Abstract
One of the key challenges of cancer biology is to catalogue and understand the somatic genomic alterations leading to cancer. Although alternative definitions and search methods have been developed to identify cancer driver genes and mutations, analyses of thousands of cancer genomes return a remarkably similar catalogue of around 300 genes that are mutated in at least one cancer type. Yet, many features of these genes and their role in cancer remain unclear, first and foremost when a somatic mutation is truly oncogenic. In this review, we first summarize some of the recent efforts in completing the catalogue of cancer driver genes. Then, we give an overview of different aspects that influence the oncogenicity of somatic mutations in the core cancer driver genes, including their interactions with the germline genome, other cancer driver mutations, the immune system, or their potential role in healthy tissues. In the coming years, this research holds promise to illuminate how, when, and why cancer driver genes and mutations are really drivers, and thereby move personalized cancer medicine and targeted therapies forward.
Highlights
Understanding oncogenicity of cancer driver genes and mutations in the cancer genomics era Eduard Porta-Pardo1,2, Alfonso Valencia1,3 and Adam Godzik4
Out of the 299 cancer driver genes recently described in the Pan-Cancer Atlas analysis of The Cancer Genome Atlas [2] (TCGA), only TP53 has a median somatic mutation frequency over 10% across all cancer types (35%) and only ten other genes have a median frequency above 1% (ARID1A, ATM, BRAF, KMT2C, KRAS, NF1, PIK3CA, PTEN, RB1, and SMARCA4)
As we near the end of the beginning of cancer genomics, new questions emerge around the role of cancer driver genes and their associated somatic mutations
Summary
Understanding oncogenicity of cancer driver genes and mutations in the cancer genomics era Eduard Porta-Pardo, Alfonso Valencia and Adam Godzik. Alternative definitions and search methods have been developed to identify cancer driver genes and mutations, analyses of thousands of cancer genomes return a remarkably similar catalogue of around 300 genes that are mutated in at least one cancer type. Dozens of computational biology and bioinformatics groups started developing tools to analyze these large datasets and distinguish the genes that contribute to tumor progression from those that are instead neutral. Genes in this first category are called driver genes, those in the latter are named passengers and the same nomenclature can be used for both individual mutations and other genetic events.
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