Originally published as JCO Early Release 10.1200/JCO.2008.16.5563 on September 2 2008

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Somatic CEBPA Mutations Are a Frequent Second Event in Families With Germline CEBPA Mutations and Familial Acute Myeloid Leukemia

Thomas Pabst, Marianne Eyholzer, Simon Haefliger, Julian Schardt, Beatrice U. Mueller

From the Departments of Medical Oncology and Internal Medicine, University Hospital; and Department of Clinical Research, University of Bern, Bern, Switzerland

Corresponding author: Thomas Pabst, MD, Department of Medical Oncology, University Hospital, 3010 Bern, Switzerland; e-mail: thomas.pabst{at}insel.ch

Purpose The transcription factor CCAAT/enhancer binding protein- (CEBPA) is crucial for normal myeloid differentiation. Mutations in the CEBPA gene are found in subsets of patients with acute myeloid leukemia (AML). Recently, three families were reported in whom several family members had germline CEBPA mutations and subsequently developed AML. Whereas familial AML is considered a rare event, the frequency of CEBPA germline mutations in AML is not known.

Patients and Methods In this study, we screened 187 consecutive AML patients for CEBPA mutations at diagnosis. We detected 18 patients (9.6%) with CEBPA mutations. We then analyzed remission samples and constitutive DNA from these patients.

Results We found that two (11.1%) of 18 AML patients with CEBPA mutations carried a germline N-terminal frameshift CEBPA mutation. Interestingly, additional members in the families of both of these patients have been affected by AML, and the germline CEBPA mutations were also observed in these patients. Additional somatic mutations in AML patients with germline CEBPA mutations in the two families comprised in-frame C-terminal CEBPA mutations in two patients, two nonsilent CEBPA point mutations in one patient, and monosomy 7 in one patient.

Conclusion This study shows, for the first time to our knowledge, that germline CEBPA mutations are frequently observed among AML patients with CEBPA mutations. Including the families with germline CEBPA mutations reported previously, additional somatic CEBPA mutations represent a frequent second event in AML with germline CEBPA mutations. Our data strongly indicate that germline CEBPA mutations predispose to AML and that additional somatic CEBPA mutations contribute to the development of the disease.

published online ahead of print at www.jco.org on September 2, 2008.

Supported by Grants No. SF 310000-109388 (T.P.) and SF 310000-113761 (B.U.M.) from the Swiss National Science Foundation and Swiss Cancer League.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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