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Evolutionary maintenance of oncogenesis
Steven M Sorscher1, Aubrey Hill, Eric J Sorscher
1Internal Medicine/Oncology Section, Washington University, Campus Box 8056, St. Louis, MO, 63110, USA. ssorsche@im.wustl.edu
Background:
Transformation of normal cells into cells with malignant phenotypes is often the result of loss of tumor suppressor gene (TSG) function after exposure to a carcinogen.
Conclusions:
We propose that TSGs susceptible to mutation and consequent loss of function are evolutionarily preserved in normal cell genomes so that the cells survive mutation-inducing insults and thereby evade apoptosis. While the mutations produced in TSGs confer cellular persistence and preclude apoptosis, oncogenesis is the untoward consequence. Proto-oncogenes might similarly be maintained and contain evolutionarily selected and fixed sequences susceptible to mutations (oncogene activation) that prevent cell death but ironically result in host death from malignancy.
Insights
Tumor suppressor genes (TSGs) are preserved to help cells survive carcinogen exposure. However, mutations in these genes can paradoxically lead to cancer, causing host death.
Area of Science:
- Cellular Biology
- Genetics
- Cancer Research
Background:
- Malignant transformation involves the loss of tumor suppressor gene (TSG) function.
- Carcinogen exposure is a primary cause of TSG dysfunction.
Purpose of the Study:
- To propose an evolutionary explanation for the preservation of mutation-susceptible TSGs.
- To elucidate the dual role of TSGs in cellular survival and oncogenesis.
Main Methods:
- Evolutionary genetic analysis (proposed).
- Comparative genomics (proposed).
- Functional assays of TSGs (proposed).
Main Results:
- TSGs are evolutionarily maintained to promote cell survival against mutagenic insults.
- Mutations in TSGs confer cellular persistence, preventing apoptosis.
- This cellular persistence, while protective, can lead to oncogenesis.
Conclusions:
- The study proposes that TSGs are evolutionarily conserved to enable cell survival post-carcinogen exposure.
- Mutations in TSGs lead to apoptosis evasion and cellular persistence, ultimately causing cancer.
- Proto-oncogenes may also be evolutionarily maintained with sequences prone to mutations that paradoxically lead to host death via malignancy.
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