The identification of genes responsible for oncogenesis is a major goal in cancer research. These genes are mostly defined as “altered genes directly promoting malignant progression”. After three decades of molecular cancer research, different strategies have been used to define the cancer genetic landscape. The catalogue of somatic mutations in cancer (COSMIC) (
http://cancer.sanger.ac.uk) is a comprehensive resource of somatic mutations in human cancer samples curated from published studies and cancer genomes sequencing [
1]. As of May 31, 2015, COSMIC reports a set of 572 genes, called the cancer gene census, for which mutations are associated with cancer development. In cancer samples, it is challenging to analyze and prioritize sequential mutation accumulation events, which occur in oncogenes and tumor suppressors genes. The mutations that provide a selective growth advantage in any step of tumorigenesis (initiation, clonal expansion, tumor formation) are known as driver mutations. Out of 572 cancer gene census, about 140 genes including 71 tumor suppressors and 54 oncogenes are well-accepted as cancer driver genes because mutations in those genes promote tumorigenesis [
2]. These numbers are not static and should increase as more cancer genomes are sequenced. Other approaches are being used to identify novel candidate cancer genes including Genome Wide Association Studies (GWAS) for the identification of cancer-associated loci [
3], in vivo transposon mutagenesis screens in mice “sleeping beauty technology”, for genes potentially implicated in tumorigenesis [
4‐
6], and protein-protein interactions screens of gene products targeted by oncogenic viruses [
7‐
9]. Integrating information from all the above resources in a “guilt-by-association” model that also considers interacting partners of cancer-associated gene products allowed prioritization of ~ 3000 genes potentially associated with cancer [
10]. However, analyzing variations of mutations in time and space in different cancer types and subtypes (e.g., what driver genes are important for what cancer type at what stage) has been challenging. Few studies led to the discovery of a number of genes implicated in specific tumor types. As an example, children medulloblastoma tumor samples exhibit an average of 11 gene alterations compared to 55–121 in adult tumors [
11], whilst lung and colorectal cancers require only 3 driver gene mutations [
12]. In liquid tumors such as leukemia and lymphomas, it believed that, one of the most prevalent category of mutations involving cancer driver genes are chromosomal rearrangements such as BCR-ABL1 in chronic mylogenous leukemia (CML) [
13], fusions involving nucleopins 98 and 124 and MLL gene fusions in acute myelogenous leukemia (AML) [
2,
14,
15], and TEL-AML1 and TCF3-PBX1 in acute lymphoblastic leukemia (ALL) [
16‐
18]. These gene fusions alone are often insufficient and may require additional genetic perturbations for leukemogenesis [
19,
20].