Carcinogenesis as an Evolutionary Process

Dear Colleagues,

In the last two decades, significant advance in genomics, epigenomics, transcriptomics, and proteomics have given us insights into the molecular details of cancer evolution. These studies have confirmed that tumors evolve from normal tissues by acquiring a series of genetic, epigenetic, transcriptomic, and proteomic changes with concomitant alterations in the control of the proliferation, survival, and spread of affected cells. In the first phase of carcinogenesis, a cell may acquire a mutation that permits it to proliferate abnormally. In the next phase, other mutations allow for the expansion of cell number and this process of mutations continues, thus generating a primary tumor that can eventually metastasize in distant organs. According to current estimates, the number of cancer-driving mutations needed for the full development of cancer ranges from two to eight, depending on the cancer type. On average, cancer genomes contain four to five driver mutations. Analyses of the mutation landscapes and evolutionary trajectories of various tumor tissues have identified a constrained set of driver genes (e.g., BRAF, KRAS, TP53, RB, or APC) as the key genes whose mutation is most likely to initiate carcinogenesis. Significantly, the mutation rate of these genes in tumors far exceeds those of other genes, suggesting that their mutations are subject to positive selection during tumor evolution. Several types of approaches exploit this principle for the identification of genes that drive carcinogenesis: the rate of mutation of ‘driver genes’ must be significantly higher in the tumor tissue than those of ‘passenger genes’ that play no role in the development of cancer but simply happen to mutate in the same tumor.  

As a result of combined efforts, in 2020 the Pan-Cancer Analysis of Whole Genomes (PCAWG) study identified a total of 722 protein-coding genes as cancer driver genes and 22 non-coding driver mutations, leading to the conclusion that the core of the mission of cancer-genome sequencing projects—to provide a catalogue of driver mutations that could give rise to cancer—has been achieved. It is noteworthy, however, that although on average cancer genomes were shown to contain four to five driver mutations, in a significant proportion of cases no drivers were identified in tumors, suggesting that a rather large fraction of cancer driver genes remain to be identified.   

Another outstanding problem concerns the existence of tumor essential genes, i.e., genes whose functional integrity is essential for the growth and survival of tumor cells that is thus expected to be subject to negative selection. Although several groups have investigated the role of negative selection in tumor evolution, the results are controversial as some studies have reached the conclusion that negative selection has no role in tumor evolution.  

This Special Issue aims to focus on the toolkit of cancer driver genes and tumor essential genes. The significance of this question is that novel driver genes and tumor essential genes may prove to be valuable targets for cancer therapy.

 

Prof. Dr. Laszlo Patthy
Guest Editor

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