TY - JOUR
T1 - Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia
AU - Malcovati, Luca
AU - Papaemmanuil, Elli
AU - Ambaglio, Ilaria
AU - Elena, Chiara
AU - Gallì, Anna
AU - Della Porta, Matteo G.
AU - Travaglino, Erica
AU - Pietra, Daniela
AU - Pascutto, Cristiana
AU - Ubezio, Marta
AU - Bono, Elisa
AU - Da Vià, Matteo C.
AU - Brisci, Angela
AU - Bruno, Francesca
AU - Cremonesi, Laura
AU - Ferrari, Maurizio
AU - Boveri, Emanuela
AU - Invernizzi, Rosangela
AU - Campbell, Peter J.
AU - Cazzola, Mario
PY - 2014/8/28
Y1 - 2014/8/28
N2 - Our knowledge of the genetic basis of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) has considerably improved. Todefine genotype/phenotype relationships of clinical relevance,westudied 308 patients with MDS, MDS/MPN, or acute myeloid leukemia evolving from MDS. Unsupervised statistical analysis, including the World Health Organization classification criteria and somatic mutations, showed that MDS associated with SF3B1-mutation (51 of 245 patients, 20.8%) is a distinct nosologic entity irrespective of current morphologic classification criteria. Conversely, MDS with ring sideroblasts with nonmutated SF3B1 segregated in different clusters with otherMDS subtypes. Mutations of genes involved in DNA methylation, splicing factors other than SF3B1, and genes of the RAS pathway and cohesin complex were independently associated with multilineage dysplasia and identified a distinct subset (51 of 245 patients, 20.8%). No recurrent mutation pattern correlated with unilineage dysplasia without ring sideroblasts. Irrespective of driver somatic mutations, a threshold of 5% bone marrow blasts retained a significant discriminant value for identifying cases with clonal evolution.Comutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to, chronic myelomonocytic leukemia. These results serve as a proof of concept that a molecular classification of myeloid neoplasms is feasible.
AB - Our knowledge of the genetic basis of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) has considerably improved. Todefine genotype/phenotype relationships of clinical relevance,westudied 308 patients with MDS, MDS/MPN, or acute myeloid leukemia evolving from MDS. Unsupervised statistical analysis, including the World Health Organization classification criteria and somatic mutations, showed that MDS associated with SF3B1-mutation (51 of 245 patients, 20.8%) is a distinct nosologic entity irrespective of current morphologic classification criteria. Conversely, MDS with ring sideroblasts with nonmutated SF3B1 segregated in different clusters with otherMDS subtypes. Mutations of genes involved in DNA methylation, splicing factors other than SF3B1, and genes of the RAS pathway and cohesin complex were independently associated with multilineage dysplasia and identified a distinct subset (51 of 245 patients, 20.8%). No recurrent mutation pattern correlated with unilineage dysplasia without ring sideroblasts. Irrespective of driver somatic mutations, a threshold of 5% bone marrow blasts retained a significant discriminant value for identifying cases with clonal evolution.Comutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to, chronic myelomonocytic leukemia. These results serve as a proof of concept that a molecular classification of myeloid neoplasms is feasible.
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U2 - 10.1182/blood-2014-03-560227
DO - 10.1182/blood-2014-03-560227
M3 - Article
C2 - 24970933
AN - SCOPUS:84907346397
VL - 124
SP - 1513
EP - 1521
JO - Blood
JF - Blood
SN - 0006-4971
IS - 9
ER -