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Section D Genes whose Mutation can lead to Initiation
Single Genes and Susceptibility Genes and Cancer Risk Definition Example Single genes Necessary and sufficient for disease causation BRCA (breast/ovary) APC (polyposis coli) RB (retinoblastoma) Susceptibility genes Gene prevalence Low Often high Gene type Mutation Mutation Alter risk but is neither necessary or sufficient for disease causation CYP1A1 (lung) CYP2D6 (lung) GST-M1 (lung, bladder) DNA repair genes Study setting Family General population/ epidemiological studies Strength of association Very high Low to moderate Absolute risk High Low Population attributable risk Low High (because mutation common) Gene-environment interaction/exposure Secondary and variable Primary and crucial 39
Two Categories of Genes in which Mutation is Associated with Cancer Gain of function: Proto-oncogenes become oncogenes Point mutation change in amino acid sequence Translocation gene or part of gene moved to another location Amplification multiple copies of gene created Loss of Function Tumor suppressor genes lose function Deletion Translocation Mutation 40
Oncogenes Presence of proto-oncogenes in normal cells Detection of activated protooncogenes (oncogenes) in tumor cells Ras gene one of the first discovered using transfection 41
Oncogenes Genes Selected Examples with Function & Location Contribute to tumor formation when expression/function enhanced Selected Examples* Genes Functions Associated Cancers Src Cytoplasmic Tyrosine Kinase Sarcomas ras G-protein; Signal transduction rash Bladder rask Lung, Ovarian, Bladder rasn Breast Myc Cell Proliferation and DNA Synthesis mycn Neuroblastoma, Retinoblastoma mycc Breast, leukemia, Lung, Cervical, Colon EGF Family Erb-2/ Membrane Receptor the stimulates DNA Her2/neu Synthesis a Tyrosine Kinase Breast, Salivary Gland, Ovarian *Adapted from Cancer Quest Tumor Suppressors, Emory University, 2008; accessed Aug, 2011 42
Oncogenes Drive Tumorigenesis Muller, W. et al. Cell 49: 465-475, 1987 43
Impact of erb2/neu Amplification on Breast Cancer 44
Suppressor Genes Selected Examples with Function & Location Contribute to tumor formation when expression/function lost or inactivated Tumor Suppressor genes Selected Examples Genes Functions Associated Cancers P53 - Transcription factor regulating genes Bladder, Breast, Liver, controlling cell division and cell death - Sensor of DNA damage - Aids in decision between repair and activation of programmed cell death Colorectal, Lung, Prostate Rb - Signal integrator related to cell cycle progression Retinoblastoma, Sarcomas, - Transduces growth inhibitory signals Bladder, Breast, Lung BRCA - Involvement in DNA repair Inherited Breast and Ovarian - Regulation of gene expression APC - Controls activity of certain transcription Familial adenomatous & nonfactors inherited colorectal cancers Adapted from Cancer Quest Tumor Suppressors, Emory University, 2008; accessed Aug, 2011 45
Slide 8 (split)
Genetic Model for Colorectal Tumorigenesis 50
Whole Exome Sequences of 100 Human Cancers* SKCCC Washington University British Columbia Cancer Research Centre Sanger Institute 11 colorectal cancers 11 breast cancers 24 pancreas cancers 22 gliomas 22 meduloblastomas 2 leukemias 1 breast cancer 1 breast cancer 4 granulosa cell tumors 1 lung cancer Sanger 1 melanoma 3142 mutated genes 286 tumor suppressors 33 oncogenes *Vogelstein B AACR Annual Meeting (2010) Slide provided by W. Nelson
Key points Section D Inherited genetic susceptibility can increase risk Mutations in key genes can lead to high individual risk, but low attributable population risk Mutations in certain genes lead to lower individual risk but high attributable population risk Oncogenes and tumor suppressor genes are key molecular/biological targets Tumors contain hundreds of mutations and contain a few common mutations 56
Key Points Section D cont d Mutations accumulate as as progression occurs Different carcinogens cause different mutations finger print Adducts of chemicals with DNA bases can serve a biomarkers of biologically effective dose 57