The average methylation levels detected at all enhancer loci were significantly higher in the recurrent tumours compared with the matched primary (n/RFS) tumours (DAXX, P<0.0001; ESR1, P<0.0005; RXRA, P<0.005; GET4, NCOR2, GATA3, MSI2, P<0.01; C8orf46, ITPK1, P<0.05; t-test), confirming that DNA methylation at ESR1-responsive enhancers is acquired in resistant disease (Fig. 4 and Supplementary Fig. 3). This evidence concerns the gene ESR1 and neoplasm.