Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms.
Myeloproliferative neoplasms (MPNs) are a group of clonal disorders characterized by aberrant hematopoietic proliferation and an increased tendency toward leukemic transformation. We used targeted next-generation sequencing (NGS) of 104 genes to detect somatic mutations in a cohort of 197 MPN patients and followed clonal evolution and the impact on clinical outcome. Mutations in calreticulin (CALR) were detected using a sensitive allele-specific polymerase chain reaction. We observed somatic mutations in 90% of patients, and 37% carried somatic mutations other than JAK2 V617F and CALR. The presence of 2 or more somatic mutations significantly reduced overall survival and increased the risk of transformation into acute myeloid leukemia. In particular, somatic mutations with loss of heterozygosity in TP53 were strongly associated with leukemic transformation. We used NGS to follow and quantitate somatic mutations in serial samples from MPN patients. Surprisingly, the number of mutations between early and late patient samples did not significantly change, and during a total follow-up of 133 patient years, only 2 new mutations appeared, suggesting that the mutation rate in MPN is rather low. Our data show that comprehensive mutational screening at diagnosis and during follow-up has considerable potential to identify patients at high risk of disease progression.
Experimental Hematology, Department of Biomedicine, University Hospital of Basel, Basel, Switzerland;
Pontus
P
Lundberg
Axel
A
Karow
Ronny
R
Nienhold
Renate
R
Looser
Hui
H
Hao-Shen
Ina
I
Nissen
Sabine
S
Girsberger
Thomas
T
Lehmann
Jakob
J
Passweg
Martin
M
Stern
Christian
C
Beisel
Robert
R
Kralovics
Radek C
RC
Skoda
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D037282:Calreticulin / Q000235:genetics; D060965:Clonal Evolution; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D016019:Survival Analysis; D055815:Young Adult
C576483:CALR protein, human; D037282:Calreticulin; C507924:JAK2 protein, human; D053614:Janus Kinase 2