Genomic Approaches To Cancer Introduction to the course Tatjana Crnogorac-Jurcevic 20th September 2017

Aims and Objectives THE AIMS OF THE MODULE To provide detailed teaching on the principles, interpretation and applications of large scale ‘omics’ approaches to study cancer   LEARNING OBJECTIVES By the end of this module students will be able to demonstrate a knowledge of: The working principles of ‘omics’ platforms The advantages and limitations of using ‘omics’ in studying cancer The application of ‘omics’ technologies in personalised medicine 10 sessions: 9 taught, last reserved for poster presentation

Genome and Genomics “A genome is an organism's complete set of DNA, including all of its genes. Each contains all of the information needed to build and maintain that organism. In humans, a copy of the entire genome-more than 3 billion DNA base pairs is contained in all cells that have a nucleus.”* London Canary islands 3,000km = length of your genome A central role of genome in cancer development emerged in the late 19th (David von Hanssemann- mitotic figures and aberrant mitoses) and early 20th century (Theodore Boveri – incorrect combination of chromosomes generate cancer cell with the ability of unlimited growth). Von Waldeyer (1836-1921) gave the chromosomes the name (chroma, body – coloured bodies) David von Hansemann and Theodor Boveri – examining dividing cells under the microscope, they observed the presence of bizarre chromosomal aberrations, which led to the proposal that cancers are abnormal chromosomes. That is why we will start our journey by looking at a chromosome 19th -20th c: A central role of genome in cancer (David von Hanssemann and Theodore Boveri: incorrect combination of chromosomes generate cancer cell with the ability of unlimited growth). *http://ghr.nlm.nih.gov/handbook/hgp/genome

Content Metabolites Protein DNA RNA David von Hansemann and Theodor Boveri – examining dividing cells under the microscope, they observed the presence of bizarre chromosomal aberrations, which led to the proposal that cancers are abnormal chromosomes. That is why we will start our journey by looking at a chromosome DNA RNA

Cytogenetics ‘toolbox’ FISH Conventional aCGH Conventional karyotyping to much higher resolution analyses SKY

Chromosomal aberrations Numerical Structural CN changes t(14;18) UPD Ring chromosome

Content Metabolites Protein DNA RNA

What are SNPs? SNP arrays genetic variation Even higher resolution down to single base pair change

Why do we care about genetic variations? 1. Genetic variations underlie phenotypic differences among different individuals 2. Genetic variations determine our predisposition to complex diseases and responses to drugs and environmental factors 3. Genetic variations reveal clues of ancestral human migration history

Genome sequencing 2003 (0.005386 Mbp)‏ First individual's sequences How has NGS changed our understanding of cancer disease, through establishment of cancer landscapes and deciphering of caner evolution through detection of underlying changes in development and progression of cancer

Cancer genome landscape and evolution Stratton et al, Nature, 2009 Yachida et al, Nature, 2010

Epigenetics Genetics alone cannot explain the diversity of phenotypes within cells (Greek: epi – over, outside of) Stable alterations in genome function that do not entail a change in the DNA sequence (chromatin modification, methylation) - a change in phenotype without the change in genotype

Transcriptomics (RNASeq and arrays) Metabolites Cell Protein DNA RNA

Gene expression profiling and applications Which treatment? What are my chances? Which class of cancer? Is it benign? Therapeutic Choice Prognosis Diagnosis Classification

MicroRNAs We will then change gear somewhat, and teach you about the relatively recently discovered class of RNA, which is non-coding - miRNA.

Metabolites Cell Protein DNA RNA Proteomics Metabolites Cell Protein DNA RNA

Proteomics “Meat on the bone of Genome” ~20,000 genes - proteome space more complex (splicing, PTMs, protein complexes) poor correlation of mRNA and protein levels health and diseases are protein-driven processes two drafts of human proteomes (ProteomicsDB; www.humanproteomemap.org)

Introduction to proteomics and applications Basic principles of separation and identification of peptides/proteins using gel and non-gel based techniques as well as the principles of MS Database search to identify proteins Separate proteins in 2nd dimension by mass Excise spots of interest LC-MS/MS A/Cy3 B/Cy5 A+B/Cy2 Run 1st dimension Tissues/body fluids You will be introduced to basic principles of separation and identification of peptides/proteins using gel and non-gel based techniques as well as the principles of MS

Phosphoproteomics

Biomarkers What are they and their role in personalised medicine Liotta&Petricoin, J Clin Invest, 2006. Rong Fanet al, Nature Biotechnology 2008

Metabolomics Metabolome Metabolites Cell Protein DNA RNA

Metabolomics MR spectrum of normal brain MRI scanners can be adapted to measure brain metabolites while the patient lies in the magnet. Nothing is injected or biopsied. The peaks in the spectrum correspond to the different metabolites. 5 4 3 2 1 ppm NAA tCr tCho mI MR spectrum of normal brain

Assessment of the Unit In-course assessment: Poster presentations (40%) Topics randomly assigned: 1. What have we learned from Next Generation Sequencing of cancer genomes 2. Epigenetics and cancer 3. Roles of microRNAs in cancer biology 4. The application of microarrays in cancer gene profiling 5. Proteomics in cancer research 6. The discovery and use of cancer biomarkers Double marked for: 1. Content (50%) 2. Presentation (20%) 3. Response to questions (30%) Of course, you will also have a chance to show us what you have learned. And you will be assessed

Assessment of the Unit Examination Paper (60%): 18 Multiple Choice Questions (MCQ) & 3 Short Answer Questions (SAQ); time = 1hr 15min Part A: MCQ weighting 35% Part B: SAQ weighting 65% MCQ: expl. What is …? a) to e); select the best single answer SAQ: expl. The success of a microarray experiment depends upon several factors. Several sub-questions; answer with couple of short sentences Of course, you will also have a chance to show us what you have learned. And you will be assessed

Housekeeping rules ENJOY THE COURSE! t.c.jurcevic@qmul.ac.uk DO attend the lectures DO ask questions DO study ENJOY THE COURSE! t.c.jurcevic@qmul.ac.uk