Abstract
As the genomic profile across cancers varies from person to person, patient prognosis and treatment may differ based on the mutational signature of each tumour. Thus, it is critical to understand genomic drivers of cancer and identify potential mutational commonalities across tumors originating at diverse anatomical sites. Large-scale cancer genomics initiatives, such as TCGA, ICGC and GENIE have enabled the analysis of thousands of tumour genomes. Our goal was to identify new cancer-causing mutations that may be common across tumour sites using mutational and gene expression profiles. Genomic and transcriptomic data from breast, ovarian, and prostate cancers were aggregated and analysed using differential gene expression methods to identify the effect of specific mutations on the expression of multiple genes. Mutated genes associated with the most differentially expressed genes were considered to be novel candidates for driver mutations, and were validated through literature mining, pathway analysis and clinical data investigation. Our driver selection method successfully identified 116 probable novel cancer-causing genes, with 4 discovered in patients having no alterations in any known driver genes: MXRA5, OBSCN, RYR1, and TG. The candidate genes previously not officially classified as cancer-causing showed enrichment in cancer pathways and in cancer diseases. They also matched expectations pertaining to properties of cancer genes, for instance, showing larger gene and protein lengths, and having mutation patterns suggesting oncogenic or tumor suppressor properties. Our approach allows for the identification of novel putative driver genes that are common across cancer sites using an unbiased approach without any a priori knowledge on pathways or gene interactions and is therefore an agnostic approach to the identification of putative common driver genes acting at multiple cancer sites.
Highlights
Cancer arises from genomic alterations that give cells a selective advantage for abnormal growth
1537 genes were selected as candidate cancer-drivers from the initial 3700 pre-selected mutated genes (Figs 1C and 2). This list consisted of 353 genes already reported in the Catalogue of Somatic Mutations in Cancer (COSMIC), with some already known to be drivers in breast, ovarian and/or prostate cancers (S1 Table–annotation table of the 1537 genes), showing the ability of our pipeline to pick up known drivers
Almost 90 of the non-COSMIC genes that we identified as potential candidate cancer genes belong to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways linked with cancer biology, despite not being previously catalogued as COSMIC genes (Fig 3A and S1 Table)
Summary
Cancer arises from genomic alterations that give cells a selective advantage for abnormal growth. Driver gene discovery from mutation and gene expression data (ref: RA004) awarded to HT, SB, ZMD, and AG, and the National Cancer Institute (NIH) grants awarded to TR (P20CA233255)and KK (K99CA245900). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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