Gcd 3022 1st edition Lecture 36Outline of Last Lecture I. Introductiona. Importance of genetic researchb. Genetic diseasesII. Study of genetic diseasesa. Inheritance Patternsb. Pedigree Analysisc. ObservationsIII. Autosomal Inheritancea. Tay-Sachs Diseaseb. Autosomal Recessive Inheritancec. Huntington Diseased. Autosomal Dominant Inheritancee. Explanations of Dominant DisordersIV. X-linked Inheritancea. X-linked Recessive Inheritanceb. Hemophiliac. X-linked Dominant InheritanceV. Locus Heterogeneitya. Example: HemophiliaVI. Detection of Disease Causing Allelesa. Genetic testing and screeningb. Problems with testing and screeningOutline of Current LectureI. Genetic basis of cancera. Characteristicsb. StatisticsII. Viruses that cause cancera. Efficiency of causing cancerb. Acutely transforming virusesc. Rous sarcoma virusIII. OncogenesThese 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.a. Development b. Patterns of expressionc. Conversion of proto-oncogenesi. Missense mutationii. Gene amplificationiii. Chromosomal locationsiv. Viral integrationIV. Tumor-suppressor genesa. Inactivation of tumor-suppressor genesi. Mutation in gene itselfii. DNA methylationiii. Aneuploidyb. Genome maintenancei. Checkpoint proteinsii. Cyclins and cyclin-dependent kinasesiii. DNA repair enzymesc. p53 genei. Functionsii. Apoptosisd. Retinoblastomai. Two typesii. Two-hit modelV. Multiple genetic changesa. Development pattern of cancersb. Colorectal cancer studyc. Genetic changes leading to cancerVI. Inherited forms of cancersa. Predisposition for developing cancerb. Loss of heterozygosityCurrent LectureI. 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 kindsof 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 tomalignant 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). II. 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 ofa viral oncogene. Since then, about 15% of all human cancers are associated withviruses.III. Oncogenesa. Development: derived from proto-oncogene (normal cellular gene that can be mutated into an oncogene). Mutations that convert proto-oncogenes are gain-of-function 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-oncogenesi. 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 andthe 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.IV. 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