• Frederik Damm, Virginie Chesnais, Yasunobu Nagata, Kenichi Yoshida, Laurianne Scourzic, Yusuke Okuno, Raphael Itzykson, Masashi Sanada, Yuichi Shiraishi, Véronique Gelsi-Boyer, Aline Renneville, Satoru Miyano, Hiraku Mori, Lee-Yung Shih, Sophie Park, François Dreyfus, Agnes Guerci-Bresler, Eric Solary, Christian Rose, Stéphane Cheze, Thomas Prébet, Norbert Vey, Marion Legentil, Yannis Duffourd, Stéphane de Botton, Claude Preudhomme, Daniel Birnbaum, Olivier A Bernard, Seishi Ogawa, Michaela Fontenay, and Olivier Kosmider.
• Institut Gustave Roussy, Villejuif, France;
• Blood. 2013 Oct 31; 122 (18): 3169-77.

AbstractPatients with low-risk myelodysplastic syndromes (MDS) that rapidly progress to acute myeloid leukemia (AML) remain a challenge in disease management. Using whole-exome sequencing of an MDS patient, we identified a somatic mutation in the BCOR gene also mutated in AML. Sequencing of BCOR and related BCORL1 genes in a cohort of 354 MDS patients identified 4.2% and 0.8% of mutations respectively. BCOR mutations were associated with RUNX1 (P = .002) and DNMT3A mutations (P = .015). BCOR is also mutated in chronic myelomonocytic leukemia patients (7.4%) and BCORL1 in AML patients with myelodysplasia-related changes (9.1%). Using deep sequencing, we show that BCOR mutations arise after mutations affecting genes involved in splicing machinery or epigenetic regulation. In univariate analysis, BCOR mutations were associated with poor prognosis in MDS (overall survival [OS]: P = .013; cumulative incidence of AML transformation: P = .005). Multivariate analysis including age, International Prognostic Scoring System, transfusion dependency, and mutational status confirmed a significant inferior OS to patients with a BCOR mutation (hazard ratio, 3.3; 95% confidence interval, 1.4-8.1; P = .008). These data suggest that BCOR mutations define the clinical course rather than disease initiation. Despite infrequent mutations, BCOR analyses should be considered in risk stratification.

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