MYC

Overview

First described 1983. Earliest sequence paper UniProt cites for the protein: Battey et al, Cell, 1983, "The human c-myc oncogene: structural consequences of translocation into the IgH locus in Burkitt lymphoma". Source.

Sources: HGNC HGNC:7553 (approved symbol, name, aliases, locus and cross-references (hgnc_complete_set.txt)); UniProt P01106 (protein name, function text, keywords and locations (REST API)); CIViC gene MYC (12 evidence items, 0 assertions, 4 variants; diseases: Lung Adenocarcinoma, Diffuse Large B-cell Lymphoma, Multiple Myeloma, Oesophageal Carcinoma, Oesophagus Squamous Cell Carcinoma and 5 more (GraphQL API, CC0)); Open Targets ENSG00000136997 (association with cancer (MONDO_0004992) 0.74; per-cancer scores at or above 0.5: prostate cancer 0.55, urinary bladder cancer 0.59, acute lymphoblastic leukaemia 0.53, diffuse large B-cell lymphoma 0.59, non-Hodgkin lymphoma 0.77, skin cancer 0.60 (GraphQL API, CC0)); IntOGen MYC (driver in 4 cohorts (Act 2, LoF 2); Compendium_Cancer_Genes.tsv release 20240920, CC0 1.0)

• Written by scripts/fetch-cancer-genes.ts from CIViC, Open Targets, IntOGen, HGNC and UniProt; the function text is UniProt's, condensed and in UK spelling. Roles: CIViC lists 9 therapies; IntOGen calls it an activating (Act) driver in 2 cohorts; IntOGen calls it a loss-of-function (LoF) driver in 2 cohorts; CIViC holds 12 clinical evidence items on its variants; UniProt disease notes describe a translocation or gene fusion involving the gene. Evidence tier "clinical-evidence" is the strongest of those signals.
• Prevalence not recorded: none of the sources gives a positivity rate.
• Diseases the sources name that have no OnCo cancer page yet, so they are not linked: High-grade B-cell Lymphoma, With MYC And BCL2 Rearrangements.
• Pancreatic ductal adenocarcinoma: amplified in 4 to 13% depending on platform (12.6% of 183 TCGA and 11.9% of 109 UTSW samples by array or exome, 4.2% on the MSK panel; cBioPortal). MYC amplification was uniquely associated with poor outcome and adenosquamous histology among 109 microdissected cancers (Witkiewicz 2015), varies between cells within squamous-feature tumours (Hayashi 2020) and lies downstream of the super-enhancers released by KDM6A loss (Andricovich 2018).
• Colorectal cancer: high-level amplification in 4 to 5% (cBioPortal), but the TCGA integrative reading is that MYC-directed transcriptional activation and repression is the common output of APC loss whether or not the gene is amplified, which is why MYC matters in a disease where it is rarely amplified (Cancer Genome Atlas Network 2012).
• Lung cancer: high-level amplification in about 7 to 8% of non-small-cell tumours (cBioPortal). In small-cell disease the three MYC paralogues are amplified in a mutually exclusive pattern and track the transcriptional state, MYCL with the ASCL1 subtype and MYC with the NEUROD1 subtype and the shift towards a less neuroendocrine phenotype (Rudin 2019).
• Lymphoma, MYC, and the double-hit and triple-hit definitions: MYC was mapped to 8q24, the region translocated to chromosome 2, 14 or 22 in Burkitt lymphoma cells, in 1982 (Dalla-Favera 1982); the partner is always an immunoglobulin locus, so the transcription factor is driven by the enhancer that should be driving antibody production. A double hit is a MYC rearrangement together with a BCL2 rearrangement, a triple hit adds BCL6. The two lesions are complementary rather than additive: MYC drives proliferation and would normally trigger apoptosis, and BCL2 removes that safeguard. Frequency: MYC rearrangement in 8.8% of 442 diffuse large B-cell lymphomas, BCL2 in 13.5% and BCL6 in 28.7% (Horn 2013). Protein overexpression is much commoner than rearrangement: MYC protein above the 40% threshold in 31.8% of the same cohort (Horn 2013), and in a separate 167-patient training cohort MYC protein in 29%, BCL2 protein in 44% and both together in 21%, against MYC translocation in only 11% (Johnson 2012). What it changes about treatment: The WHO fifth edition separates high-grade B-cell lymphoma with MYC and BCL2 rearrangements as its own entity (Alaggio 2022), and in practice a double hit moves most patients off R-CHOP onto a more intensive regimen, although the randomised evidence for doing so is thin. Double expression of the two proteins without rearrangement is prognostic, not a separate entity, and does not by itself change the regimen: in the trial cohort MYC protein predicted worse survival only when BCL2 protein was present too (Johnson 2012).
• Lymphoma, TP53 loss, in mantle cell lymphoma and in Richter transformation: TP53 is the commonest route by which a lymphoma stops responding to chemotherapy, because chemotherapy kills largely by provoking a p53-dependent death. In mantle cell lymphoma it travels with blastoid morphology, a high Ki-67 and CDKN2A deletion. In Richter transformation it is one of two lesions that dominate the genetics, and the transformed clone is usually the same clone as the leukaemia rather than a second cancer. Frequency: In 183 younger mantle cell lymphoma patients from the Nordic MCL2 and MCL3 trials, TP53 mutation in 11% and TP53 deletion in 16%, with CDKN2A deletion in 20% and NOTCH1 mutation in 4%; only TP53 mutation kept its prognostic weight in multivariable analysis, with a hazard ratio of 6.2 for overall survival, a median overall survival of 1.8 years against 12.7 years for unmutated cases, and half the mutated group relapsing within a year (Eskelund 2017). In 86 cases of Richter syndrome, TP53 disruption in 47.1% and MYC abnormality in 26.2%; clonally unrelated transformations had both a longer median survival, 62.5 against 14.2 months, and less TP53 disruption, 23.1% against 60.0% (Rossi 2011). What it changes about treatment: In mantle cell lymphoma, yes in practice if not yet on any label: a TP53 mutation is the usual reason to abandon intensive cytarabine-based induction and autologous transplant and to go to a BTK inhibitor, a BCL-2 inhibitor or CAR-T instead. In Richter transformation it is the main prognostic variable, and establishing whether the large-cell clone is related to the leukaemic one changes the expected outcome more than any drug does.
• Lymphoma, Epstein-Barr virus and its latency programmes: Epstein-Barr virus persists for life in the memory B-cell pool of almost everyone, and what it expresses while it is there decides what it can cause. In latency I only EBNA1 is made, which is enough to keep the episome but gives the immune system almost nothing to see; this is the Burkitt pattern, where the virus coexists with a MYC translocation. In latency II, EBNA1 with LMP1 and LMP2, LMP1 mimics a permanently engaged CD40 receptor and drives NF-kB; this is the Hodgkin and NK/T-cell pattern. In latency III the full set of nuclear antigens and membrane proteins is expressed and will immortalise a resting B cell outright, which is what happens when T-cell surveillance is removed, as in post-transplant lymphoproliferative disorder and HIV-associated lymphoma. The virus was found in the first place by electron microscopy of cells cultured from Burkitt lymphoma, whose geographic distribution matching holoendemic malaria had suggested a viral cause (Young and Rickinson 2004). Frequency: The share of each disease that is EBV-positive varies by subtype, by geography and by age, and this layer does not state a single figure because the published ranges are wide and cohort-dependent. What is consistent is the direction: the proportion rises with immunosuppression and with age, and endemic Burkitt lymphoma in equatorial Africa is almost uniformly positive while sporadic Burkitt lymphoma usually is not. What it changes about treatment: Reducing immunosuppression is the first treatment of post-transplant lymphoproliferative disorder, which is the only place where acting on the virus changes the plan. Plasma EBV DNA is used to monitor response in NK/T-cell lymphoma and in post-transplant disease. EBV-specific T cells are licensed for post-transplant disease after transplant failure.
• Lymphoma, TCF3, ID3 and CCND3 in Burkitt lymphoma: A MYC translocation alone does not make a Burkitt lymphoma; it needs a partner that supplies survival. In Burkitt the partner is tonic B-cell receptor signalling through TCF3, the transcription factor also known as E2A: mutations either activate TCF3 or inactivate its negative regulator ID3, and TCF3 then switches on the PI3K pathway partly by augmenting tonic receptor signalling. A second, independent lesion drives the cell cycle directly, through CCND3 mutations that produce unusually stable cyclin D3. Frequency: TCF3 or ID3 mutation in 70% of sporadic Burkitt lymphoma cases and oncogenic CCND3 mutations in 38%, in a study combining high-throughput RNA sequencing with RNA interference screening (Schmitz 2012). What it changes about treatment: Not yet, and the gap is uncomfortable, because the regimens that cure Burkitt lymphoma are the most toxic in lymphoma and are the reason the disease is hard to treat in older patients and in low-resource settings, which is exactly where the endemic form occurs.