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More is less: inactivation and deletion events and the search for tumor suppressor genes
W Edward C Bradley1, Domenic Di Paola, Emmanouil Rampakakis
1Centre de Recherche du CHUM, Research, JA deSeve Bldg., Montreal, Quebec, Canada. edward.bradley@umontreal.ca
Abstract:
Tumor suppressor genes are frequently inactivated in cancer by large-scale deletion events or epigenetic silencing, and experimental demonstration of such inactivation has historically been considered as support for assigning tumor suppressive function to a given gene. However, the discovery of a number of chromosomal domains wherein large deletions naturally occur at frequencies up to 100 times the average for the genome as a whole leads us to reevaluate the significance of sporadic deletions found within genes associated with these hotspots. Similarly, our recent demonstration that epigenetic chromatin silencing frequently spreads in cancer cells from gene-poor into gene-rich regions with apparent indifference to the gene content of the affected domain raises questions about the pertinence of inactivation as a criterion for ascribing tumor suppressor function to a given gene. We suggest that a number of putative suppressor genes for which inactivation and/or deletion events have been documented may simply be victims of collateral damage when these events occur, and the implication that these genes are being selected against during cancer progression should in some cases be reassessed.
Insights
Cancer gene inactivation via deletion or silencing may not always indicate tumor suppressor function. Some genes are victims of "collateral damage" from broader genomic events, requiring reassessment of their role in cancer progression.
Area of Science:
- Oncology
- Genetics
- Epigenetics
Background:
- Tumor suppressor genes are crucial in cancer, with inactivation often linked to their function.
- Historically, gene inactivation (deletion, silencing) has been primary evidence for tumor suppressor roles.
Purpose of the Study:
- To re-evaluate the significance of gene inactivation as evidence for tumor suppressor function.
- To question the assumption that documented inactivation directly implies selection against a gene in cancer.
Main Methods:
- Analysis of chromosomal domains with high deletion frequencies.
- Investigation of epigenetic silencing spread in cancer cells.
- Reassessment of inactivation data in light of genomic instability and silencing patterns.
Main Results:
- Certain chromosomal regions exhibit deletions at rates up to 100x higher than the genome average.
- Epigenetic silencing can spread across gene-rich regions irrespective of gene content.
- These phenomena suggest some gene inactivations may be incidental, not selected events.
Conclusions:
- Sporadic deletions and epigenetic silencing in cancer may not always target specific tumor suppressor genes.
- Genes affected by these broad events might be 'collateral damage,' not under direct selection.
- The criterion of inactivation for assigning tumor suppressor function needs critical reassessment.
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