XXXX / @entity5316 -positive relapses evolve from an ancestral clone and frequently acquire deletions of genes implicated in glucocorticoid signaling.

@entity1 @entity981 @entity4738 @entity9604 @entity58800 @entity1778 @entity5316
Approximately 25% of childhood @entity981 carry the @entity9604 / @entity5316 fusion gene. Despite their excellent initial treatment response, up to 20% of @entity1 relapse. To gain insight into the relapse mechanisms, we analyzed single nucleotide polymorphism arrays for DNA copy number aberrations (CNAs) in 18 matched diagnosis and @entity1778 . CNAs were more abundant at relapse than at diagnosis (mean 12.5 vs 7.5 per case; P=.01) with 5.3 shared on average. Their patterns revealed a direct clonal relationship with exclusively new aberrations at relapse in only 21.4%, whereas 78.6% shared a common ancestor and subsequently acquired distinct CNA. Moreover, we identified recurrent, mainly nonoverlapping deletions associated with glucocorticoid-mediated apoptosis targeting the @entity58800 ( @entity58800 ) (n=3), glucocorticoid receptor @entity4738 (n=4), and components of the mismatch repair pathways (n=3). Fluorescence in situ hybridization screening of additional 24 relapsed and 72 nonrelapsed @entity9604 / @entity5316 -positive cases demonstrated that @entity58800 deletions were significantly more common in relapse cases (16.6% vs 2.8%; P=.02). Unlike @entity58800 deletions, which were always already present at diagnosis, @entity4738 and mismatch repair aberrations prevailed at relapse. They were all associated with @entity1778 , which poorly responded to treatment. These findings implicate glucocorticoid-associated drug resistance in @entity9604 / @entity5316 -positive relapse pathogenesis and therefore might help to guide future therapies.
