Association between expression of random gene sets and survival is evident in multiple cancer types and may be explained by sub-classification

Yishai Shimoni, Bing Zhang
2018 PLoS Computational Biology  
One of the goals of cancer research is to identify a set of genes that cause or control disease progression. However, although multiple such gene sets were published, these are usually in very poor agreement with each other, and very few of the genes proved to be functional therapeutic targets. Furthermore, recent findings from a breast cancer gene-expression cohort showed that sets of genes selected randomly can be used to predict survival with a much higher probability than expected. These
more » ... ults imply that many of the genes identified in breast cancer gene expression analysis may not be causal of cancer progression, even though they can still be highly predictive of prognosis. We performed a similar analysis on all the cancer types available in the cancer genome atlas (TCGA), namely, estimating the predictive power of random gene sets for survival. Our work shows that most cancer types exhibit the property that random selections of genes are more predictive of survival than expected. In contrast to previous work, this property is not removed by using a proliferation signature, which implies that proliferation may not always be the confounder that drives this property. We suggest one possible solution in the form of data-driven sub-classification to reduce this property significantly. Our results suggest that the predictive power of random gene sets may be used to identify the existence of sub-classes in the data, and thus may allow better understanding of patient stratification. Furthermore, by reducing the observed bias this may allow more direct identification of biologically relevant, and potentially causal, genes. Author summary Multiple gene sets have been published as predictive of cancer progression and metastasis in several cancer types. Although many of these sets proved to be highly predictive of survival, even gene sets for the same cancer (but from different data-sets or different analyses) exhibit very little overlap and to date did not provide functional therapeutic targets. Recent studies found that in breast cancer, even random gene sets can predict survival much better than would be expected, and on average are better than many published gene PLOS Computational Biology | https://doi.
doi:10.1371/journal.pcbi.1006026 pmid:29470520 pmcid:PMC5839591 fatcat:ymn7mmk6qremvbo4hibqtk6yae