Gcd 3022 1st edition Lecture 36 Outline of Last Lecture I Introduction a Importance of genetic research b Genetic diseases II Study of genetic diseases a Inheritance Patterns b Pedigree Analysis c Observations III Autosomal Inheritance a Tay Sachs Disease b Autosomal Recessive Inheritance c Huntington Disease d Autosomal Dominant Inheritance e Explanations of Dominant Disorders IV X linked Inheritance a X linked Recessive Inheritance b Hemophilia c X linked Dominant Inheritance V Locus Heterogeneity a Example Hemophilia VI Detection of Disease Causing Alleles a Genetic testing and screening b Problems with testing and screening Outline of Current Lecture I Genetic basis of cancer a Characteristics b Statistics II Viruses that cause cancer a Efficiency of causing cancer b Acutely transforming viruses c Rous sarcoma virus III Oncogenes These notes represent a detailed interpretation of the professor s lecture GradeBuddy is best used as a supplement to your own notes not as a substitute IV V VI a Development b Patterns of expression c Conversion of proto oncogenes i Missense mutation ii Gene amplification iii Chromosomal locations iv Viral integration Tumor suppressor genes a Inactivation of tumor suppressor genes i Mutation in gene itself ii DNA methylation iii Aneuploidy b Genome maintenance i Checkpoint proteins ii Cyclins and cyclin dependent kinases iii DNA repair enzymes c p53 gene i Functions ii Apoptosis d Retinoblastoma i Two types ii Two hit model Multiple genetic changes a Development pattern of cancers b Colorectal cancer study c Genetic changes leading to cancer Inherited forms of cancers a Predisposition for developing cancer b Loss of heterozygosity Current Lecture I Genetic basis of cancer cancer is a disease that is characterized by uncontrolled cell division It is a genetic disease at the cellular level and there are more than 100 kinds of human cancers known classified by the type of cell that has become cancerous a Characteristics most cancers originate in a single cell clonal growth Development of cancer is usually a multistep process beginning with precancerous genetic change benign growth which then progresses to II III malignant cancerous growth These malignant cells are invasive and can metastasize invade healthy cells in other parts of the body b Statistics about 1 million Americans are diagnosed with cancer each year and about half of these will die from the disease 5 10 of cancers are due to inherited predisposition runs in the family 5 10 are due to spontaneous mutations and viruses and 80 are due to exposure to mutagens that alter the structure and expression of genes an environmental agent that causes cancer is termed a carcinogen Viruses that cause cancer not a common way of getting cancer Process of converting a normal cell to a malignant cell is called transformation a Efficiency of causing cancer most cancer causing viruses are not very effective at inducing cancer and most viruses are inefficient at transforming or are unable to transform normal cells grown in the lab b Acutely transforming viruses viruses that can rapidly induce tumors in animals and efficiently transform cells in culture There are about 40 ACVs known the first of which is the Rous sarcoma virus RSV c Rous sarcoma virus isolated from chicken sarcomas by Peyton Rous in 1911 RSV research in the 1970s led to the discovery of oncogenes genes that promote cancer The src gene is also called the v src for viral src It is the first example of a viral oncogene Since then about 15 of all human cancers are associated with viruses Oncogenes a Development derived from proto oncogene normal cellular gene that can be mutated into an oncogene Mutations that convert proto oncogenes are gain offunction mutations b Patterns of expression oncogene may be overexpressed which yields too much of the encoded protein The oncogene may also produce an aberrant protein Or the oncogene may be expressed in a cell type where it is not normally expressed c Conversion of proto oncogenes i Missense mutation can convert ras genes into oncogenes by decreasing the protein s GTPase activity or increasing the rate of exchange of bound GDP for GTP resulting in constant expression of the gene The human genome contains four different but evolutionarily related ras genes and missense mutations in these genes are associated with certain cancers ii Gene amplification occurs in N myc in neuroblastoma and erbB 2 in breast carcinomas iii Chromosomal locations relationship with cancer was first discovered in 1960 in the study of the correlation between myelogenous leukemia and IV the translocation between chromosomes 9 and 22 generating the Philadelphia chromosome This translocation put proto oncogene abI under the control of the bcr promoter which is active in white blood cells leading to leukemia iv Viral integration can activate oncogenes by integrating into the host DNA as part of their life cycle This can lead to direct transcription from the viral promoter or activation of the cellular promoter by viral enhancer Tumor suppressor genes normal cellular genes that play important roles in regulating the cell cycle and cell division to maintain the integrity of the genome a Inactivation of tumor suppressor genes can lead to unregulated cell growth and division as well as DNA damage and increases the likelihood of cancer occurring All three ways of inactivation affect both copies of the gene and result in the loss of function of that gene i Mutation in gene itself the promoter could be inactivated or an early stop codon could be introduced into the coding sequence ii DNA methylation methylation of CpG islands near the promoters of tumor suppressor genes which inhibits transcription iii Aneuploidy chromosome loss may contribute to the progression of cancer if the lost chromosome carries one or more tumor suppressor genes b Genome maintenance mechanisms that prevent mutations or mutant cells from surviving and dividing Can detect DNA breaks improperly segregated chromosomes and other abnormalities i Checkpoint proteins monitor cell cycle at check points of the cycle M G1 G2 and look for DNA damage If damage is found the proteins prevent the formation of cyclin Cdk complexes ii Cyclins and cyclin dependent kinases responsible for advancing a cell in the cell cycle iii DNA repair enzymes involved in genome maintenance and can be inactivated in forms of cancer that involve an accumulation of mutations in a cell that cause the