EP300

Overview

First described 1994. Earliest sequence paper UniProt cites for the protein: Eckner et al, Genes Dev, 1994, "Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor". Source.

Sources: HGNC HGNC:3373 (approved symbol, name, aliases, locus and cross-references (hgnc_complete_set.txt)); UniProt Q09472 (protein name, function text, keywords and locations (REST API)); CIViC gene EP300 (2 evidence items, 0 assertions, 2 variants; diseases: Diffuse Large B-cell Lymphoma, Oesophagus Squamous Cell Carcinoma (GraphQL API, CC0)); Open Targets ENSG00000100393 (association with cancer (MONDO_0004992) 0.87; per-cancer scores at or above 0.5: colorectal cancer 0.74, oesophageal cancer 0.54, urinary bladder cancer 0.65, cervical cancer 0.60, melanoma 0.60, head and neck squamous cell carcinoma 0.62 (GraphQL API, CC0)); IntOGen EP300 (driver in 30 cohorts (Act 10, LoF 20); 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: IntOGen calls it an activating (Act) driver in 10 cohorts; IntOGen calls it a loss-of-function (LoF) driver in 20 cohorts; CIViC holds 2 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.
• Lymphoma, BCL6 and the germinal-centre programme: BCL6 is the master transcriptional repressor of the germinal centre: it switches off the DNA-damage response and the differentiation programme so that a B cell can tolerate deliberate mutation of its own immunoglobulin genes. A lymphoma that keeps BCL6 on keeps a cell in a state where mutation is permitted and apoptosis is suppressed. The protein is normally switched off by acetylation, which is one reason CREBBP and EP300 loss matters here. Frequency: BCL6 rearrangement in 28.7% of 442 diffuse large B-cell lymphomas, the commonest of the three translocations (Horn 2013); BCL6 fusions with NOTCH2 mutations define the BN2 subtype (Schmitz 2018). What it changes about treatment: Nothing yet. There is no approved BCL6 inhibitor or degrader, and the group's prognosis in the genetic classification is comparatively favourable, which is a reason to study de-escalation rather than a reason to change treatment now.
• Lymphoma, CREBBP, EP300 and the rest of the chromatin machinery: CREBBP and EP300 are acetyltransferases. Losing one allele lowers the dose of acetylation, which leaves BCL6 acetylated less often and therefore active more often, and leaves p53 acetylated less often and therefore working less well; the same lesion also turns down the enhancers that would let a germinal-centre cell present antigen to T cells. KMT2D, formerly MLL2, writes H3K4 monomethylation at enhancers and is the single most frequently mutated gene in follicular lymphoma. Frequency: Genomic deletion or somatic mutation removing or inactivating the acetyltransferase domain of CREBBP or, more rarely, EP300 in about 39% of diffuse large B-cell lymphoma and 41% of follicular lymphoma, usually on one allele only (Pasqualucci 2011). KMT2D mutated in 32% of diffuse large B-cell lymphoma and 89% of follicular lymphoma in the discovery series, with MEF2B in 11.4% and 13.4% (Morin 2011); the coding genome of diffuse large B-cell lymphoma carries more than 30 clonally represented alterations per case (Pasqualucci 2011, Nat Genet). What it changes about treatment: Not yet. The pairing of CREBBP loss with HDAC3 dependency is the clearest synthetic-lethal hypothesis in B-cell lymphoma and is in trials; no approval depends on a CREBBP result.