[1441] Prevalence and Prognostic Implications of CEBP Mutations in Pediatric AML. Session Type: Poster Session, Board #595-I

Phoenix A. Ho, Todd A. Alonzo, Robert B. Gerbing, Jessica Pollard, Derek L. Stirewalt, Nyla A. Heerema, Beverly Lange, Jerald Radich, Soheil Meshinchi Fred Hutchinson Cancer Research Center, Seattle, WA, USA; University of Washington, Seattle, WA, USA; University of Southern California, Los Angeles, CA, USA; Childrens Oncology Group, Arcadia, CA, USA; Ohio State University, Columbus, OH, USA; Childrens Hospital of Philadelphia, Philadelphia, PA, USA

CCAAT/enhancer binding protein- (C/EBP) is a transcription factor that regulates granulocytic differentiation. Molecular alterations of the CEBP gene which alter its function have been identified in AML; their presence may have prognostic implications in AML. We evaluated the prevalence and prognostic significance of CEBP mutations in a cohort of 428 pediatric AML patients treated on pediatric AML trials CCG-2941 and CCG-2961. Initial screening of 100 samples by direct sequencing of the entire coding region of the CEBP gene identified mutations in 8/100 (8%) of the patients tested. All 8 mutations were insertional or deletional mutations. A multiplex micro-capillary electrophoresis was devised to facilitate further screening of an additional 328 samples. Of the 428 samples analyzed, 65 mutations were identified in 57 patients (13%). 16/65 mutations (25%) were insertions or deletions in the N-terminal region, 14 of which would cause a frameshift resulting in a premature stop codon. 32/65 (49%) mutations involved the second transactivation domain (TAD2); except for one case, all were 6 bp insertions, and except for one case, all occurred at the same location. 17/65 (26%) mutations were in-frame insertions (N=16) or deletions (N=1) in the basic region leucine zipper (bZip) domain. This resulted in the insertion of one to twelve amino acids, or the deletion of six amino acids, which would be expected to disrupt the leucine zipper. 6/57 (11%) patients with mutations harbored more than one distinct mutation; all such instances of combined mutations included at least one mutation in the N-terminal region coupled with at least one mutation in the bZip domain. Presence of mutations was correlated with laboratory and clinical characteristics and clinical outcome. There were no differences in median age, sex, race, median diagnostic blast % or median diagnostic WBC between those with and without CEBP mutations, although such mutations were less common in the younger patients between ages of 0-2 years (p=0.02). CEBP mutations were more common in those with normal karyotype (38% vs. 21%, p=0.03) and less common in those with 11q23 abnormalities (8% vs. 26%, p=0.01). Of the 57 patients with CEBP mutations, 15% and 10% had t(8;21) and inv(16), respectively, no different than those without mutations. Four of the 57 patients with CEBP mutations had FLT3/ITD (7%) compared to 41/363 (11%) of the CEBP-WT patients (p=0.46). Response to induction therapy was similar for those with and without mutations (91% vs. 86%, p=0.43). Actuarial overall survival (OS) from study entry was 63% for those with and 52% for those without CEBP mutations (P=0.12). Of those who achieved an initial remission, cumulative incidence of relapse from remission was 25% vs. 39% for those with and without CEBP mutations (p=0.069) with a corresponding OS at 5 years from remission of 67% vs. 58%, (p=0.27). CEBP mutations are frequent events in pediatric AML and are highly associated with normal karyotype. Analysis of a larger cohort of patients may determine whether those with CEBP mutations have a lower relapse rate and improved survival.
Abstract #1441 appears in Blood, Volume 110, issue 11, November 16, 2007
Keywords: CCAAT/Enhancer Binding Protein alpha (C/EBPa)|Molecular Markers|Mutation Analysis
Disclosure: No relevant conflicts of interest to declare.

Saturday, December 8, 2007 5:30 PM

Session Info:  Poster Session: Molecular and Cytogenetic Markers and MRD in Pediatric AML and ALL (5:30 p.m.-7:30 p.m.)