MYC Deregulation in Primary Human Cancers

Abstract

MYC regulates a complex biological program by transcriptionally activating and repressing its numerous target genes. As such, MYC is a master regulator of many processes, including cell cycle entry, ribosome biogenesis, and metabolism. In cancer, the activity of the MYC transcriptional network is frequently deregulated, contributing to the initiation and maintenance of disease. Deregulation often leads to constitutive overexpression of MYC, which can be achieved through gross genetic abnormalities, including copy number alterations, chromosomal translocations, increased enhancer activity, or through aberrant signal transduction leading to increased MYC transcription or increased MYC mRNA and protein stability. Herein, we summarize the frequency and modes of MYC deregulation and describe both well-established and more recent findings in a variety of cancer types. Notably, these studies have highlighted that with an increased appreciation for the basic mechanisms deregulating MYC in cancer, new therapeutic vulnerabilities can be discovered and potentially exploited for the inhibition of this potent oncogene in cancer.

Keywords: MYC; cancer; cell signaling; deregulation; enhancers; gene amplification; translocation.

Figure 1

MYC, MYCN, MYCL amplifications in cancer. (a) A heatmap depicting the frequency of copy number alterations (CNAs) in MYC, MYCN, and MYCL loci across multiple cancers grouped based on tissue of origin (data mined from cbioportal.org [34,35]). The source of the genomic data is indicated in parentheses. (b) MYC amplification identified in four molecular subtypes of breast cancer [30]. (c) Long-term survival analysis of 2051 breast cancer patients (over 30 years) with MYC-amplified and non-MYC-amplified cancers (data accessed through cbioportal.org and METABRIC [29]). (d) Amplification of MYC, MYCN, and MYCL identified in two molecular subtypes of prostate cancer, castration-resistant prostate cancer (CRPC) adenocarcinoma and neuroendocrine-CRPC [36]. (e) Amplification of MYC, MYCN, and MYCL identified in four molecular subtypes of medulloblastoma [37]. (f) Correlation of MYC mRNA expression with the type of copy number alteration CNA (deletion, ploidy, gain, or amplification) in breast cancer (left, METABRIC) and prostate cancer [38] (right).

Figure 2

Enhancer alterations deregulating MYC transcription. (a) In B-cells, the immunoglobulin (Ig) gene locus (left) is controlled by an upstream enhancer that ensures constitutive high expression levels of antibodies. In Burkitt Lymphoma, the Ig and MYC loci translocate rendering MYC under the influence of a highly active enhancer (right). Translocation can be visualized on a chromosomal level when comparing the length of sister chromatids in anaphase spread assays. (b) Deregulation of MYC by regulatory elements at the MYC locus. Lineage-specific super-enhancers have been mapped to the gene desert area surround MYC at the 8q24.21 locus, as indicated by colored cartoon peaks representing H3K27 acetylation. Two single nucleotide polymorphisms (SNPs) have been linked to altered MYC transcription: rs6983267, located 335 kb upstream of the MYC locus, and rs55705857, located within an enhancer 1.7 Mb downstream of MYC.

Figure 3

Tabulated summary of genomic alterations (copy number alterations and mutations) in genes known to influence the expression of the MYC gene or regulate the MYC protein in 32 cancer types profiled by the TCGA. The data was collected from the TCGA provisional datasets indicated using cBioPortal [34,35]. The “aggregate” column refers to the percentage of tumors of a specific cancer-type that contain genomic alterations in at least one of the genes present in the table.

Figure 4

Signaling pathways regulating MYC transcription and MYC protein stability in cancer. (a) MYC protein stability can be altered through the RAS/PI3K signaling pathways. (b–e) MYC transcription is deregulated by multiple signaling pathways in many cancer types. Specific signaling pathways are highlighted to demonstrate transcriptional deregulation of the MYC gene in the context of (b) chronic myeloid leukemia (CML) (c) breast cancer, (d) colorectal cancer, and (e) T-cell acute lymphoblastic leukemia (T-ALL). Proteins deregulating MYC are highlighted, with red-colored proteins indicating oncogenic alterations (mutation or copy number alteration in greater than 10% of any TCGA cancer dataset) and tumor suppressors shown in blue (mutations and deletions; greater than 10% of any TCGA cancer dataset). Signaling receptors are black and all other proteins are colored grey. RSBE (repressive SMAD binding element), ERE (estrogen response element), WRE (WNT response element), P (Promoter).