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Nutrient-sensitive, antagonistically pleiotropic genes and their contribution to malignant behavior.
Sean M McBride1, Daphne A Haas-Kogan
1Department of Radiation Oncology, University of California at San Francisco, 2340 Sutter Street, San Francisco, CA 94115, USA. sean.mcbride@ucsf.edu <sean.mcbride@ucsf.edu>
Genetic lesions in Phakomatoses may limit cancer malignancy by inhibiting cell motility. Inactivating mutations in these genes (repressors of proliferation/promoters of motility) lead to benign growths, not invasive cancers.
Area of Science:
- Oncology
- Genetics
- Cell Biology
Background:
- Malignant potential of neoplastic cells is linked to somatic mutations or constitutional polymorphisms.
- Phakomatoses, characterized by benign neoplasms, harbor initiating genetic lesions that may limit malignant behavior.
Purpose of the Study:
- To investigate the role of initiating genetic lesions in Phakomatoses in limiting malignant behavior.
- To propose a model where specific gene functions (antagonistic pleiotropy) influence tumor progression.
Main Methods:
- Analysis of microarray data.
- Theoretical modeling of gene function and mutation dynamics within the tumor microenvironment.
Main Results:
- Identified genes with antagonistic pleiotropy: inhibiting proliferation while promoting motility (RPPMs).
- Inactivating mutations in RPPMs (repressors of proliferation/promoters of motility) lead to benign growths by unconstrained proliferation but limited migration/invasion.
- Wild-type RPPMs can synergize with oncogenes to promote malignancy.
Conclusions:
- Antagonistic pleiotropy of RPPMs may be an evolutionarily conserved mechanism to limit neoplasia spread.
- This model explains oncogene addiction, tumor dormancy, and spontaneous regression.
- Tumor microenvironment selective pressures can suppress mutations in RPPMs during progression.
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