cancer genome.pdf

Cancer Genes & Genomics C. R. Hemalatha  Cancer Genomics It is the study of the human cancer genome It is a search within "cancer families" & patients for a full collection of genes and mutations  inherited and  Sporadic that contribute to the development of a...

Cancer Genes & Genomics C. R. Hemalatha  Cancer Genomics It is the study of the human cancer genome It is a search within "cancer families" & patients for a full collection of genes and mutations  inherited and  Sporadic that contribute to the development of a cancer cell & its progression  It usually progresses from a localized cancer to a one that grows uncontrolled and metastasizes (spreads throughout the body)  Oncogenes Genes responsible for the cancer phenotype - ‘oncogenes (growth promoting) & tumour suppressor genes’ (growth suppressing) Genetic basis of cancer has been revealed from the contributions of viral carcinogenesis in animals It has been known that transforming retroviruses carry genes with oncogenic capabilities Many cancer genes & their products - useful ‘tumour markers’ & some as targets for cancer therapy  Key Concepts Human karyotype Genes Coding vs. non-coding DNA Genetic codes Central dogma Transcription & translation Mitosis & meiosis Epigenetic factors Mutation  Tumours are Clonal On dividing, each cell generates 2 identical new cells When a cell acquires a mutation, it passes that mutation on to its progeny during cell growth and division Cells with cancer-linked mutations tend to proliferate more than normal cells, accumulate & are copied to descendant cells If one cell finally acquires enough mutations to become cancerous, subsequent cancer cells will be derived from that one single transformed cell So all tumors are clonal, which means that they originate from a single parent cell, whether that first mutant cell was of germline or somatic origin  Somatic mutations Majority of human cancers - accumulation of somatic mutations & it is not passed on to the next generation An 80-year cancer-free lifespan is no small accomplishment as it requires as many as 10 million billion body cells to copy themselves correctly Exposures to carcinogens and other mutagens, or from random unrepaired errors that occur during routine cell growth and division Occasionally, one of these somatic mutations alters the function of some critical genes, providing a growth advantage to the cell in which it has occurred A clone then arises from that single cell  de novo Mutation Inherited mutations had to start somewhere, and that somewhere is a de novo mutation A de novo mutation is a new mutation that occurs in a germ cell and is then passed on to an offspring All germline mutations started as a de novo mutation in some ancestor De novo mutations are common in a few inherited cancer susceptibility syndromes  Regulatory Mutations Although mutations in the non-coding region are generally silent, that is not always the case Some of the most important regulatory regions are in the 5' non-coding flanking region of the gene Promoter sequences that regulate the gene are located there Enhancer sequences that regulate the rate of gene activity are in present in non-coding regions, from a considerable distance from the gene Gene repressor regions, which negatively regulate gene activity, also exist Mutations in any of these regions can change the rate of protein production  Regulatory Mutations Her2 protein expression - e.g. of how gene amplification can have a regulatory impact upon tumor's growth In breast cancer, over expression of Her2 protein results from gene amplification in chromosome 17 This increase in production of growth-signaling molecules speeds up the rate of the cancer's progress  Translocation of Bcr-Abl Genes In chronic myelogenous leukemia, a translocation occurs between chromosomes 9 & 22 This rearrangement of genomic material creates a fusion gene call Bcr-Abl It produces a protein (tyrosine kinase) thought to promote the development of leukemia The drug Gleevec blocks the activation of the Bcr-Abl protein  Genotypes and Phenotypes Cancer may start as a new genotype That is, as a change in the genetic makeup of a person But it ultimately produces a new phenotype as well A phenotype is the physical manifestation of a genotype in the form of a trait or disease Cancer is known for its ever-changing genotypes & phenotypes Thank you!