A major goal of large-scale cancer sequencing studies is to identify the genetic and epigenetic alterations that drive cancer development and to distinguish these events from random passenger mutations that have no consequence for cancer. Identifying driver mutations is a significant challenge due to the mutational heterogeneity of tumors: different combinations of somatic mutations drive different tumors, even those of the same cancer type. This mutational heterogeneity arises because driver mutations target genes in biological pathways, such that each pathway can be perturbed in numerous ways. Since there are relatively few driver mutations in a tumor sample, and these are distributed over multiple pathways/hallmarks of cancer , driver mutations in the same pathway are often mutually exclusive across samples. This observation forms the basis for de novo approaches to find putative combinations of driver mutations without prior biological knowledge of pathways or protein interactions.
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