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Journal of Clinical Oncology, Vol 25, No 17 (June 10), 2007: pp. 2493-2494 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.7227
Genetic Changes of CEBPA in Cancer: Mutations or Polymorphisms?Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
Institute of Molecular Pathology and Immunology of the University of Porto; and Faculty of Medicine, Porto, Portugal
Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
Institute of Molecular Pathology and Immunology of the University of Porto; and Faculty of Medicine, Porto, Portugal To the Editor: We read with great interest the article by Fröhling et al1 on the mutational screening of the transcription factor CEBPA in patients with acute myeloid leukemia (AML). The authors demonstrated that mutations in CEBPA predict a favorable prognosis in AML with normal cytogenetics. They identified 36 (15%) of 236 AML patients to have at least one mutation of CEBPA, a result that is in accordance with those previously reported.2,3 Because CEBP family members play a crucial role in the control of differentiation and proliferation of various cell types,4-6 including gastric epithelial cells,7 we sought to establish if CEBPA mutations identified in AML could also be present in gastric carcinoma. For this purpose, we sequenced the entire coding region of CEBPA in 142 patients with gastric carcinoma. Mutation screening was performed as described in the work of Fröhling et al1 and genomic DNA was extracted from samples of both tumor tissue and blood for each patient. Table 1 summarizes the results of CEBPA mutation screening. We found alterations 1164C>T and 1281G>T in three and 38 patients, respectively, that were previously reported as polymorphisms.1 The 1302del7 mutation was detected in one patient and has not been previously reported in the literature, to our knowledge. This mutation originates a truncated protein that lacks the terminal part of the bZIP domain, which is fundamental for the DNA binding of the CEBPA protein. The 1302del7 alteration was tumor specific since it was not present in constitutional DNA from the same patient.
Alteration 1175-1180dup was observed in 7% (10 of 142) of the patients. This alteration was previously reported as a pathogenic mutation by Fröhling et al1 (detected in six of 236 AML patients) and by Lin et al3 (present in one of 104 AML patients). We sequenced constitutional DNA of the patients with this alteration and found that it was present in the germline of all 10 patients. This result suggests that the 1175-1180dup is not a mutation but is instead a polymorphism. To verify this hypothesis, we screened a series of 25 healthy blood donors for the presence of this alteration. The 1175-1180dup was observed in six (24%) of the 25 controls, confirming that we are indeed dealing with a common population polymorphism. The pathogenic role of this alteration in AML has thus to be re-evaluated. Interestingly, there are other genetic alterations of the CEBPA gene, reported as pathogenic in AML patients, that may also correspond to nonpathogenic polymorphisms. As example, the alterations 902-904del and 1153-1155del were also reported in more than one patient.1 Like 1175-1180dup, they correspond to in-frame alterations in repetitive regions of the CEBPA gene, that do not lead to any aminoacid alteration of the protein nor the formation of premature termination stop codons. In summary, the difficulty of studying constitutional DNA from blood samples of AML patients probably explains why 1175-1180dup has so far been reported as a pathogenic mutation. This problem is likely to preclude a fair judgement of other CEBPA alterations as well. Hence, extreme caution should be taken when classifying genetic alterations as either mutations or polymorphisms in patients with blood cancers. Desirably, the analysis of constitutional DNA from tumor-free tissue should always be included in somatic mutation screening studies. If at all not possible, the analysis of disease-free population controls should be considered instead. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS Supported by funding under Fundação para a Ciência e Tecnologia (POCTI/CBO/41550/2001), Programa Operacional Ciência, Tecnologia e Inovação, Fundo Comunitário Europeu, Programa Operacional de Saúde/SAUDE XXI, and the Associação Portuguesa da Industria Farmacêutica. REFERENCES
1. Fröhling S, Schlenk RF, Stolze I, et al: CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: Prognostic relevance and analysis of cooperating mutations. J Clin Oncol 22:624-633, 2004 2. Pabst T, Mueller BU, Zhang P, et al: Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein- 3. Lin L, Chen C, Lin D, et al: Characterization of CEBPA mutations in acute myeloid leukemia: Most patients with CEBPA mutations have biallelic mutations and show a distinct immunophenotype of the leukemic cells. Clinical Cancer Res 11:1372-1379, 2005 4. Tenen DG, Hromas R, Licht JD, et al: Transcription factors, normal myeloid development, and leukemia. Blood 90:489-519, 1997 5. Lekstrom-Himes J, Xanthopoulos KG: Biological role of the CCAAT/enhancer-binding protein family of transcription factors. J Biol Chem 273:28545-28548, 1998 6. Nerlov C: C/EBPalpha mutations in acute myeloid leukemias. Nat Rev Cancer 4:394-400, 2004[CrossRef][Medline] 7. Regalo G, Canedo P, Suriano G, et al: C/EBPbeta is over-expressed in gastric carcinogenesis and is associated with COX-2 expression. J Pathol 210:398-404, 2006[CrossRef][Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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