Premium
Immunohistochemical loss of 5‐hydroxymethylcytosine expression in acute myeloid leukaemia: relationship to somatic gene mutations affecting epigenetic pathways
Author(s) -
Magotra Minoti,
Sakhdari Ali,
Lee Paul J,
Tomaszewicz Keith,
Dresser Karen,
Hutchinson Lloyd M,
Woda Bruce A,
Chen Benjamin J
Publication year - 2016
Publication title -
histopathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.626
H-Index - 124
eISSN - 1365-2559
pISSN - 0309-0167
DOI - 10.1111/his.13046
Subject(s) - 5 hydroxymethylcytosine , epigenetics , somatic cell , biology , gene expression , immunohistochemistry , epigenesis , gene , cancer research , regulation of gene expression , myeloid leukaemia , myeloid , dna methylation , genetics , immunology
Aims Genes affecting epigenetic pathways are frequently mutated in myeloid malignancies, including acute myeloid leukaemia ( AML ). The genes encoding TET 2 , IDH 1 and IDH 2 are among the most commonly mutated genes, and cause defective conversion of 5‐methylcytosine into 5‐hydroxymethylcytosine (5hmC), impairing demethylation of DNA , and presumably serving as driver mutations in leukaemogenesis. The aim of this study was to correlate 5hmC immunohistochemical loss with the mutation status of genes involved in epigenetic pathways in AML . Methods and results Immunohistochemical staining with an anti‐5hmC antibody was performed on 41 decalcified, formalin‐fixed paraffin‐embedded ( FFPE ) bone marrow biopsies from patients with AML . Archived DNA was subjected to next‐generation sequencing for analysis of a panel of genes, including TET 2 , IDH 1 , IDH 2 , WT 1 and DNMT 3A . TET 2 , IDH 1 , IDH 2 , WT 1 and DNMT 3A mutations were found in 46% (19/41) of the cases. Ten of 15 cases (67%) with TET 2 , IDH 1 , IDH 2 or WT 1 mutations showed deficient 5hmC staining, whereas nine of 26 cases (35%) without a mutation in these genes showed loss of 5hmC. It is of note that all four cases with TET 2 mutations showed deficient 5hmC staining. Conclusions Overall, somatic mutations in TET 2 , IDH 1 , IDH 2 , WT 1 and DNMT 3A were common in our cohort of AML cases. Immunohistochemical staining for 5hmC was lost in the majority of cases harbouring mutations in these genes, reflecting the proposed relationship between dysfunctional epigenetic pathways and leukaemogenesis.