TY - JOUR
T1 - Clinical and biological implications of driver mutations in myelodysplastic syndromes
AU - Papaemmanuil, Elli
AU - Gerstung, Moritz
AU - Malcovati, Luca
AU - Tauro, Sudhir
AU - Gundem, Gunes
AU - Van Loo, Peter
AU - Yoon, Chris J.
AU - Ellis, Peter
AU - Wedge, David C.
AU - Pellagatti, Andrea
AU - Shlien, Adam
AU - Groves, Michael John
AU - Forbes, Simon A.
AU - Raine, Keiran
AU - Hinton, Jon
AU - Mudie, Laura J.
AU - McLaren, Stuart
AU - Hardy, Claire
AU - Latimer, Calli
AU - Della Porta, Matteo G.
AU - O'Meara, Sarah
AU - Ambaglio, Ilaria
AU - Galli, Anna
AU - Butler, Adam P.
AU - Walldin, Gunilla
AU - Teague, Jon W.
AU - Quek, Lynn
AU - Sternberg, Alex
AU - Gambacorti-Passerini, Carlo
AU - Cross, Nicholas C.P.
AU - Green, Anthony R.
AU - Boultwood, Jacqueline
AU - Vyas, Paresh
AU - Hellstrom-Lindberg, Eva
AU - Bowen, David
AU - Cazzola, Mario
AU - Stratton, Michael R.
AU - Campbell, Peter J.
PY - 2013/11/21
Y1 - 2013/11/21
N2 - Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling. We sequenced 111 genes across 738 patients with MDS or closely related neoplasms (including chronic myelomonocytic leukemia and MDS-myeloproliferative neoplasms) to explore the role of acquired mutations in MDS biology and clinical phenotype. Seventy-eight percent of patients had 1 or more oncogenic mutations. We identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers. Coupled with inferenceson subclonal mutations, these data suggest a hypothesis of genetic "predestination," in which early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes. Driver mutations had equivalent prognostic significance, whether clonal or subclonal, and leukemia-free survival deteriorated steadilyas numbersof driver mutations increased. Thus, analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application.
AB - Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling. We sequenced 111 genes across 738 patients with MDS or closely related neoplasms (including chronic myelomonocytic leukemia and MDS-myeloproliferative neoplasms) to explore the role of acquired mutations in MDS biology and clinical phenotype. Seventy-eight percent of patients had 1 or more oncogenic mutations. We identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers. Coupled with inferenceson subclonal mutations, these data suggest a hypothesis of genetic "predestination," in which early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes. Driver mutations had equivalent prognostic significance, whether clonal or subclonal, and leukemia-free survival deteriorated steadilyas numbersof driver mutations increased. Thus, analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application.
UR - http://www.scopus.com/inward/record.url?scp=84888219405&partnerID=8YFLogxK
U2 - 10.1182/blood-2013-08-518886
DO - 10.1182/blood-2013-08-518886
M3 - Article
C2 - 24030381
AN - SCOPUS:84888219405
SN - 0006-4971
VL - 122
SP - 3616
EP - 3627
JO - Blood
JF - Blood
IS - 22
ER -