Aberrant gene promoter methylation in acute promyelocytic leukaemia: profile and prognostic significance

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Abstract
Summary.Acute promyelocytic leukaemia (APL) has distinct clinicopathological and molecular features. However, the profile of aberrant gene promoter methylation is undefined. In this study, methylation‐specific polymerase chain reaction (MSP) was used to define the methylation status of a panel of nine genes, comprisingp15,p16,RARβ,oestrogen receptor(ER),E‐cadherin (E‐CAD),p73,caspase 8 (CASP8),VHLandMGMT, in 29 patients with APL. Aberrant methylation ofp15,ER,RARβ,p16andE‐CADoccurred, respectively, in 23 (79%), 14 (48%), six (21%), six (21%) and two (7%) patients at diagnosis, butp73,VHL,CASP8andMGMTwere not methylated in any patients. There was methylation of one gene in 13 patients (45%), two genes in four patients (14%), three genes in six patients (21%) and four genes in three patients (10%). Concurrent methylation of two or more genes occurred in 13 patients (45%). No association was identified between gene methylation and presenting clinicopathological features. However,p15methylation was significantly associated with an inferior disease‐free survival (DFS,P = 0·008), and remained the only poor prognostic factor in multivariate analysis (P = 0·019). In APL,p15,p16,ERandRARβwere most frequently methylated. This profile is distinct from other types of myeloid leukaemias.p15methylation has a poor prognostic impact on DFS.