DOTS-Finder project

In the last few years, the massive sequencing of several cancer genomes led to the identification of more than 5000 mutated genes. However, only a minority of the identified mutations is considered to impact the fitness of the cancer cells and lead the clonal expansion (drivers), while the majority is thought to have no role in the development of cancer and to occur by genetic hitchhiking in an unstable environment (passengers).
Several statistical strategies have been recently developed to properly identify driver mutations and genes. Some are based on the prediction of the impact of the specific mutation on the coding protein, some on the frequency of mutation in a gene compared to the background mutation-rate in the same tumor and some on the analysis of the co-occurrence of mutated genes in a pathway center view.

Here, we propose a new tool called DOTS-Finder (Driver Oncogene and Tumor Suppressor Finder) that combines a functional and a frequentist procedure, using a two-step approach. First, it identifies putative candidate driver genes, calculating a Tumor Suppressor Gene Score and an Oncogene Score, based on the type and location of the mutations occurring in each gene. These scores are inspired by the concepts of a recent study by ​Vogelstein et al., Science, 2013. Second, several tests are performed to assess if the mutational pattern in each gene shows a statistically defined “driver behavior” (e.g. mutation rate higher than background mutation rate for that tumor type, non-silent/silent rate higher than expected by chance).

The method has been applied to data from ​The Cancer Genome Atlas and its results have been compared to other strategies. Our approach shows consistent results according to the literature both in high and low mutation rate cancers and it is able to avoid the so-called “fishy genes” like the Mucins, Titin and most of the olfactory receptors. Furthermore, it provides clues on the behavior of the driver gene, as gain or loss of function.

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Publication

Detailed statistical information about DOTS-Finder can be found in our paper ​here

If you want to cite us, please use doi:10.1186/gm563 923 Melloni et al.: DOTS-Finder: a comprehensive tool for assessing driver genes in cancer genomes. Genome Medicine 2014 6:44.

Software Download

You can download our tool from ​here.

Documentation

Project documentation here.