Abstract
Background A major goal of cancer genomics is to identify all genes that play critical roles in carcinogenesis. Most of the approaches aimed to achieve this goal focused on genes that are positively selected for mutations that drive carcinogenesis and neglected the role of negative selection. Some studies have actually concluded that negative selection has no role in cancer evolution.
Results We have re-examined the role of negative selection in tumor evolution through the analysis of the patterns of somatic mutations affecting the coding sequences of human protein-coding genes. Our analyses have confirmed that the vast majority of human genes do not show detectable signals of selection, whereas tumor suppressor genes are positively selected for inactivating mutations. Oncogenes, however, were found to display signals of both negative selection for inactivating mutations and positive selection for activating mutations. Significantly, we have identified numerous human genes that show signs of strong negative selection during tumor evolution, suggesting that their functional integrity is essential for the growth and survival of tumor cells. It is worthy of note that the group of negatively selected genes includes several genes that play a central role in the Warburg effect characteristic of cancer cells as well as genes involved in the proliferation, immortalization, invasion and metastasis of tumor cells.
Conclusions Our analyses suggest that the approach reported here will promote the identification of numerous novel tumor suppressor genes, oncogenes and pro-oncogenic genes that may serve as targets in cancer therapy.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
banyai.laszlo{at}ttk.mta.hu, csuka{at}oncol.hu, kerekes.krisztina{at}ttk.mta.hu, patthy.laszlo{at}ttk.mta.hu, trexler.maria{at}ttk.mta.hu