Exam 2 Questions
Which of the imaging options we discussed in class would NOT be a good choice for imaging a colon (large intestine) tumor & why
X-rays/CAT scan, because they are not good at differentiating soft tissues, like those found in the abdomen.
Remember that epidemiology can suggest a cause of a disease by telling us who gets the disease. You are an epidemiologist interested in studying a rare type of cancer that is surprisingly common on the (imaginary) island nation of Blefuscu. Your research finds that people who are born on Blefuscu and live there all their lives develop this cancer at a rate of 4%. Conversely, people who are born on Blefuscu but move to another part of the world by age 10 get this cancer at a rate of 0.002%. In the paper you're writing to publish your results, will you suggest that the cause of this cancer is mainly genetic or mainly environmental? Why?
You suggest that it is mainly environmental. Moving to another part of the world does not change someone's genetic makeup, but it does change what carcinogens they are exposed to in their environment, and it could possibly also change their lifestyle.
What is loss of heterozygosity, and how does it relate to tumor suppressor genes?
- A person is heterozygous for a certain gene if they have two different versions of it, for instance, one normal version and one inactivated version. - Loss of heterozygosity (LOH) means that one of the two versions of the gene is lost or deleted. - In the two-hit hypothesis, the first hit is often a point mutation, whether inherited or acquired. The second hit is LOH.
How does increasing the rate of cell division increase the likelihood of getting a mutation in a given period of time?
- Every time DNA is copied, there is a fixed likelihood of getting a mutation - Increasing the rate of cell divisions means that you increase the # of mutations/time period - increase cell proliferation also increases DNA replication - number of mutations = number of cell divisions x number of mutations over cells division - mutagens directly cause mutations, chemically cause DNA damage - carcinogens that aren't mutagens: cause mutations indirectly, promote proliferation, increase number of DNA is copied
Explain why alcohol is a strong carcinogen for the mouth and throat when used by people who are also smokers.
- High concentrations of alcohol kill the cells lining the mouth & throat, then other cells proliferate to replace the dead cells. - Some chemicals in cigarette smoke are mutagens. - Here, you're increasing both the # of cell divisions (with alcohol) and the rate of mutations (with cigarette smoke), so your overall likelihood of getting mutations more quickly goes way up - alcohol kills cells in the esophagus, more cells proliferate to fix cigarette smoke: mutagens, increase rate of mutation
Your text states that "oncoproteins fool the cell into thinking it has encountered growth factor molecules," then over the next few pages, discusses at least five ways this can happen. List as many of these as you can.
- Inducing the cancer cell to release growth factors into its surroundings - Mutations that make growth factor receptors constitutively active - Overexpression of growth factor receptors that need to associate with a second molecule of the same receptor in order to send a signal to the inside of a cell - Mutations that make downstream/intracellular components of signaling pathways constitutively active (i.e. ras oncogene) - Driving expression of a transcription factor (like myc) that promotes transcription of genes required for cellular proliferation
Explain the rodent carcinogen test
- Mice & rats exposed to potential carcinogens repeatedly over months/years to see if they get tumors - testing of potential carcinogens - revealed a lot about the chemical species that trigger cancer
all mutagens are carcinogens, but not all carcinogens are mutagen. Based on your reading of this chapter, what do the carcinogens that are not mutagens do?
- They promote cell division (in a way that doesn't increase the rate of mutation per cell division) - all mutagens are carcinogens, but not all carcinogens are mutations - carcinogens that aren't mutagens - favor cell proliferation, increase rate of cell proliferation
What are the five ways pro-growth pathways are activated in cancer?
1. Higher expression of pro-growth transcription factors. 2. Higher expression of certain receptors. 3. Mutation in receptor makes it constituitively active. 4. Mutation in downstream protein makes it constitutively active. 5. Cancer cell produces own growth factor.
Would a tumor cell be more likely to develop a mutation that leads to increased or decreased expression of the gene for VEGF? Explain.
A tumor cell would likely develop a mutation that leads to increased expression of VEGF. VEGF is the ligand that tells blood vessel cells to grow toward the tumor, providing the tumor with its own blood supply, which is necessary if the tumor is to grow beyond a certain size.
What type of screening should be used to check for cancer in body parts filled with fluid? I.e. Colon, prostate, breast
A: Ultrasound
What is one disadvantage and one advantage of PET scan?
Advantage: The scan doesn't uses a harmful wave of energy to produce test but, radioactivity. Radioactivity is from a safe radioactive sugar molecule. The sugar then accumulates in the tumor because the tumor needs a higher sugar content to survive. Disadvantage: There needs to be a second test administered to put the scan in an anatomical context.
Give two examples of carcinogens that are not mutagens
Alcohol Estrogen Asbestos
Explain why compounds such as alcohol are not mutagens but are carcinogens.
Alcohol promotes cell proliferation which in turn leads to an increase in natural DNA replication errors. In proliferation, there are always going to be replication errors but by increasing this, the number of mutations increases as well. This increase in proliferation occurs in the mouth and throat cells. Alcohol is especially good at causing cancer when combined with cigarettes, becuase then you have two carcinogens present: alcohol (non-mutagens) and chemicals in cigarette smoke (mutagens).
What would be a good screening method for a cancer in the brain?
An MRI would be a good screening method because MRIs use radio waves that work best for soft tissues, such as muscles or the brain .
What is angiogenesis?
Angiogenesis is the formation of new blood vessels to feed a tumor.
Which of the following screenings are best used to evaluate fluid filled soft tissues, such as the colon, prostate and breast? A. X-ray B. Ultrasound C. MRI D. PET scan
B. Ultrasound
Explain how can the natural increase in cell proliferation in the lining of the throat from alcohol consumption means that alcohol can be considered a carcinogen?
Because alcohol causes increased cell death and therefore proliferation to replace these cells, the odds that a genetic mutation would occur increases. Alcohol doesn't directly attack and damage the DNA, but the more cell proliferation that occurs, the more times the DNA is copies, and the greater likelihood that one of these new cells would develop a mutation due to an error in DNA replication.
What do chemical carcinogens and X-rays have in common that allow them to cause cancer?
Both cause mutations in genes (They are mutagens.)
Among scientists in the mid-1970s, what were the two opposing views about the cause of cancer?
Cancer is caused by viruses (Viral tumorigenesis theory) vs. cancer is caused by chemicals (Chemical carcinogen theory)
Which cancers are screened for?
Cancers that are... - common in the general population - develop relatively slowly - have few symptoms until they progress to a late stage - have a big difference in treatment outcome if they are caught early
Cells can evolve over time. Why do we call clonal evolution...evolution?
Clonal Evolution means that there is a change in properties of population of cells overtime. This results when a mutation makes gives the cell with that mutation a growth advantage, so that cell divides more times than its neighbors, and cells with that mutaiton become more prevalent
Explain how the process of clonal evolution in a tumor can lead to drug resistance.
Clonal evolution acts on natural genetic variation to select the cells that are most likely to reproduce. The result is that these cells become more prevalent in the tumor. When a tumor is treated with a drug, it kills all the cells except those that are resistant to the drug. Therefore, eventually, the only cells left in the tumor are resistant, and those cells grow out so that treatment eventually stops working.
The CDC (Center for Disease Control) is deciding whether or not to recommend implementation of a proposed cancer screening program. What is the major outcome of the program they will look for?
Decrease in cancer deaths when the program is used
Epidemiology is the study of disease incidence/frequency in specific groups of people. Why is studying cancer epidemiology useful?
Epidemiology can give clues to causes of disease b/c it tells you who gets the disease - Factors external to the body can actively induce cancer; in other words, cancer is not a random bodily degeneration
True or False: All carcinogens are mutagens, but not all mutagens are carcinogens.
False. All mutagens are carcinogens, but not all carcinogens are mutagens.
True or False: When researchers hybridized normal cells with cancer cells, they found that the resulting cells were not cancerous because of the normal copies of proto-oncogenes that came from the normal cells' DNA
False. It is because of the normal copies of tumor suppressor genes that came from the normal cells' DNA.
What is the technique of cell hybridization?
Fusing two cells to obtain a cell with a single outer membrane, but two nuclei
Explain what genetic diversity is. Is genetic diversity only present within a tumor?
Genetic diversity is the idea that in any given population of cells, not all cells will have exactly the same genome. Due to the commonality of mutations, normal tissue will display genetic diversity with some mutated and some normal cells. Just because some of the cells have mutations does not mean they are cancer cells.
What is the name for the class of signaling molecules (ligands) that kick off the signaling pathways that promote cell proliferation?
Growth factors (type of oncogene)
Why is it more useful to screen for cancers that develop relatively slowly than those that develop quickly?
If a cancer develops slowly, there is a greater likelihood that it will be caught in its early stages by screening, before symptoms arise. A cancer that develops quickly will likely show symptoms before it would be caught by routine screening.
In breast cancer the growth factor receptor erbB2/neu is often overexpressed and leads to uncontrolled proliferation even in the absence of ligand. If individual copies of the protein are isolated, they do not signal in the absence of ligand. What does this imply about how erbB2/neu functions? (Refer to our discussion from class of what can go wrong with signaling pathways to cause cancer.)
In class, we discussed two different ways growth factor receptors can contribute to cancer development. One was if they have a mutation that makes them constitutively active. Here, that is not the case, because individual copies of the protein do not signal in the absence of ligand. Therefore, it probably works by the other mechanism we discussed: Some receptors are activated when two or more copies of the protein associate with each other. Usually this requires a ligand, but if the protein is overexpressed to a high degree, it can happen spontaneously without receptor. There must be enough erbB2/neu on the cell surface that the receptors will associate with each other and send signals downstream without the ligand being present.
What is cell hybridization and how was this technique used in an experiment by Henry Harris?
It is the technique that forces cells to fuse together to create one cell with multiple sets of DNA. He wanted to find out if a hybrid cell will be cancerous or not. He observed they were not, as tumor suppressors stopped the oncogenes from proliferating, therefore it was not cancerous.
What is the process in which a tumor acquires the nutrient supply to fuel itself?
It works by sending out signals of VegF to blood vessels cells, which begin to proliferate towards the tumor. These blood vessels begin to feed the tumor in a similar way in which they would feed an organ. This process is known as angiogenesis
If the risk of cancer increased linearly with age, what would this imply about how many mutations were required to develop a tumor? Explain.
It would imply that a single mutation is needed to turn a cell cancerous. Assuming that risk of mutation in a given period of time is constant, a person who is 20 would have twice as much risk of a single mutation as a person who is 10. A person who is 30 would have three times the risk. Therefore, the overall risk of developing cancer in this scenario would increase linearly over time.
Why is it that longer developing cancers are good choices for public screening programs? Provide an example of one of these.
Longer developing cancers allow for the screening to be done less often and therefore be less of an inconvenience for the patient. As it is done less often, it is also more realistic to be done to the entire public, unlike expensive screenings that have to be done regularly. Also, since these type of cancers develop slowly, screening is more likely to catch them in an earlier stage. An example of one of these cancers is Colon Cancer.
Explain how ionizing radiation can be used for cancer imaging and cancer treatment, but can also be a cause of cancer.
Low level ionizing radiation is used for imaging. This level of radiation doesn't cause a lot of DNA damage, and the damage that is caused can be easily repaired by healthy cells. On the other end of the spectrum, high dose radiation is used for radiation therapy. This level of radiation causes so much DNA damage that cells can't survive at all. The beam is focused on the cancer cells, which ideally die from the therapy. The problematic kind of radiation is when the dose is somewhere in between: enough to cause mutations, but not enough to kill the cells. As we now know, cells that live with mutations are more likely to develop into cancer cells than non-mutated cells.
What is the Seed and Soil theory?
Metastatic cells that can only become new tumors if they land in a new tissue environment that supports their growth with the right nutrients.
Using the Knudson two-hit theory, explain why people with familial retinoblastoma usually get tumors in both eyes, whereas people with sporadic (non-familial) retinoblastoma almost never do.
People with familial retinoblastoma already have one inactivated copy of the tumor suppressor Rb when they are born. In order for a retinoblastoma tumor to form, both copies of Rb need to be inactivated. In people who are born with two intact copies, the likelihood of a single cell losing both copies is low enough that it is unlikely to happen in both eyes. However, in those with familial retinoblastoma, only the remaining single good copy of Rb needs to be inactivated for a tumor to form. The likelihood of this happening is high enough that it is likely to occur independently in each eye.
Explain the three types of mutations/genetic changes you book discusses that can convert proto-oncogenes to oncogenes and give an example of each.
Point mutation: Change in a single nucleotide in a DNA sequence • Ras oncogene: most frequent in human cancers Gene amplification: Multiple copies of the same gene leads to more of that protein & more of its pro-growth effects • Myc oncogene Translocation: Gene moves to another place & can be driven by a different promoter • Myc oncogene in Burkett's lymphoma
In class, we discussed how # of mutations = # of mutations/division (in other words, rate of mutation) x # of divisions. The greater # of mutations you have, the greater your likelihood of cancer. Name at least one specific example of something that affects # of divisions and at least two specific examples of things that affect the rate of mutation. (I don't want you to name just classes of things, but specific compounds and/or genes.)
Possible answers: Things that affect # of divisions are carcinogens that are not mutagens, like alcohol and estrogen. Also, activated oncogenes, of which you could name a number of specific examples, like activated ras. Things that affect rate of mutation are chemical mutagens like cigarette smoke, errors in DNA replication or defects in DNA repair, like the mutation of the BRCA1 and 2 genes.
How did cell hybridization further scientists' understanding of cancer?
Scientists hybridized pairs of cells--one normal cell and one cancer cell. Although they expected that hybridized cells would become cancerous because they contained activated oncogenes, the opposite came true. The tumor suppressor genes that restricted cell growth (from the normal cells) were enough to keep the hybridized cells from becoming cancerous even though they still contained cancer cell DNA.
What is the difference between screening and diagnostic tests?
Screening is a procedure that routinely tests people who have no symptoms or no reason to think they have cancer. It is used to catch any pre-cancerous or cancerous cells at an early and more easily treatable stage. A diagnostic test is used to gather more information on a person who has symptoms and is already suspected of having cancer. It helps formulate a treatment plan.
Describe the "seed and soil" theory?
The "seed & soil" theory is where metastatic cells (in this scenario the "seeds") will only develop into new tumors if they end up in a new tissue environment ("soil") that supports their growth with the proper nutrients, growth factors, etc.
What is the "seed and soil" theory? What does it have to do with metastasis?
The "seed and soil" theory states that a "seed" (a metastatic cell) will only grow and develop into a tumor if it lands in new "soil" (a tissue environment) that supports its growth with proper nutrients and other growth factors. Thus, metastasis will not occur unless the metastatic cells find a suitable tissue environment in which to grow.
You are testing 3 chemicals by the Ames test as we discussed in class. The results of your experiment are shown below (# of bacterial colonies growing on a plate without histidine). What can you conclude from this experiment?
The Ames test is used to determine whether a certain chemical is a mutagen. We know that water is not a mutagen. The water control shows how many colonies will be present on the plate as background noise. When bacteria are treated with chemical B, the result is a plate with the same number of colonies as water, meaning it is not a mutagen. We can conclude that chemicals A and C are both mutagens, since plates of bacteria treated with those chemicals show more colonies than the water control. We can also conclude that chemical A is a more potent (stronger) mutagen (i.e. the same amount of it causes more mutations) than chemical C, beacause the plate treated with chemical A shows more colonies. Importantly, without any other information about whether these chemicals cause actual tumors (i.e. on rodents), we cannot also definitely conclude that they are carcinogens, although it is very likely they are.
Explain the purpose and process/results of the Ames Test.
The Ames test was created in order to determine what chemical compounds are mutagens. Ames tested different carcinogens one by one with a bacterial assay. If the bacteria was able to grow without histidine, the chemical was considered a mutagen and can cause cancer. If the bacteria needed histidine to grow, the chemical is not a mutagen.
What are the biggest differences between using X-ray/CT scans and an MRI to image tumors?
The X-ray is good for bones but is also slightly dangerous due to the ionizing radiation. It is not good for distinguishing soft tissues, which is the MRI's specialty. The MRI uses radio waves to detect atoms. It is safe unless you have metal in your body from surgery, but claustrophobia and price is often a problem.
There are certain genes in our cells that affect the cell's ability to move, or migrate. (This makes sense, right? Some cells have to move around, and many stay put where they are.) Would a tumor cell be more likely to develop an activating or inactivating mutation in a gene that increases its ability to migrate? Explain.
The ability to migrate promotes the tumor cell's ability to successfully metastasize. Therefore, the cell would be more likely to develop an activating mutation in a gene that increases motility.
What are the advantages and disadvantages of the Ames test compared to the rodent carcinogen test?
The advantages of the Ames test over the rodent carcinogen test are that it can be done quickly, (whereas the rodent test requires months to see results,) it is less expensive, and there is less harm done to animals. The disadvantages of the Ames test are that carcinogens that are not mutagens would not be detected by the test since it tracks the growth of bacterial colonies, and that rodents are more biologically similar to people than bacteria.
Experiments show that the enzymes that actually copy our DNA may make mistakes (insert the wrong nucleotide) as frequently as 1 in every 1000 base pairs. However, by the time a cell has completed the process of DNA replication, less than 1 in 1 million nucleotides appears to have been miscopied. What accounts for this discrepancy?
The existence of DNA repair mechanisms
We discussed in class how adding an activated ras oncogene to cells growing in culture was sufficient to turn these cells cancerous. We agreed that this was only possible because these cells had already acquired some of the mutations necessary to become cancerous before the ras gene was added. Were these early mutations likely to be activation of oncogenes or inactivation of tumor suppressor genes? Explain.
They were likely to be inactivation of tumor suppressor genes. Both activation of oncogenes and inactivation of tumor suppressor genes are required to turn a cell cancerous. Since in this scenario we are adding and activated oncogene and the cell becomes cancerous right away, the cells must already have inactivated tumor suppressor genes.
Explain how specificity and sensitivity rules out positives and negatives.
Think of the mnemonic device. SpIN- specificity rules positivity IN. If a person tests positive on a test with high specificity, the chances are high that the person has the disease. SnOUT- sensitivity rules negatives OUT. If a person tests negative on a highly sensitive test, it is likely that the person does not have the disease (this is used a lot in screening)
Describe the two hit theory?
This theory was proposed by Alfred Knudson. This idea states that in order for a tumor to come to form, both copies of the same tumor suppressor gene need to be inactivated or lost. The first mutation inactivates one copy of the tumor suppressor gene. The second mutation that has to occur, inactivates the the other copy of the gene.
True or False: In the process of adapting to growth in culture, normal cells become immortalized, which means they can divide indefinitely.
True
What are Ultrasounds good for? What are their downsides?
Ultrasounds are good for imaging soft tissue and those filled with fluids (i.e. colon, prostate, breast). The downsides to Ultrasounds is their overall imaging; it is very blurry and not sharp.
Why were Varmus & Bishop shocked when they discovered a copy of the src gene in normal chicken cells?
Varmus & Bishop were part of the camp of scientists that believed that tumors were caused by viruses and that oncogenes that were contained ONLY in viruses, not in animal/human cells. It had been proven that the src oncogene in RSV was responsible for causing infected cells to develop into tumors, so they certainly didn't expect to find a version of src in uninfected cells!
In women who menstruate, the hormone estrogen drives monthly rounds of proliferation (and death) in breast tissue. Explain why women who begin menstruating early in their lives and/or who experience menopause later in life have a higher risk of breast cancer.
We discussed in class how anything that increases the likelihood of mutation will also act as a carcinogen, because more mutations = higher risk of cancer. We also said that # of mutations/division is constant. Therefore, anything that can increase the # of cell divisions will also increase cancer risk. The question tells us that estrogen drives proliferation in menstruating women, so the more years during her life that a woman menstruates, the more cell divisions in the breast will occur, and the higher her risk of mutations in the breast cells. More mutations in breast cells = higher risk of breast cancer.
You are a professor and a geneticist studying oncogenic mutations in a new form of a muscle sarcoma that your medical colleague discovered. You have evidence that this sarcoma is driven by a translocation of the myc oncogene. Your 1st-year graduate student brings you data from one of these tumors that he says suggests myc expression is being driven by the promoter for synaptin. The synaptin gene is normally only expressed in nerve cells. Why are you skeptical that his explanation is the correct one?
We know that increasing myc expression is oncogenic. Therefore, for a translocation to be oncogenic, it has to result in increased expression of myc. In a muscle cell, the synaptin gene is normally not being expressed, so its promoter will not be active. Therefore, if myc expression is being controlled by the inactive synaptin promoter, it will NOT be highly expressed, which would not explain the presence of a tumor. His explanation doesn't make sense.
How does the rise of lung cancer in women after WWII support the multistep tumorigenesis model?
Women began smoking in greater #s following WWII, but their actual rates of lung cancer didn't increase until decades later. They got the initial mutation from smoking, but decades had to pass for enough mutations to accumulate to actually give them cancer. - took many years after for women to actually succumb to lung cancer, process needed to create lung tumors from beginning to end took decades - exposed over a period of time, took over a century to develop - if single mutation required, smoking goes up = immediate number in lung cancer goes up
Which of the following family histories would NOT prompt an oncologist to check for a familial cancer syndrome in one of her patients: a. Mother with breast cancer at age 40, Maternal grandmother with ovarian cancer at age 36 b. Sibling with retinoblastoma in both eyes at age 5 c. Father (with history of smoking) with lung cancer at age 65, First cousin (on father's side) with prostate cancer at age 70, Aunt (on mother's side) with breast cancer at age 55 d. The patient herself presents with both colorectal and stomach cancers (Two primary tumors - neither is a metastasis)
c. Father (with history of smoking) with lung cancer at age 65, First cousin (on father's side) with prostate cancer at age 70, Aunt (on mother's side) with breast cancer at age 55
5. Which of the following is NOT true about Li-Fraumeni syndrome? a. Caused by mutation in the tumor suppressor p53 b. People with this syndrome have an almost 100% risk of developing cancer in their lifetime c. The mutation that causes the syndrome is relatively frequent d. Cancers develop relatively young
c. The mutation that causes the syndrome is relatively frequent
which cancers are screened for?
those that are... ~ common in the general population ~ develop relatively slowly ~ have few symptoms until they progress to late stage ~ have big difference in treatment outcome if they're caught early ~ and of course, you can only screen effectively if a good text exists
a familial syndrome should be considered if there are...
~ multiple cases of a single type of cancer in a family, especially a rare type ~ cancers occurring younger than usual ~ multiple types of cancers in a single individual ~ cancers occurring in both of a pair of organs (i.e. both eyes, both kidneys)
minimize your risk:
• no tobacco use in any form • maintain a healthy weight • regular physical activity • eat healthy with plenty of fruits + vegetables • limit alcohol intake • protect your skin • get the HPV vaccine • get regular checkups + cancer screening tests • know yourself, family history, and your risks
when might someone have a higher-than-normal cancer risk?
• previous cancer or precancerous lesions ~ staying alert for return of previous cancer type - or for a secondary cancer to develop due to radiation or other treatment during past cancer • known exposure to carcinogens (smoker, other acute or chronic exposure, etc)
who should get tested / when?
• the purpose of routine screening is to catch cancer early enough to make a difference in treatment outcome • for a screening regimen to be recommended as part of normal medical care for healthy, normal-risk individuals, it has to be proven to reduce cancer deaths in the general population