Explain the key discovery in the paper by Stehelin, et al. (Nature, 1976) in eReserves and how this accelerated our understanding of the origins of cancer.

Genetic basis of cancer

2.) Read the paper by Stehelin, et al. (Nature, 1976) in eReserves. Prior to this paper, there were three competing hypotheses about the origins of cancer in humans. Cancer was thought to be directly caused by viral infection, exogenous agents (smoking, pollution, etc.) or in rare cases where there was a family history, a genetic component was acknowledged. From the results in this paper, the “oncogene hypothesis” was born and we now know “cancer is a genetic disease.” Explain the key discovery in this paper (8 points) and how this accelerated our understanding of the origins of cancer (8 points).

3. Genes involved in tumorigenesis

a.) How do we broadly categorize the genes involved in tumorigenesis? Compare and contrast these two categories with regard to number of hits to activate/inactivate, types of events leading to activation or inactivation, and functions of proteins encoded by the genes (8 points).

p53 and pRb are two important proteins involved in tumorigenesis. Please explain:

b.) How each of these proteins works to constrain cell proliferation

c.) The physiological stresses or inputs that impact p53 and pRb signaling.

In your explanation also include:

d.) An example of how each protein is activated (molecules upstream) and the downstream consequences of this and conversely

e.) What inactivates (molecules upstream) the protein and the downstream consequences of the protein being inactivated

(8 pts each for p53 and pRb, 2 pts from each of the four parts).

4. Immortalization

a.) Describe the steps necessary for a cell to become “immortal.” Include in your description the molecular alterations correlated with the steps in this process (8 points).

b.) Based on your knowledge of how the genes involved in cancer become activated and inactivated, describe why the breakage-fusion-breakage cycles could lead to a growth advantage for cells on the path from normal to cancer (4 points).

c.) Explain the consequences of these breakage-fusion-breakage cycles on the subsequent population of cancer cells (4 points).

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