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BSCI222 – Lecture 24 (missed L. 23) (12/3/13)- Chapter 23: Cancer Genetics- Cancer is an abnormal proliferation of cells (outcompeting normal cells, grabbing all the nutrients, which will ultimately kill you). Even after National Cancer Act in 1971, cancer rates still rising (probably better detection), but survival is getting better. o Lots of diversity in cancers, different tissues. Prostate least likely to kill you, pancreatic most likely.o Lots of environmental and genotypic variation. Even though humans have essentially the same genome, have cancer at different rates. Bladder cancer has 25.2/1000 incidence rate in the US and only 2.8/1000 in the Philippines. Diet, smoking, etc., differ among cultures. When people move, they typically acquire the new cancer rate because they adopt the new lifestyle. Environmental contaminants in natural products like food too. o Fundamentally a genetic disease, but not usually not inherited. Due to somatic mutations. First recognized by Alfred Newston who was studying retinoblastomas. He noticed two kinds of cases in his practice: usually, a “Type 1”case (sporadic, only one eye, in older patients) or a Type 2 (ran in families, often affected children, both eyes). He developed a hypothesis for cancer genetics: in the type 1 case, have to have one somatic mutation in a cell, and then a second mutation in the same cell, in order to produce a tumor (chance of about 10^-6 * 10^-6, happens once in 10^12 cells. Small chance  one eye affected more likely). In the type 2 case, these individuals were already carrying a germline mutation, and now it only takes ONE somatic mutation to get a tumor (just 10^-6, so once in 10^6 cells).o As a tumor evolves, it might experience a first mutation that causes the cell to divide at a higher rate, and a second mutation that changes its structure (now not as tightly associated with the membrane of the tissue it is in), basically tumor cellsare competing with each other. Whichever cells grow the fastest will dominate thetumor, though the tumor will not be homogenous.- So how do genes cause cancer?o 2 groups: genes that will encourage cell growth and division (proto-oncogenes, have a normal cell function, but if they’re mutated they essentially over-encourage cell growth because not regulated), and genes that normally control growth and division (tumor suppressors mutated, can no longer suppress that growth).o Oncogenes normally promote the growth of cells, normal cell division. A mutation in one of the copies (which increases expression)  excess cell proliferation. That one mutant copy can turn on a cell signaling pathway and encourage excess growth, dominant mutation.o Tumor-suppressors: normally one copy is enough to keep cell growth in check, normally only become a problem when both copies are mutated (recessive mutation.- Typically have a lot of chromosome breakage/loss/rearrangement/mutation in cancer; loss of chromosome heterozygosity. If you are heterozygous for the tumor suppressors, then it only takes the loss of one allele for the recessive allele to be expressed (hemizygous). - People didn’t anticipate that there would be so many different kinds of genes, so many different ways to initiate a cancer and for the tumor to be promoted.o Early focus: cell cycle regulators. The cell cycle is normally very tightly regulated, cells have to pass a series of checkpoints to make sure that they’re competent to divide and that it is necessary to do so. Anything that overrides thesecheckpoints would allow cells to multiply out of control. Tightly regulated by cyclins. Cyclin B gradually increases all through interphase, and near the end of G2 have a rapid rise of MPF (mitosis promoting factor), allowing the cell to go into mitosis. Carefully controlled degradation of cyclins in different points of the cycle are regulating the levels of MPF. Retinoblastoma: RB protein, which normally binds E2F (transcription factor, promotes DNA replication genes),’s shape is normally modulated by cyclins and is only phosphorylated at the right times, such that the shape changes and can no longer hold E2F, allowing E2F to bind and stimulate the transcription of genes required for DNA replication. Mutations  constant replication. P53 is a transcription factor, part of another checkpoint. Before the cell goes into the synthesis phase, it needs to make sure that all DNA damage has been repaired – p53 is the key sensor of whether the damage has all been repaired. If the DNA is damaged, the inactive form of p53 is activated  transcription factor  promotes p21 expression  p21’s major effect is to inhibit the transition from G1 to synthesis (S phase), because p53 is saying the DNA is damaged and should not be replicated until the damage is repaired. P21 also blocks PCNA protein, a part of polymerase (by blocking it, physically blocking replication directly). P53 is a big target for pharmaceuticals; if we can prevent S phase, then we stoptheir growth. MDM2 is normally promoting the destruction of p53, so a lotof work is trying to design molecules to go between MDM2 and p53 to prevent the binding. Dangerous to mess with, because if we stop blocking cell division, might kill the tumor but will have toxicity effects from cells that need to divide. o Signal transduction pathways: Signaling in growth factors: growth factor  receptors  shape change and addition of phosphate groups. Addition of adaptor molecule (RAS), will pass the signal through this chain of phosphorylation (converting inactive forms into active forms), ultimately leads to kinase inside the nucleus activating transcription factors. Cascade. Growth factor tells the cell it’s time to divide  pass the signal all the way to the nucleus to tell the cell to do so. RAS is the first step on the internal pathway (after themembrane receptor), and it’s a proto-oncogene. If we change its shape  constantly on  initiate cancer. 75% of tumors have a mutant form of RAS, pathway constantly on. o DNA repair genes: Problems with these will increase problems with transduction pathways and cell cycle regulators. Have to have a good repair system or will create a mutation in proto-oncogene. 90% of hereditary colon cancer is due to mutations in components of the mismatch repair apparatus. One way to characterize a tumor is to see if it still HAS a mismatch repair system, by looking at microsatellite markers (have a standard

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UMD BSCI 222 - Chapter 23: Cancer Genetics

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