Circuits of cancer drivers revealed by convergent misregulation of transcription factor targets across tumor types

Abel Gonzalez-Perez

doi:10.1186/s13073-015-0260-1

Abstract

BackgroundLarge tumor genome sequencing projects have now uncovered a few hundred genes involved in the onset of tumorigenesis, or drivers, in some two dozen malignancies. One of the main challenges emerging from this catalog of drivers is how to make sense of their heterogeneity in most cancer types. This is key not only to understand how carcinogenesis appears and develops in these malignancies to be able to early diagnose them, but also to open up the possibility to employ therapeutic strategies targeting a driver protein to counteract the alteration of another connected driver.MethodsHere, I focus on driver transcription factors and their connection to tumorigensis in several tumor types through the alteration of the expression of their targets. First, I explore their involvement in tumorigenesis as mutational drivers in 28 different tumor types. Then, I collect a list of downstream targets of the all driver transcription factors (TFs), and identify which of them exhibit a differential expression upon alterations of driver transcription factors.ResultsI identify the subset of targets of each TF most likely mediating the tumorigenic effect of their driver alterations in each tumor type, and explore their overlap. Furthermore, I am able to identify other driver genes that cause tumorigenesis through the alteration of very similar sets of targets.ConclusionsI thus uncover these circuits of connected drivers which cause tumorigenesis through the perturbation of overlapping cellular pathways in a pan-cancer manner across 15 malignancies. The systematic detection of these circuits may be key to propose novel therapeutic strategies indirectly targeting driver alterations in tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0260-1) contains supplementary material, which is available to authorized users.

Highlights

Large tumor genome sequencing projects have uncovered a few hundred genes involved in the onset of tumorigenesis, or drivers, in some two dozen malignancies
The repertoire of driver transcription factors across 28 tumor types We had previously carried out an exhaustive analysis of whole-exome mutations of 48 cohorts of tumors obtained from 28 different malignancies employing three computational methods that exploit complementary signals of positive selection and identified 459 mutational driver genes [10]
I started with this list of cancer driver genes obtained from the Integrative Oncogenomics (IntOGen) platform

Summary

Introduction

Large tumor genome sequencing projects have uncovered a few hundred genes involved in the onset of tumorigenesis, or drivers, in some two dozen malignancies. The catalog of driver genes involved in the development of several malignancies has grown in recent years, as a result of whole-exome and whole-genome analyses of cohorts of tumors, mainly within the framework of large international consortia [3, 4] This has opened up the possibility to carry out systematic studies to uncover the repertoire of functionally related groups of driver genes. While the most frequent drivers in these lists have been long known and studied in their involvement in tumorigenesis, many novel mid- and lowfrequent drivers have emerged whose roles in cancer need to be systematically clarified One step in this direction is to understand exactly which downstream genes and cellular processes become affected in the outcome of driver alterations. Uncovering the catalog of driver genes has revealed that at the level of genomic alterations, tumorigenesis possesses a very heterogeneous nature, with

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