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2011 RFA Links and Provocative Questions  

PQ - 8
Why do certain mutational events promote cancer phenotypes in some tissues and not in others?

Background: Cancer-causing mutations arise under different selection pressures during tumor development. It has been recognized for some time that the frequency or timing of various cancer mutations differs widely among tissues, but we have little mechanistic understanding about why this occurs. These observed variations presumably are imparted by such factors as different physiology of the cell of origin, different selective pressures generated from the surrounding microenvironment, or various changes established by earlier mutational events. This question seeks mechanistic explanations for these differences in selective pressures.

Feasibility: Modern molecular and cellular biological methods should allow many of these tissue-specific events to be identified and studied. Cell and tissue dependence on protein function is seen in many animal models of tumor development, and in many cases we understand the signaling pathways in sufficient detail to design experiments to tease out the key steps that allow for tissue specificity. Proscribed mutational order presumably is due to changes imposed by earlier events in tumor development. Direct measures within animal models and in human tumors should allow differences to be confirmed and evaluated.

Implications of success: Understanding why certain tissues rely so uniquely on one protein promises to help us understand the different roles of cancer mutations. How are these dependencies established? Why are these dependencies paramount in some tissues? Do these dependencies relate to oncogene addiction? Knowing how these dependencies develop also promises to allow us to lock-in these dependencies within tumors and strengthen therapeutic responses.

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