Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype

• Published in: Blood 2011-12, Vol.118 (23), p.6153-6163
• Main Authors: Grossmann, Vera, Tiacci, Enrico, Holmes, Antony B., Kohlmann, Alexander, Martelli, Maria Paola, Kern, Wolfgang, Spanhol-Rosseto, Ariele, Klein, Hans-Ulrich, Dugas, Martin, Schindela, Sonja, Trifonov, Vladimir, Schnittger, Susanne, Haferlach, Claudia, Bassan, Renato, Wells, Victoria A., Spinelli, Orietta, Chan, Joseph, Rossi, Roberta, Baldoni, Stefano, De Carolis, Luca, Goetze, Katharina, Serve, Hubert, Peceny, Rudolf, Kreuzer, Karl-Anton, Oruzio, Daniel, Specchia, Giorgina, Di Raimondo, Francesco, Fabbiano, Francesco, Sborgia, Marco, Liso, Arcangelo, Farinelli, Laurent, Rambaldi, Alessandro, Pasqualucci, Laura, Rabadan, Raul, Haferlach, Torsten, Falini, Brunangelo
• Format: Article
• Language: English
• Subjects: Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Cohort Studies; Core Binding Factor Alpha 2 Subunit - genetics; DNA (Cytosine-5-)-Methyltransferases - genetics; Exome - genetics; Fatal Outcome; Female; fms-Like Tyrosine Kinase 3 - genetics; Gene Expression Regulation, Leukemic - genetics; Genetic Testing - methods; Hematologic and hematopoietic diseases; Humans; Karyotyping; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - mortality; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Nuclear Proteins - genetics; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Survival Analysis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-07-365320

Among acute myeloid leukemia (AML) patients with a normal karyotype (CN-AML), NPM1 and CEBPA mutations define World Health Organization 2008 provisional entities accounting for approximately 60% of patients, but the remaining 40% are molecularly poorly characterized. Using whole-exome sequencing of one CN-AML patient lacking mutations in NPM1, CEBPA, FLT3-ITD, IDH1, and MLL-PTD, we newly identified a clonal somatic mutation in BCOR (BCL6 corepressor), a gene located on chromosome Xp11.4. Further analyses of 553 AML patients showed that BCOR mutations occurred in 3.8% of unselected CN-AML patients and represented a substantial fraction (17.1%) of CN-AML patients showing the same genotype as the AML index patient subjected to whole-exome sequencing. BCOR somatic mutations were: (1) disruptive events similar to the germline BCOR mutations causing the oculo-facio-cardio-dental genetic syndrome; (2) associated with decreased BCOR mRNA levels, absence of full-length BCOR, and absent or low expression of a truncated BCOR protein; (3) virtually mutually exclusive with NPM1 mutations; and (4) frequently associated with DNMT3A mutations, suggesting cooperativity among these genetic alterations. Finally, BCOR mutations tended to be associated with an inferior outcome in a cohort of 422 CN-AML patients (25.6% vs 56.7% overall survival at 2 years; P = .032). Our results for the first time implicate BCOR in CN-AML pathogenesis.