Lecture 22 - HMB265: Human & General Genetics...

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Unformatted text preview: HMB265: Human & General Genetics Lecture 22: Genetics of Cancer Prof. Maria Papaconstantinou Lecture Outline Phenotypic changes in cancer cells Multi-hit model of cancer development Cancer genes: Proto-oncogenes Tumour-suppressor genes Reading: Griffiths et al., 10th edition, Chapter 16 (emphasis on pages 580-583). Cancer More than one hundred diseases in which cells grow out of control and can destroy healthy tissue Caused by failures in the mechanisms that control growth, proliferation, and/or cell death Results from genetic damage (mutation) or altered gene expression Changes found in cancer cells a) Uncontrolled growth b) Genomic instability ignores inhibiting signals repaired ==>stop dividing contact inhibition cancer cells don't respond to programmed cell death mechanism no gap junctions Hartwell et al. (2007) Genetics: From Genes to Genomes Changes found in cancer cells c) Potential for immortality many cancer cells can divide indefinitely d) Ability to disrupt local tissue and invade distant tissues moving out into neighbour tissue metastasis Hartwell et al. (2007) Genetics: From Genes to Genomes Blood vessel through the blood stream Multi-hit model of cancer development Induction of a tumour requires several mutations each of which increases the cells chances of becoming malignant a series of mutation usually occurring in somatic cells Hartwell et al. (2007) Genetics: From Genes to Genomes Evidence for multi-hit model: Incidence of cancer in humans increases with age Lodish et al. (2003) Molecular Cell Biology Evidence continued: Human colorectal cancer— later stages have more mutations Lodish et al. (2003) Molecular Cell Biology Evidence (cont): Cancers are clonal descendents of one cell in cancer tissue, only 1 Hartwell et al. (2007) Genetics: From Genes to Genomes Most cancers result from exposure to environmental mutagens Evidence: 1) If one sibling or twin gets cancer, the other usually does not. 2) Populations that migrate – incidence of developing specific type of cancer becomes more like that of people indigenous to new location 3) Exposure to known mutagens increases the risk of developing cancer But: An individual may inherit a mutated gene that increases the probability that cancer will occur Incidence of common cancers varies between countries highest Hartwell et al. (2007) Genetics: From Genes to Genomes Examples of environmental mutagens (1) radiation -- including x-rays and ultraviolet light (as in sunbathing and tanning salons) (2) certain chemicals e.g. asbestos and cigarette tars, and chemical mutagens (3) certain viruses e.g. the Epstein-Barr virus (EBV) and human papilloma virus (HPV) Increases in lung cancer deaths— following increases in cigarette smoking Females 1940s females began to smoke frequently 1970s lung cancer rate began to increase around 20-30 lag time, cancer needs time to develop Males 1920s males began to smoke frequently, 1940s lung cancer rate began to increase Many genes found to be mutated in cancer Cell adhesion DNA repair Growth and survival factors Lodish et al. (2003) Molecular Cell Biology Cell cycle Cell death Cancer genes Mutated genes that are causally implicated in cancer development More than 350 genes have been identified Two classes: 1) Proto-oncogenes — gain-of-function dominant control cell proliferation and cell growth mutation converts these genes to oncogenes 2) Tumour-suppressor genes — loss-of-function many are DNA repair genes Genetics of oncogenes & tumour-suppressor genes Hartwell et al. (2007) Genetics: From Genes to Genomes Examples of oncogenes (1) Mutated receptor tyrosine kinase (RTK) genes (2) ras (3) bcr / c-abl reciprocal translocation between bcr / c-abl produces leukemia 1) Receptor tyrosine kinases two domains receptor proteins dimerize activate in the cytosolic domain valine=>glutamine in the transmembrane domain Her2 receptor dimerize even without ligand intrinsic protein uncontrolled cell proliferation Lodish et al. (2003) Molecular Cell Biology activating downstream signal transduction cascade ras normally is a G protein subunit 2) ras oncogene contains normally GTPase activity GAP Ignores GAP Gly--->Val Ras is always bound to GTP, inhibiting GAP activity Griffiths (2005) Introduction to Genetic Analysis See Figure 16-31 in Griffiths Examples of tumour-suppressor genes (1) RB – mutations found in retinoblastoma (2) DNA repair genes Function of wild-type Rb E2F+RB==> inactivate Rb+P ==> leaves E2F E2F is no longer inhibited promotes G1 to S phase If Rb protein is absent then E2F is active for longer – cell enters S phase more quickly Hartwell et al. (2007) Genetics: From Genes to Genomes Mutations in RB can be inherited Predisposes individual to developing retinoblastoma wild type copy probably also has a mutat loss/mutation at wild type copy is almost 100% early childhood cancer mutation in cone cells in retina 1 defective copy of RB allele==> penetrance is almost 100%! Hartwell et al. (2007) Genetics: From Genes to Genomes Examples of missense and small deletion/insertion mutations in RB promoter and coding regions Richter et al. (2003) Am. J. Hum. Genet. 72: 253–269. Examples of splicing mutations and large deletions in RB promoter and coding regions Richter et al. (2003) Am. J. Hum. Genet. 72: 253–269. Diagnostic tests for mutations in the RB gene diagnostic tests http://www.retinoblastomasolutions.org/rbgene.html DNA repair defects Xeroderma pigmentosum (XP) = defect in nucleotide excision repair prone to UV-induced skin cancers sensitive to UV light Hereditary nonpolyposis colorectal cancer tumor suppressor genes lost 2 functional copies (HNPCC) = defect in mismatch repair mutations in MSH2 or MLH1 genes are most common predisposition to colon and ovarian cancer Lewis (2007) Human Genetics ...
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