Abstract
Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role astumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN.
Highlights
The MYC gene was initially discovered as an oncogene (v-MYC) acquired from the host cell genome by a subgroup of avian leukemia viruses
The cellular MYC gene and its paralogs (MYCN and MYCL) were found to be subject to genetic alterations, such as amplification, chromosomal translocation, and viral integration, in a broad spectrum of cancers leading to tumorigenesis
Pan-cancer Analysis of Copy-Number Alterations MYC oncoproteins in solid tumors are mainly activated by copy gains, and it is well established that even small changes in MYC levels can drive ectopic proliferation of somatic cells and oncogenesis (Bazarov et al, 2001; Hofmann et al, 2015; Murphy et al, 2008)
Summary
The MYC gene was initially discovered as an oncogene (v-MYC) acquired from the host cell genome by a subgroup of avian leukemia viruses. Many of the genetic alterations that occur in tumors act to uncouple MYC expression from its normal regulatory constraints, thereby resulting in high levels of MYC protein that are less sensitive to normal cellular and extracellular signals (for reviews see Dang and Eisenman, 2014). Such alterations include (1) point mutations in the MYC coding region that appear to increase MYC protein stability and activity as secondary events to translocations in lymphoma (Bahram et al, 2000; Hemann et al, 2005); (2) mutation or rare amplification of distal enhancers (Sur et al, 2012; Zhang et al, 2016); and (3) activating mutations in signal transduction pathways (e.g., Wnt, Notch) that augment MYC expression (Herranz et al, 2014; Muncan et al, 2006; Weng et al, 2006). Experiments in a number of tumor lines and in animal models of cancer indicated that, in many cases, MYC expression is required for tumor initiation, progression, or maintenance
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