New lesions detected by single nucleotide polymorphism array-based chromosomal analysis have important clinical impact in acute myeloid leukemia.
OBJECTIVE
Cytogenetics is the primary outcome predictor in acute myeloid leukemia (AML). Metaphase cytogenetics (MC) detects an abnormal karyotype in only half of patients with AML, however. Single nucleotide polymorphism arrays (SNP-A) can detect acquired somatic uniparental disomy (UPD) and other cryptic defects, even in samples deemed normal by MC. We hypothesized that SNP-A will improve detection of chromosomal defects in AML and that this would enhance the prognostic value of MC.


METHODS
We performed 250K and 6.0 SNP-A analyses on 140 patients with primary (p) and secondary (s) AML and correlated the results with clinical outcomes and Flt-3/nucleophosmin (NPM-1) status.


RESULTS
SNP-A is more sensitive than MC in detecting unbalanced lesions (pAML, 65% v 39%, P = .002; and sAML, 78% v 51%, P = .003). Acquired somatic UPD, not detectable by MC, was common in our AML cohort (29% in pAML and 35% in sAML). Patients with SNP-A lesions including acquired somatic UPD exhibited worse overall survival (OS) and event-free survival (EFS) in pAML with normal MC and in pAML/sAML with abnormal MC. SNP-A improved the predictive value of Flt-3 internal tandem duplication/NPM-1 status, with inferior survival seen in patients with additional SNP-A defects. Multivariate analyses confirmed the independent predictive value of SNP-A defects for OS (hazard ratio [HR] = 2.52; 95% CI, 1.29 to 5.22; P = .006) and EFS (HR = 1.72; 95% CI, 1.12 to 3.48; P = .04).


CONCLUSIONS
SNP-A analysis allows enhanced detection of chromosomal abnormalities and provides important prognostic impact in AML.
Tiu
Ramon V
RV
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Gondek
Lukasz P
LP
O'Keefe
Christine L
CL
Huh
Jungwon
J
Sekeres
Mikkael A
MA
Elson
Paul
P
McDevitt
Michael A
MA
Wang
Xiao Fei
XF
Levis
Mark J
MJ
Karp
Judith E
JE
Advani
Anjali S
AS
Maciejewski
Jaroslaw P
JP
D002869:Chromosome Aberrations; D020732:Cytogenetic Analysis; D018572:Disease-Free Survival; D006801:Humans; D053208:Kaplan-Meier Estimate; D007621:Karyotyping / Q000379:methods*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012680:Sensitivity and Specificity; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3