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Alec's Discussion Questions

Week 2 Discussion Questions on Bad Luck and Cancer

1. Is there any experimental evidence supporting this model stating R contributes to the majority of the mutations for oncogenesis when compared to H and E? What would an experiment like this look like?

      There isn't much experimental evidence supporting the conclusions in the papers, the conclusions were drawn from data analysis and making conservative assumptions about variables that weren't known, the main one being total stem cell division.  Experiments that could test the conjectures made in the papers could vary, but would need to test the correlation between stem cell division number and oncogenesis/tumorigenesis (such as growing stem cells under the same conditions, except one group would be exposed to mild UV light and the other group would not; if R is the major factor contributing to tumorigenesis then the UV exposure would not affect tumorigenesis development over time).

2. These papers seem to be examining population data for all cancer types. Were there any similar studies correlating total number of stem cell divisions (which correlates with age) with cancer incidence for one cancer type? For example, is there a correlation between age and incidence of pancreatic cancer, or cancers that are prevalent in children such as ALL?

    Again there doesn't seem to be much more studies about this, it is a relatively new idea that R is a major contributing factor to cancer formation in tissues.  

3. During the presentation, a graph was shown with three different categories of correlation - groups of tissue where a major contributing factor is environment (making cancer incidence higher that expected for the total number of stem cell divisions), tissues where stem cell division and cancer incidence is well correlated, and a group where the cancer incidence is lower than expected for the number of stem cell divisions. How do the authors explain the last group?

    The authors determined that there must be some factor that helps prevent oncogenesis in these tissues, such as better DNA repair mechanisms or less error rate during replication.

After thinking about the answer for a bit (And discussing it with other classmates), a follow-up to this answer would be why isn't there emphasis on these tissue types? There seems to be some factor that is helping prevent cancer formation in these tissues, and if we can elucidate these mechanisms this could be a potential therapy path by introducing some of the preventative mechanisms into other tissues.

  • Maureen 12:20, 11 October 2017 (PDT) cool idea. I wonder how you might go about this?
  • Maureen 12:20, 11 October 2017 (PDT)nice job, reasonable questions/answers and comments.


Discussion Questions - TZAP

1. Why can't the ChIP experiment determine telomere length dependent Shelterin density? The paper states:

    "As a result, cells with long telomeres have a lower density of the shelterin complex compared to cells with shorter telomeres, a difference that is not detected by ChIP (11)."

ChIP will only enrich for bound DNA up to the point that all of the proteins are bound - therefore ChIP couldn't detect unbound extra DNA and so a different technique needed to be used.


2. How did the authors figure out that three last zinc finger motifs are all needed for binding, instead of just one (or different combinations of two such as 9 and 10 or 9 and 11)? The supplementary material as well as the article indicates that this was not tested.

    Both the presenters as well as other students answered that they assume these were tested but the results were not published.

I don't find this an acceptable response. I feel that if the authors tested many different combinations of the zinc finger motifs they would have published it in the supplemental information at the very least. Just saying "well I think that it was done" is not evidence that it was done - it is pure speculation.


3. How does the new model of telomere regulation apply to somatic cells that don't have active telomerase?

    The idea now is that telomerase is now transiently active in all cells, and telomere degradation is thought to occur due to a buildup of mutations in the shelterin and TZAP proteins instead of chromosomal shortening due to replicaiton.