Dear Editor,

Exome sequencing of sporadic pancreatic neuroendocrine tumours (PNETs) has identified mutually exclusive mutations in the chromatin regulators α-thalassaemia/mental retardation X-linked (ATRX) and death-associated protein 6 (DAXX) genes in 43% of cases (18 and 23% of cases respectively in 68 cases studied) (Elsässer et al. 2011, Jiao et al. 2011). ATRX and DAXX are chromatin remodellers; their loss leads to alternative lengthening of telomeres (ALT) and chromosomal instability (CIN) (Heaphy et al. 2011). ALT is a telomerase-independent mechanism for the maintenance of telomere stabilisation. Although it was initially reported that ATRX/DAXX mutant tumours had superior 10-year survival and outcome (Jiao et al. 2011), a recent larger study on 243 tumours demonstrated that ATRX and DAXX loss and associated ALT in PNETs correlates with CIN, advanced tumour stage, the development of metastases and poorer progression-free survival (PFS) and overall survival (OS) (Marinoni et al. 2014).

ATRX interacts with DNA methyltransferases 3A and 3L (DNMT3A/3L), known as ATRX-DNMT3A-DNMT3L (ADD) (Hashimoto et al. 2010). DNMT3A and its accessory protein, DNMT3L, contain a histone H3 lysine 4 (H3K4) methyl-interacting ADD domain which links DNA methylation with unmodified H3K4. This interaction is one of the three described protein domains that provide a functional link between DNA methylation and histone modification. These interactions are pivotal for maintaining accurate replication of histone methylation patterns in newly replicated chromatin and in the subsequent fidelity of gene expression. ATRX interacts directly with DAXX, which functions as a chaperone for the deposition of the histone variant H3.3 at repeat sequences across the genome, including CpG islands and telomeric, pericentric and ribosomal repeats (Clynes et al. 2013). DAXX is a highly specific histone chaperone that discriminates H3.3 from other H3 variants. Mutually exclusive mutations in ATRX and DAXX are also found in neurological …