Model How Environment and Genetics Change the Chances of Getting Cancer

Building the Starting Cancer Disease Model

1. You will be building your cancer disease model using a simple programming language called Scratch. Create a Scratch account.
2. Optionally, if you have never used Scratch before, you can follow some of these Scratch programming tutorials to learn how to use it, or look over this Getting Started with Scratch reference guide.
3. Figures 1 and 2 show all the things our basic cancer disease model needs to represent.
   1. In Figure 1 we see that when cells divide, the DNA from the original (mother) cell is unchanged but the daughter cell may accumulate mutations. In each cell division, more mutations may accumulate in the daughter cells until finally there are enough mutations that a cancer cell develops. It takes many cell divisions to get a cancer cell.
   2. In Figure 2 we zoom in to take a closer look at what happens during each cell division.
      1. Gene mutations arise in the daughter cell. In our cancer model, we will need to assign a normal mutation rate.
      2. The mutated daughter cell may trigger apoptosis. If it does, it dies. If it does not trigger apoptosis, it continues on. If it continues on, the immune system may detect and destroy the mutated daughter cell. In our cancer model, we can simplify and combine these two events into a single chance of escaping cell death.
      3. If the mutated daughter cell escapes cell death, it can go through the cell cycle again. If it does, the resulting daughter cell will accumulate even more mutations. In our cancer model, we will need to assign a mutation threshold. If the number of mutations in a daughter cell is greater than the threshold, it will be considered a cancer cell.

Image Credit: Sandra Slutz, Science Buddies / Science Buddies
Figure 1. Cancer comes from the accumulation of mutations over many cell cycles.

Image Credit: Sandra Slutz, Science Buddies / Science Buddies
Figure 2. This diagram shows how a cell could accumulate mutations through cell division.

4. Now that we have outlined what our model does and the data we need to plug in, we can look in the literature to see if that data exists. We have done this step for you in Table 1. If you want to build a more complex model (some suggestions for this can be found in the Variations), you will need to find additional data.

5. You are now ready to build the starting model. Follow steps six through ten to write the starting model yourself, or you can remix this Science Buddies Scratch Project.
6. Open Scratch and create five variables:
   1. Mutation Rate: use this variable to set the rate at which daughter cells accumulate mutations every cell division.
   2. Cancer Mutation Threshold: use this variable to set the number of mutations a daughter cell must accumulate to become a cancer cell.
   3. Total Number of Mutations: use this variable to count how many mutations are in the DNA of the cells in your model.
   4. Number of Cell Cycles: use this variable to count how many cell cycles have passed before a cancer cell appears.
   5. Cell death: use this to set the chance of a mutated daughter cell escaping cell death.
   Image Credit: Sandra Slutz, Science Buddies / Science Buddies
   Figure 3. Scratch blocks for the five variables needed to build the starting model.
7. Set the starting values for all your variables. The Mutation Rate and Cancer Mutation Threshold should be set according to Table 1. The rest of the variables should be set to zero.
   Image Credit: Sandra Slutz, Science Buddies / Science Buddies
   Figure 4. Scratch code showing the starting values of the variables.
8. Program what happens during a single cell division. One possible solution is shown in Figure 5.
   1. The Number of Cell Cycles increases by one.
   2. The Total Number of Mutations in the daughter cell increases by the Mutation Rate.
   3. We check to see if the cell survives Cell Death.
      1. As explained in Table 1, we have set the chances of escaping Cell Death to 0.1% or 1 in 1000. You can do the same or look for a value based on real-world data in the literature.
      2. One way to represent a 0.1% chance of escaping cell death is to randomly pick a number between 0.000 and 1.000 for the variable Cell Death. If the value that is randomly picked is greater than 0.001 then the daughter cell dies.
      3. If the daughter cell dies, then we are left with the mother cell which has fewer Total Number of Mutations. To represent this in the model, we must decrease the Total Number of Mutations by the same amount we added in step 7b.
   Image Credit: Sandra Slutz, Science Buddies / Science Buddies
   Figure 5. Scratch code for what should happen during a single cell cycle.
9. Now that we have the code for a single cell division, we need to add code to make the cancer model continuously repeat cell cycles until the conditions for cancer are met. In our simple cancer model, we have set a threshold of 10 mutations to be the point at which the daughter cell becomes a cancer cell (see Table 1). One possible solution is shown in Figure 6.
   Image Credit: Sandra Slutz, Science Buddies / Science Buddies
   Figure 6. The scratch code for a single cell cycle will be repeated until the cancer mutation threshold is met.
10. Optional: You can put in graphics as well to make the program visually appealing and clear to users when the model is finished running.
11. Run your model at least ten times. Each time, record in your lab notebook how many cell cycles it takes for a cancer to appear. You can also try running the model here:

Modifying the Cancer Disease Model

1. Once you have your starting cancer disease model built, you are ready to modify it to see what happens to the chances of developing cancer under different environmental and genetic conditions.
2. Smoking cigarettes is an environmental factor that changes a person's chances of getting lung cancer. Table 1 has information about how smoking affects the mutation rate of cells. Use this information to modify your cancer disease model.
3. Run your model for people who smoke at least ten times. Each time, record in your lab notebook how many cell cycles it takes for a cancer to appear.
4. Some families with a history of breast cancer have mutations that change the function of the BRCA1 or BRCA2 genes. Using the information in Table 1, modify your starting cancer disease model to see what happens to the chances of getting breast cancer with a BRCA1 or BRCA2 mutation.
5. Run your model for people with BRCA1 or BRCA2 mutations at least ten times. Each time, record in your lab notebook how many cell cycles it takes for a cancer to appear.
6. Compare your results for the three cancer disease models you built (starting model, smokers' model, and genetic mutation in BRCA1 or BRCA2 model). What is the cell cycle range for each one? What is the average number of cell cycles before cancer appears in each model?

Validating Your Model

1. To see if your models are valid (make sense), you will need to compare the results of your models with real-world data. Look up:
   1. The average age at which smokers versus non-smokers are diagnosed with lung cancer.
   2. The average age that people with mutations that change the function of BRCA1 or BRCA2 are diagnosed with breast cancer versus people that do not have mutations in either of those genes.
2. Do your models match the real-world data? Explain how or how not.
3. Optional: Check out the Variations section to see how you can keep improving your models.