Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms

TY - JOUR

T1 - Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms

AU - Malcovati, Luca

AU - Papaemmanuil, Elli

AU - Bowen, David T.

AU - Boultwood, Jacqueline

AU - Della Porta, Matteo G.

AU - Pascutto, Cristiana

AU - Travaglino, Erica

AU - Groves, Michael J.

AU - Godfrey, Anna L.

AU - Ambaglio, Ilaria

AU - Galli, Anna

AU - Da Via, Matteo C.

AU - Conte, Simona

AU - Tauro, Sudhir

AU - Keenan, Norene

AU - Hyslop, Ann

AU - Hinton, Jonathan

AU - Mudie, Laura J.

AU - Wainscoat, James S.

AU - Futreal, P. Andrew

AU - Stratton, Michael R.

AU - Campbell, Peter J.

AU - Hellstrom-Lindberg, Eva

AU - Cazzola, Mario

AU - Assoc Italiana Ricerca Canc Grp, Int Canc Genome Consortium

PY - 2011/12/8

Y1 - 2011/12/8

N2 - In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P < .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positive predictive value for ring sideroblasts of 97.7% (95% confidence interval, 93.5%-99.5%). In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049). The close association between SF3B1 mutations and disease phenotype with ring sideroblasts across MDS and MDS/MPN is consistent with a causal relationship. Furthermore, SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS. (Blood. 2011;118(24):6239-6246)

AB - In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P < .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positive predictive value for ring sideroblasts of 97.7% (95% confidence interval, 93.5%-99.5%). In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049). The close association between SF3B1 mutations and disease phenotype with ring sideroblasts across MDS and MDS/MPN is consistent with a causal relationship. Furthermore, SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS. (Blood. 2011;118(24):6239-6246)

KW - PROGNOSTIC SCORING SYSTEM

KW - WORLD-HEALTH-ORGANIZATION

KW - RING SIDEROBLASTS

KW - MYELOID NEOPLASMS

KW - HUMAN 5Q-SYNDROME

KW - CD34(+) CELLS

KW - ANEMIA

KW - CLASSIFICATION

KW - GENE

KW - TET2

U2 - 10.1182/blood-2011-09-377275

DO - 10.1182/blood-2011-09-377275

M3 - Article

C2 - 21998214

SN - 0006-4971

VL - 118

SP - 6239

EP - 6246

JO - Blood

JF - Blood

IS - 24

ER -