Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes

Damm, F., Kosmider, O., Gelsi-Boyer, V., Renneville, A., Carbuccia, N., Hidalgo-Curtis, C., Della-Valle, V., Couronne, L., Scourzic, L., Chesnais, V., Guerci-Bresler, A., Slama, B., Beyne-Rauzy, O., Schmidt-Tanguy, A., Stamatoullas-Bastard, A., Dreyfus, F., Prebet, T., de Botton, S., Vey, N., Morgan, M. A., Cross, N. C. P., Preudhomme, C., Birnbaum, D., Bernard, O. A. and Fontenay, M. (2012) Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes. Blood, 119 (14), 3211-3218. (doi:10.1182/blood-2011-12-400994).

Abstract

A cohort of MDS patients was examined for mutations affecting four splice genes (SF3B1, SRSF2, ZRSR2 and U2AF35) and evaluated in the context of clinical and molecular markers. Splice gene mutations were detected in 95 of 221 patients. These mutations were mutually exclusive and less likely to occur in patients with complex cytogenetics or TP53 mutations. SF3B1mut patients presented with lower hemoglobin levels, increased WBC and platelet counts and were more likely to have DNMT3A mutations. SRSF2mut patients clustered in RAEB-1 and RAEB-2 subtypes and exhibited pronounced thrombocytopenias. ZRSR2mut patients clustered in IPSS int-1 and int-2 risk-groups, had higher percentages of bone marrow blasts and more often displayed isolated neutropenias. SRSF2 and ZRSR2 mutations were more common in TET2mut patients. U2AF35mut patients had an increased prevalence of chromosome 20 deletions and ASXL1 mutations. Multivariate analysis revealed an inferior overall-survival (OS) and a higher AML transformation rate for the genotype ZRSR2mut/TET2wt (OS: HR 3.3; 95%CI 1.4 - 7.7; P=.006; AML transformation: HR 3.6; 95%CI 2 - 4.2; P=.026). Our results demonstrate that splice gene mutations are among the most frequent molecular aberrations in MDS, define distinct clinical phenotypes and show preferential associations with mutations targeting transcriptional regulation.

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Contributors

Author: N. C. P. Cross

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