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TOPIC 10.docx

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University of Waterloo
HLTH 101
Glenn Ward

TOPIC 10: THE GENETIC BASIS OF CANCER 1. INTRODUCTION  in the previous lecture, we saw that: i. cancer originates from a single cell ii. control over cell division is lost iii. this loss is related to changes in DNA  however, the genome is the same for all cells o therefore, mutations must originate in a single cell during cell division*  two different kinds of genes produce two kinds of mutations, and these two kinds of mutations reflect the two possible ways in which the rate of cell division can be altered:* i. Stimulatory Genes*  these are genes that would normally stimulate cell division*  in their “normal” state, they are called proto-oncogenes  a mutation, however, can lead to an overactive gene (called an oncogene)*  these are usually dominant o therefore, only one copy will be needed for the cell to increase its rate of division ii. Inhibitory Genes*  these are genes that would normally inhibit cell division*  they are also called tumor repressor (or suppressor) genes  a mutation makes these gene defective so that they no longer effectively inhibit division  these are usually recessive: tumor growth will still be repressed if there is one functioning allele of the gene in the cell 2. ONCOGENES  oncogenes cannot be inherited (since every cell in the body would then have an allele causing poorly controlled cell division and the embryo would never survive)* o therefore, they are derived from the normal genes necessary for growth & development  to become oncogenes, they must be activated  there are at least 4 mechanisms of oncogene activation:* i. Over-expression of the proto-oncogene*  proto-oncogenes produce proteins which stimulate cell division*  production of these proteins is normally controlled and regulated (by regulator genes)*  they become oncogenes when some agent causes an over-production of these stimulatory proteins o eg.: the human T-cell leukemia virus (HTLV)  HTLV is a retrovirus and alters cellular DNA to cause the overexpression of the proto-oncogene ii. Changed protein product*  the altered protein product now stimulates cell division o eg.: the c-ras family of genes (rat sarcomas)*  code for the p-21 proteins*  these proteins mediate signals from growth factor receptors*  their normal function is inhibitory and reduces cell division  however, common mutations cause changes in base #'s 12 or 61, leading to the production of an altered protein which leads to a loss of inhibition  the cell is transformed and can now undergo uncontrollable cell division* iii. Chromosomal translocation*  part of the chromosome is removed and re-inserted in the wrong place*  these translocations are commonly seen in tumour cells*  the coding sequence of genes near the translocated part of the chromosome is now unaltered  there also could be a new adjacent gene, leading to over-activation of the gene* o eg.: Burkitt's lymphoma* iv. Multiple mutations  more than one proto-oncogene is affected* o eg.:  c-ras is a gene that mediates cell membrane signals*  c-myc is a gene that mediates nuclear signals*  if only one of these genes undergoes a mutation, it will lead to increased susceptibility to uncontrolled cell division  if the second gene undergoes a mutation, the cell is now highly susceptible to uncontrolled cell division 3. TUMOUR SUPPRESSOR GENES  these genes are recessive, so both alleles need to be in the form of the mutation*  in this case we can inherit the allele* o if we inherit one allele, development will not be affected o over time, there will be a somatic mutation of other allele, and no active protein will then be produced in that cell o the cell will then undergo transformation  therefore, we can inherit susceptibility to cancer  to actually get cancer, require both the inherited and the somatic mutation  this creates a paradox: the mutation appears to show a dominant pattern of inheritance even though we inherit only one copy of the mutated allele o this paradox is explained by the "two hits" theory*  while we inherit one mutated allele, we eventually acquire the other mutation during cell division in a somatic cell*  examples: i. Retinoblastoma o rapidly dividing cells of the retina o this is a childhood cancer in which the individual inherits a recessive allele* o during development, the child usually acquires the 2nd mutation in a single cell that divides rapidly during growth, and the child gets cancer ii. Li-Fraumeni syndrome o individuals with this syndrome have a 50% probability of getting cancer before the age of 30 yrs.  again it is due to the inheritance of a recessive allele o this allele is of a gene that codes for the p53 protein* o this allele is either absent or in a mutated form in more than 50% of human cancers o 2 mechanisms (hypothesized)* a) the allele is of a DNA repair gene*  if the allele is nonfunctional, then the rate of formation of new mutations will increase because damaged DNA cannot be repaired
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