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BIOl 314 – Molecular biology of an oncogene.docx

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Biology (Sci)
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BIOL 314
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Dr.Jabado

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BIOL 314 – Molecular biology of an oncogene LECTURE 1 – INTRODUCTION TO ONCO-GENES Introduction: 1. 1 in 5 people are destined to die from one form of cancer or another. 2. Cancer is the age related, the older you get the more likely you’ll get cancer. 3. Better grouping of patients in different typologies in cancer may help easier diagnosis and help us to catch cancer in its early stages. 4. Predisposition of our genes help us promote/prevent cancer according to how we’re exposed to mutagens in the environment. 5. Impact of cancer depends on chemical, physical and other agents – Both genome and epigenome are important elements that help us understand cancer. 6. Nature of cancer and way of progression differs from one cancer to another. 7. PET scan is an important tool in cancer as it picks up locations metabolically active substrate, for example in glucose, (for example) to light up organs that are using the substrate for metabolis Classification of cancer: 1. Tumors arise from normal tissues: it is an abnormal cell growth in a normal tissue. 2. Tumors arise from one of the specialized cell types deriving from the 3 layers of the embryo – Ectoderm (neural and non-neural), mesoderm and endoderm. 3. Four major sub groups of tumors – a. Epithelial (>80%) b. Non epithelial i. Mesenchymal ii. Hematopoietic iii. Neuro-ectodermal c. Non classified – Couldn’t be classified based on the biopsy. 4. Carcinomas – Epithelial tumors: a. External protecting cell layers/ squamous cell carcinoma b. Secreting cells carcinomas/adenocarcinoma. E.g. – Breast cancer and rectal cancers. c. Important carcinomas: d. Cancer cells not only grow but completely engulf these regions: e. 5. Non epithelial tumors: a. Mesenchymal: SARCOMAS i. Bone, fat, muscle etc. ii. Rise from the mesoderm iii. b. Hematopoietic i. Leukemia iii. Lymphomas c. Neuro-ectodermal tumors i. ii. Brain tumors 6. Non-classified malignancies: a. Neural crest derivatives: i. Melanomas ii. SCLC (Small Cell Lung Cancer) b. Switch in tissue lineage? i. Trans-differentiation ii. Epithelial-mesenchymal transition – The distinction of where the epithelial ends and where the mesenchyme starts is very important for organ development – A switch in tissue lineage due to gene plasticity at this point can be very disasterous. c. Dedifferentiation up to anaplasia. 7. Important to understand the basic progenitors: a. 8. CML one of the most dangerous forms of leukemia is directly related to Philadelphia chromosome/translocation i.e., is the result of a reciprocal translocation between chromosome 9 and 22 – It is thus very important to see which cancers are linked to which components of the genome. CML has a survival rate of less than 10% in adults. 9. Glioblastoma is a very fatal form of cancer but now can be treated for if identified early. Identification of the different kinds of cancer may not necessarily be the easiest thing as most of the blastomas look alike but identifying which kind can be a key diagnosis for the patient. 10.Benign or Malignant? a. Malignancy determined by: i. Lack of Differentiation ii. Proliferation in situ, invasion of adjacent structures: basement membrane than stroma. iii. Ability to move and disseminate at a distance: metastasis iv. Creation of its own vascular network: neoangiogenesis. b. Carcinoma in situ: If the basement membrane has not been not breached and there is presence of localized growth only, this is the best prognosis one could possibly expect. c. Tumour types vary across lifespans. d. ALL is the most common cancer in children, is rare in adults e. Different molecular alterations is present for the same cancer between adults and children f. Behaviour of cancer will vary with age and gender  breast cancer is more aggressive in young females as is prostrate cancer with younger men. Breast cancer is way more aggressive in men but his is very rare. g. Progressive development: initially localized to a cell layer which disseminates locally, regionally then at a distance Shows us the Importance of early detection and potential efficiency of prevention. h. Metastasis is responsible for 90% of cancer related mortality, while only 10% are due to the primary tumor Disseminated disease (or Metastasis) is the main cause of death in cancer patients i. Benign can transform into malignant especially in regions of high metabolic activity and with age. Benign polyps present in the mucosa of the GIT must be removed else they have a potential of becoming malignant in the future. 11.Adult Glioblastoma: a. Most common CNS tumor in adults with a life expectancy is less than 1Y b. Extensive data on molecular aspects like the Tumoral Genome, Tumoral transcriptome and Signaling pathways have ben conducted. c. Models of multistep process illustrate the links between cytogenetic changes and disease stage 12.Tumors result from an initial monoclonal growth: Genetic changes accumulate during tumor progression and make the Kc more aggressive. Importance for prevention and treatment in most epithelial cancers (breast, colon, prostate etc.) In other cancer groups like astrocytomas progression seems unstoppable. 13.In rare cancers with a single genetic change can lead to a tumour growth like CML, subset of pediatric cancer. 14.Risk factors in cancer - Genetic element 10 cell division in a lifespan, 10 events/s a. All cells retain a full genome even though they use 10% of it at best b. When we are tinkering with our genome  Mistakes will happen and some genes will become oncogenes. 15.Genetic element - Our genome has to evolve to maintain our population and this is also the reason why our population has exploded. It’s constantly being altered and the mutations in turn are constantly being altered and cancers result because of different mutations. A similar mutation in one individual does not necessarily mean s/he will develop cancer but in the right environmental conditions they might. 16.Combination of environmental and genetic components in cancer: Japan has a very low incidence of prostate and colon cancer but people with similar genes living in Hawaii have a much higher incidence. Thus we can conclude that the Japanese genetic component along with the Hawaiian environmental conditions/lifestyle increase the incidence of these cancers dramatically. a. b. For stomach cancer on the other hand the Japanese living in Japan seem to have a higher incidence. 17.Cancers occur with different frequencies based on geography: Several Cancers have a different incidence based on geography. A given type of cancer will have a different prevalence based on a. Gender b. Race c. Geographical situation d. Some increase with time, decrease for others in a particular region e. Type varies with the geographical origin f. Immigrants acquire the risk factors of natives for some cancers g. Influence of outside factors on our genome 18.Genetic and epigenetic factors – This is why cancer is such a hard disease to understand, there is a different mutation and a different environmental condition that favors one condition over the other. For example – In the Japanese example, prostrate cancer incidence has increased over time whereas stomach cancer has actually decreased. We don’t’ understand it completely but clearly something changed in the environment to promote this change. 19.How are chromatin is organized and which parts of the genome is used the most determines how our fetal development occurs – this is the same factor that is exploited by cancer. Some regions in our DNA are exploited more than others by cancer and this is what we have to look into and study this susceptibility to understand the mechanisms of cancer. This also explains why cloning doesn’t necessarily mean the exact same copy of the parent organism – a. Environmental conditions differ. b. The genetic component of the egg used in cloning has a different DNA.Prostrate cancer incidence has increased over time whereas stomach cancer has actually decreased. We don’t’ understand it completely but clearly something changed in the environment to promote this change. c. 20.Carcinogens: Cancer inducing substances – a. Occupational hazards : i.Simple changes - chimney sweepers were asked to wash themselves after sweeping chimneys on a daily basis and this drastically decreased the incidence of scrotal cancer in the sweepers. Thus the soot contained a certain carcinogen. ii.Nuns have very high incidence of breast cancer – The breast tissue is more likely to atrophy, when it isn’t used. This along with predisposition and environmental factors together is the reason for this high incidence. iii.Tobacco use and its connection with lung and mouth cancer. 1. 2. 21.Healthcare system rut – Aging, people are living to an older age and thus most of the resources are in maintaining these people and helping them live longer 22.Pioneer of mutagenesis – K. Yamagiwa – kept painting the chemical on a rabbit’s ear everyday until it developed cancer at that region and this was the first proof of mutagens of chemicals. 23.Example of viral inducing cancer – HPV (cervical cancer), BRACA1 and BRACA2 – gatekeepers of breast cancer, BRACA1 (Jolie had this with an 80% chance to obtain breast cancer) 24.Quick summary – Risk factors of cancer: a. Occurs with variable frequency in populations based on i.Race ii.Gender iii.Geography b. Geographical distribution of a given cancer influences incidence, type and outcome c. Influence of lifestyle on the risk of cancer i.Occupational ii.Non-occupational d. Known factors: i.Genetic ii.Chemical iii.Physical iv.Viral 25.General mechanism regulation gene expression – a. What is a proto-oncogene? A normal gene whose product has the capacity to induce cellular transformation that can sustain genetic result. b. What is an Oncogene? A gene that has sustained some genetic damage which results in the abnormal protein, capable of cellular transformation and cancer. 26.Mendel’s legacy – Mendelian genetics: a. In sexual organisms: i. Information is organized in packets: genes ii. Genetic organization: genome forming our genotype iii. Redundancy: 2 copies of the same gene: diploid iv. 2 versions of the same gene: alleles A and B 1. Same version: homozygous (AA) (BB) 2. Different version: heterozygous (AB) b. Alleles are differentially expressed: phenotype i. Dominant ii. Recessive iii. Co-dominant iv. Incomplete Dominance 27.Darwinian evolution: a. Origin of life, evolution of organismic complexity and the relatedness of the species. b. How did alleles arise? i. Our genome is corruptible: we are tinkering constantly and randomly with our genome: Mutations. c. Wild type = allele that is the most frequently found in a given population. Selection of the one that is going to confer a survival advantage to the species. The other will be lost through time from the gene pool. d. The older the species the more diverse it is. e. Survival of the fittest and adaptation to the environment 28.Human genome and Cancer: a. Junk DNA is the region of the DNA that hasn’t been studied much and we need to revisit it after a particular mutation manifests. i. 97% of our DNA is termed junk DNA – these are the regions responsible for our diversity. ii. 1.5% of our DNA is ‘coding’ DNA and thus encodes a specific gene. iii. 2% of the rest of the DNA are regulatory in function. b. Change in the DNA sequence – that may be harmful or not. c. Mutations that are transmittable – germ-line mutations. Basic types of mutations: i. Neutral mutations – no change in function but they can potentially tell us about predisposition to disease. GENETIC POLYMORPHISM 1. ii. Selected mutation – A mutation which has a physiological or physical phenotype. 1. GENETIC POLYMORPHISM iii. Silent mutations – give rise to genetic polymorphism. GENETIC POLYMORPHISM Silent and no silent mutations gives rise to our polymorphism. 1. 2. Most genetically diverse genetic pool – Africans a. Caucasians retain a very small set of selective variable polymorphism. d. Evolutionary forces dictate that certain genes are highly conserved in their coding sequence amino acid sequence and their function  conservation of genetic structure and gene function through the species is a key determinant of silent mutations and common ancestors. e. Zebra fish, mice and drosophila are the 3 main genetic models used. i. Drosophila – Pax- 6 in humans 1. Highly conserved in both humans and drosophila. Controls the expression of the eye. 2. Having a mutation in a conserved sequence is disastrous Genes orchestrating a specific function can be interchangeable. 2. From Genotype to Phenotype a. Similar functional protein are located closer to each other on a chromosome or these are the regions that are activated more often than not for the particular organ. b. Gastrulation – Migration of cells to form 3 layers, these cells move very fast and are totipotent. Transcription activates the differentiation in particular cells moving the cells that have to and making the others implant themselves all over the others. c. Exon sequencing – It is very important these regions of the coding region have a fixed and often regulatory sequence that need to determine the introns that need be spliced out. 3. Chromosomal changes in cancer a. Number – euploidy, aneuploidy (hyperpliody/hypodiploidy) b. Structures – Translocations, amplifications and deletions. c. Loss of heterozygosity – area of a genome becomes homozygous, increases with endogamy d. How do we test for chromosomal changes? i. A synthetic library made of oligonucleotides of all organisms is created. They then hybridize two species of DNA within a genome and we see how the hybridize and then gives rise to red/yellow/green markers on microarray analysis. e. Exon sequencing will remove all the current sequencing and when the next generation sequencing sets, prices will go down a lot for genome ID. LECTURE 2 – 4. Terms to know: i. Acetylation – Addition of a functional acetyl group into an organic compound. It is the post-translational chemical modification of histones, tubulins and the tumor suppressor p53. ii. Deacetylation – Removal of the acetyl group. iii. Chromatin – A condensed complex of DNA and protein that composes chromosomes. Chromatin packages DNA into a volume that fits into the nucleus. It helps in Meiosis and mitosis and controls gene expression. Changes in the chromatin structure are affected by DNA methylation and histone modifications. iv. CpG islands – Regions of the DNA that are rich in C and G nucleotides. ‘p’ refers to the phosphodiester bond b/w the cytosine and the guanine. These islands occur approximately 40% of the promoters of human genes. 5. Organization of the human genome – a. 23 chromosomes – 22 autosomes and 1 pair of sexual chromosomes (XX/XY) b. All cells carry our genetic legacy – information is reproduced with utmost fidelity. c. Genes can be classified as: Housekeeping (E.g. Actin) or tissue specific (<1000) d. Sexual chromosomes: i. X~900 gens and Y ~ 78 genes. ii. Males are at a biological disadvantage? 1. Absence of redundancy can cause more diseases in males in the case of a non-functional gene on the sole X chromosome  more susceptible to more X-linked diseases. 2. In females one of the X chromosomes is randomly selected and silenced. This causes the inactivation of one set of alleles.  creation of Barr bodies, attenuating the genetic advantage. 3. Diseases in females where the entire X chromosome is cancelled results in sterility and low IQ e.g. Turner’s syndrome. e. Gene conversion - f. Genetic information is thus: i. Organized  genotype/phenotype coordinate expression and tissue specificity . ii. Redundant  Phenotype variations, homo/heterzygosity, variable ploidy. iii. Evolving  Mutations and selection. iv. Diversity: Double stranded DNA Allele A What helps create our Allele B diversity? Transcription A and B at the same level A less than B or reverse in all tissues A less than B or reverse in some tissues Never A Timing during lifespan RNA splicing: Preferential product in given tissue or during development Stringent or leaky Translation Allelic imbalance AUG, CAPs etc. Post-Translational changes 1. 6. From genotype to phenotype: a. Genes embodies in DNA will create an individual’s phenotype through proteins. b. Transcription  DNA is converted into RNA (Expressed and repressed genes) c. Translation  RNA is translated in ribosomes leading to protein synthesis. d. Proteins are conformationally altered. transcription Exon splicing Heterogeneous Nuclear RNA (HnRNA or pre-mRNA) Mature mRNA translation e. f. From a single cell repeated cycles of cell division leads to growth with a high migration potential  motility. g. When the embryo is formed cellular differentiation starts  commitment to a lineage and a physical location leading to tissue formation is set. h. Cells within a tissue are highly differentiated with a small % of stem cells. i. Gene expression patterns control: i. What is going to be transcribes  which gene? Which splice? ii. When is the product needed to be transcribed  At development? After? iii. Where is it
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