Acute Myeloid Leukemia (AML) via the CEBPA Gene

Acute Myeloid Leukemia (AML) comprises a phenotypically and genetically heterogeneous group of neoplastic disorders characterized by the accumulation of myeloid precursor cells in the bone marrow and blood. The malignant precursor cells display increased proliferation and a block in normal differentiation and maturation. Accumulating malignant cells replace normal bone marrow and interfere with normal blood cell production causing a decrease in red blood cells and platelets. Symptoms include easy bruising and bleeding, fatigue, and increased risk of infection due to a lack of normal white blood cells. Pathogenic variants have been identified in several genes in AML patients. Approximately 13,000 cases of AML per year are diagnosed in the United States, and according to the results of several studies, CEBPA variants have been identified in 15-18% of cytogenetically normal AML cases (Leroy et al. Leukemia 19(3):329-334, 2005; Frohling et al. J Clin Oncol 22(4):624-633, 2004). CEBPA variants are found in cases of both familial AML and sporadic AML, though instances of the former are rare. The age of onset of AML resulting from CEBPA mutations varies, but is generally earlier in cases of familial AML (early childhood to adult onset) than in cases of sporadic AML (onset around fifth or sixth decade) (Klein and Marcucci. GeneReviews, 2010). Studies so far have indicated that the prognosis of patients with CEBPA-related AML is favorable (Preudhomme et al. Blood 100(8):2717-2723, 2002; Frohling et al., 2004; Bienz et al. Clin Cancer Res 11(4):1416-1624, 2005) thereby highlighting the importance of cytogenetic and molecular testing for AML patients.

CEBPA gene mutations are identified in 15-18% of cytogenetically normal AML cases (Leroy et al., 2005; Frohling et al., 2004). Only a few cases of familial AML have been reported (Smith et al. N Engl J Med 351(23):2403-2407, 2004; Renneville et al. Leukemia 23(4):804-806, 2009), and pathogenic variants in CEBPA displayed a dominant mode of inheritance with high penetrance. CEBPA encodes the transcription factor and tumor suppressor CCAATT enhancer binding protein alpha (C/EBPα) which is upregulated during granulocyte differentiation (Scott et al. Blood 80(7):1725-1735, 1992; Radomska et al. Mol Cell Biol 18(7):4301-4314, 1998). The CEBPA protein consists of two N-terminal transactivation domains and C-terminal leucine zipper and basic domains mediating homo- and hetero-dimerization and DNA-binding. Mutations in CEBPA typically involve either N-terminal frameshifts that result in truncated protein or C-terminal in-frame insertions or deletions that affect the DNA binding domain (Pabst et al. Nat Genet 27(3):263-270, 2001). No obvious genotype-phenotype correlations have been identified.

CEBPA mutations are found in approximately 9% of AML cases and in 15-18% of normal karyotype AML (Klein and Marcucci. Gene Reviews 2010; Leroy et al. Leukemia 19(3):329-334, 2005; Frohling et al. J Clin Oncol 22(4):624-633, 2004).

To date, no gross deletions or duplications have been reported in CEBPA (Human Gene Mutation Database).

This test involves bidirectional Sanger sequencing of all coding exons and splice sites of the CEBPA gene. The full coding sequence of each exon plus ~10 bp of flanking DNA on either side are sequenced. We will also sequence any single exon (Test #100) in family members of patients with a known pathogenic variant or to confirm research results.

NOTE: Mutations identified in blood specimens during active AML cannot be categorized as acquired or familial without additional information such as a family history and pedigree, and/or results from testing a non-involved specimen such as skin fibroblasts. Also, in cases of sporadic AML resulting from CEBPA variants, low levels of leukemic cells in bone marrow or blood specimens for example, may not produce a signal that exceeds our limits of detection; negative results from testing should be interpreted in the context of this caveat.