

2. PRECISION MEDICINE 2.1. KEY CONCEPTS - Tailoring disease treatment or prevention strategies for an individual based on their genes, environment and lifestyle - Some applications include: - Assess disease risk, prevent disease, early diagnosis of disease, targeted treatme...

2. PRECISION MEDICINE 2.1. KEY CONCEPTS - Tailoring disease treatment or prevention strategies for an individual based on their genes, environment and lifestyle - Some applications include: - Assess disease risk, prevent disease, early diagnosis of disease, targeted treatments, monitor treatment response - Factors making precision medicine possible: - Effective medicine involves: - Patient values and preferences - Evidence - Clinical expertise - New technologies are improving evidence for molecular mechanisms underlying diseases, such as genomic testing - New instruments such as robotic surgery are allowing clinicians to perform more precise operations on patients - Big data and wearable devices are giving patients more information about their own health - Capturing and using data underlies precision medicine: - As individuals, we have an enormous amount of data associated with ourselves - This spans basic phenotypes such as our age, weight, height, etc., to our genome, to our interaction with the environment - Linking these data to clinical and health information is a major goal of precision medicine - Case Study – Mary: - 45 years old, with type 2 diabetes - Metformin [reduces gluconeogenesis] is the general first line of treatment - Mary has a variant of the OCT1 gene, and has reduced response to metformin - So she was given sulfonylurea [increases insulin production] instead - There is no ‘one size fits all’ for all patients with a certain condition: - A key mission of precision medicine is to give the right drug, to the right patient at the right time - For most diseases there are alternative treatment options: - Conventional medicine often follows a trial-error-approach and many patients may not respond to a chosen therapy or even show adverse effects - Precision medicine takes the genome sequence of patients and other health data into account to group/ classify patients and select individualised therapies 30 2.2. EXAMPLES OF THE APPLICATION OF PRECISION MEDICINE 1. Precision medicine in cystic fibrosis: - Cystic fibrosis is a monogenic (Mendelian) disease caused by mutations in the CFTR gene - CFTR encodes for an ion channel that transports chloride and other ions across the cellular membrane - Subclasses of cystic fibrosis are defined according to the functional effects of specific genetic variants on the cystic fibrosis transmembrane conductance regulator (CFTR) channel - The first drug approved for a subclass of cystic fibrosis was ivacaftor, which increases the opening probability of channels on the cell surface - It was initially approved for patients with Class III cystic fibrosis (G551D patients), for which the trafficking of CFTR to the cell surface is intact but the major defect is in regulation - The most common variant, F508del, results in the destruction of a misfolded channel in the cytoplasm (Class II) - For this variant, a combination of lumacaftor (to enhance intracellular processing and trafficking) and ivacaftor may be optimal - Classifying patients according to their mutations within the CFTR gene helps deciding which drug combination is best. 2. Genetic test directed treatment for lung cancer patients: - Tumour samples are analysed to find out which genes are mutated - In lung cancer, the tyrosine kinases EGFR (epidermal growth factor receptor) or ALK (anaplastic lymphoma kinase) are frequently mutated and become hyperactive, often activating EGFR mutations and ALK rearrangements - EGFR and ALK are actionable driver oncogenes (genes become hyperactive) - Other relevant genes aside from ALK and EGFR are BRAF, ROS1, and PD-L1 - Based on the evidence which gene is mutated treatment choices are made (Drugs [small molecules, antibodies] that suppress the specific hyperactive genes can be used) 3. Personal ‘omics’ profiling for disease prevention: 31  - Another aspect of precision medicine is the profiling of health and omics (genomics, transcriptomics, proteomics) data over extended periods (aka longitudinal profiling) - Professor Snyder and his team have done this for a single person in a widely publicised pilot study (using a single individual): - Longitudinal profiling, RNA sequencing, look at metabolites - Through genome sequencing it was found that he was at risk for diabetes, with increased glucose (prediabetes) - Through lifestyle changes (diet, exercise) he could lower his blood glucose and stay healthy - This showed that it is possible to prevent the development of a disease through careful monitoring of individuals using the tools of precision medicine - A larger scale study on 109 individuals detect a number of health issues that could be managed more effectively through early detection - Early prevention rather than treatment when it’s possibly too late is an emerging theme in precision medicine - Now we can start monitoring our DNA expression and take action before we get sick - E.g. QBio genome testing, with 59 actionable genes 2.3. THE HUMAN GENOME 2.3.1. HUMAN GENETIC INFORMATION - Human Genome Project: - Published in 2003 - First complete human genome - 3 billion base pairs – 2 m from end to end but compacted in a cell nucleus (15 um) - Chromosomes: - Base pairs → Histones → Chromosomes - P arm of chromosome is short - Q arm of chromosome is long - Telomere: ends of chromosome - Centromere: between p and q arms of chromosome - Telomeres and centromeres have highly repetitive DNA sequences - Human genome: - Diploid (46 chromosomes): - 22 autosomes (x2) - 2 allosomes (sex chromosomes) - Organised, usable (regulated and expressed), stable, and copied accurately to the next generation of cells - Structure of a gene: 32  - 1.2% of our genome are coding regions, comprised of 20,000 coding genes - Gene is divided into exons, introns, and gene regulatory elements - Gene regulatory elements, e.g. regulatory elements and promoters, are important for regulating gene expression - Example representation of a gene: - 3p22.1 – Chromosome 3, P Arm, Codon 22, Base Pair 1 - Inheritance of genetic information: - Meiosis - Germ cells have cell division - Haploid gametes formed - Diploid zygotes formed after fertilisation [Mitotic cell division into somatic cells] 2.3.2. GENETIC VARIATION - Describes the difference in DNA among individuals or cells - Account for most phenotypes that are observed - Includes most diseases and health conditions in humans, e.g. height, susceptibility to diseases - Interaction with the environment is also a major contribution to phenotype - Types of genetic variation: 1. Copy number variation - Affects complete whole or whole arms of chromosomes (gain/loss) - E.g. Down Syndrome: - Associated with characteristic facial features physical growth delays and mild to moderate intellectual disability - Trisomy 21 – gain of extra chromosome 21 (50% increase in gene expression) - Unknown which genes contribute to physical characteristics of down syndrome 2. Structural variation - Affect large segments of chromosomes - May involve deletion, duplication, inversion, and translocation - Changes from 1 kilobase to 3 megabase in size - E.g. Facioscapulohumeral muscular dystrophy (FSH) - Characterised by adolescent onset of progressive weakness of muscles in the face, shoulders and arms - Genetic basis: deletion of a region in chromosome 4 – repeating units of a piece of 30 kilobase DNA (D4Z4) - Healthy: 11-100 copies of D4Z4 repeats - FSHD: