No Prognostic Impact of the WT1 Gene Single Nucleotide Polymorphism rs16754 in Pediatric Acute Myeloid Leukemia

2010 ◽  
Vol 28 (28) ◽  
pp. e523-e526 ◽  
Author(s):  
Iris H.I.M. Hollink ◽  
Marry M. van den Heuvel-Eibrink ◽  
Martin Zimmermann ◽  
Brian V. Balgobind ◽  
Susan T.C.J.M. Arentsen-Peters ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Impact ◽  
Wt1 Gene ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Pediatric Acute Myeloid Leukemia ◽  
Gene Single Nucleotide Polymorphism ◽  
Acute Myeloid

Adverse Prognostic Impact of Abnormal Lesions Detected by Genome-Wide Single Nucleotide Polymorphism Array–Based Karyotyping Analysis in Acute Myeloid Leukemia With Normal Karyotype

2011 ◽  
Vol 29 (35) ◽  
pp. 4702-4708 ◽  
Author(s):  
Jun Ho Yi ◽  
Jungwon Huh ◽  
Hee-Jin Kim ◽  
Sun-Hee Kim ◽  
Hyeoung-Joon Kim ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Single Nucleotide Polymorphism Array ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Acute Myeloid

Purpose This study attempted to analyze the prognostic role of single nucleotide polymorphism array (SNP-A) –based karyotying in 133 patients with acute myeloid leukemia with normal karyotype (AML-NK), which presents with diverse clinical outcomes, thus requiring further stratification of patient subgroups according to their prognoses. Patients and Methods A total of 133 patients with AML-NK confirmed by metaphase cytogenetics (MC) and fluorescent in situ hybridization analysis were included in this study. Analysis by Genome-Wide Human SNP 6.0 Array was performed by using DNAs derived from marrow samples at diagnosis. Results Forty-three patients (32.3%) had at least one abnormal SNP lesion that was not detected by MC. One hundred thirteen abnormal SNP lesions included 55 losses, 23 gains, and 35 copy-neutral losses of heterozygosity. Multivariate analyses showed that detection of abnormal SNP lesions by SNP-A karyotyping results in an unfavorable prognostic value for overall survival (hazard ratio [HR], 2.69; 95% CI, 1.50 to 4.82; P = .001); other significant prognostic factors included secondary AML (HR, 5.55; 95% CI, 1.80 to 17.14; P = .003), presence of the FLT3 mutation (HR, 3.17; 95% CI, 1.71 to 5.87; P < .001), and age (HR, 1.03; 95% CI, 1.01 to 1.05; P = .020). Conclusion Our data demonstrated that abnormal SNP lesions detected by SNP-A karyotyping might indicate an adverse prognosis in patients with AML-NK, thus requiring a more sophisticated treatment strategy for improvement of treatment outcomes.

scholarly journals WT1Synonymous Single Nucleotide Polymorphism rs16754 Correlates With Higher mRNA Expression and Predicts Significantly Improved Outcome in Favorable-Risk Pediatric Acute Myeloid Leukemia: A Report From the Children's Oncology Group

2011 ◽  
Vol 29 (6) ◽  
pp. 704-711 ◽  
Author(s):  
Phoenix A. Ho ◽  
Julia Kuhn ◽  
Robert B. Gerbing ◽  
Jessica A. Pollard ◽  
Rong Zeng ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Risk ◽  
Oncology Group ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Pediatric Acute Myeloid Leukemia ◽  
Improved Outcome ◽  
Acute Myeloid

PurposeTo analyze the prevalence and clinical implications of Wilms' tumor 1 (WT1) single nucleotide polymorphism (SNP) rs16754 in the context of other prognostic markers in pediatric acute myeloid leukemia (AML).Patients and MethodsAvailable diagnostic marrow specimens (n = 790) from 1,328 patients enrolled in three consecutive Children's Cancer Group/Children's Oncology Group trials were analyzed for the presence of SNP rs16754. SNP status was correlated with disease characteristics, WT1 expression level, and clinical outcome.ResultsSNP rs16754 was present in 229 (29%) of 790 patients. The SNP was significantly more common in Asian and Hispanic patients and less common in white patients (P < .001). SNP rs16754 was also less common in patients with inv(16) (P = .043) and more common in patients with −5/del(5q) (P = .047). WT1 expression levels were significantly higher in patients with rs16754 or with WT1 mutations compared with WT1 wild-type patients (P = .021). Five-year overall survival (OS) for patients with and without the SNP was 60% and 50%, respectively (P = .031). Prognostic assessment by risk group demonstrated that in patients with low-risk disease, OS for those with and without SNP rs16754 was 90% versus 64% (P < .001) with a corresponding disease-free survival of 72% versus 53% (P = .041).ConclusionThe presence of SNP rs16754 was an independent predictor of improved OS; outcome differences were most pronounced in the low-risk subgroup. The high prevalence of WT1 SNP rs16754, and its correlation with improved outcome, identifies WT1 SNP rs16754 as a potentially important molecular marker of prognosis in pediatric AML.

scholarly journals New Lesions Detected by Single Nucleotide Polymorphism Array–Based Chromosomal Analysis Have Important Clinical Impact in Acute Myeloid Leukemia

2009 ◽  
Vol 27 (31) ◽  
pp. 5219-5226 ◽  
Author(s):  
Ramon V. Tiu ◽  
Lukasz P. Gondek ◽  
Christine L. O'Keefe ◽  
Jungwon Huh ◽  
Mikkael A. Sekeres ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Acute Myeloid Leukemia ◽  
Predictive Value ◽  
Myeloid Leukemia ◽  
Single Nucleotide Polymorphism Array ◽  
Uniparental Disomy ◽  
Prognostic Impact ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Acute Myeloid

PurposeCytogenetics 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.Patients and MethodsWe 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.ResultsSNP-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).ConclusionSNP-A analysis allows enhanced detection of chromosomal abnormalities and provides important prognostic impact in AML.

scholarly journals Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A

Blood ◽  
2011 ◽  
Vol 118 (14) ◽  
pp. 3932-3941 ◽  
Author(s):  
Anna M. Jankowska ◽  
Hideki Makishima ◽  
Ramon V. Tiu ◽  
Hadrian Szpurka ◽  
Yun Huang ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Myelomonocytic Leukemia ◽  
Molecular Heterogeneity ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Mutant Genotype ◽  
Myelomonocytic Leukemia ◽  
Acute Myeloid

Abstract Chronic myelomonocytic leukemia (CMML), a myelodysplastic/myeloproliferative neoplasm, is characterized by monocytic proliferation, dysplasia, and progression to acute myeloid leukemia. CMML has been associated with somatic mutations in diverse recently identified genes. We analyzed 72 well-characterized patients with CMML (N = 52) and CMML-derived acute myeloid leukemia (N = 20) for recurrent chromosomal abnormalities with the use of routine cytogenetics and single nucleotide polymorphism arrays along with comprehensive mutational screening. Cytogenetic aberrations were present in 46% of cases, whereas single nucleotide polymorphism array increased the diagnostic yield to 60%. At least 1 mutation was found in 86% of all cases; novel UTX, DNMT3A, and EZH2 mutations were found in 8%, 10%, and 5.5% of patients, respectively. TET2 mutations were present in 49%, ASXL1 in 43%, CBL in 14%, IDH1/2 in 4%, KRAS in 7%, NRAS in 4%, and JAK2 V617F in 1% of patients. Various mutant genotype combinations were observed, indicating molecular heterogeneity in CMML. Our results suggest that molecular defects affecting distinct pathways can lead to similar clinical phenotypes.

Single Nucleotide Polymorphism in the Mutational Hotspot of WT1 Predicts a Favorable Outcome in Patients With Cytogenetically Normal Acute Myeloid Leukemia

2010 ◽  
Vol 28 (4) ◽  
pp. 578-585 ◽  
Author(s):  
Frederik Damm ◽  
Michael Heuser ◽  
Michael Morgan ◽  
Haiyang Yun ◽  
Anika Großhennig ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Acute Myeloid Leukemia ◽  
Healthy Volunteers ◽  
Myeloid Leukemia ◽  
Minor Allele ◽  
Risk Marker ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Risk Patients ◽  
Acute Myeloid

Purpose We assessed the prognostic impact of a known single nucleotide polymorphism (SNP) located in the mutational hotspot of WT1 in patients with cytogenetically normal acute myeloid leukemia (CN-AML) in the context of other prognostic markers. Patients and Methods WT1 exons 7 and 9 from 249 CN-AML patients from multicenter treatment trials AML-SHG Hannover 0199 (Clinical Trials Identifier NCT00209833) and 0295, and 50 healthy volunteers were analyzed by direct sequencing. NPM1, FLT3, CEBPA, and MLL were assessed for mutations and WT1 expression was quantified. Results The minor allele of SNP rs16754 (WT1AG/GG) was found in 25.7% of CN-AML patients' blasts and germline DNA and in 36% of healthy volunteers. Patient characteristics, frequencies of mutations, or WT1 expression levels were similarly distributed between patients homozygous for the major allele compared with patients heterozygous or homozygous for the minor allele. SNP rs16754 status was an independent predictor of relapse-free survival (RFS; hazard ratio [HR], 0.49; 95% CI, 0.3 to 0.81; P = .005) and overall survival (OS; HR, 0.44; 95% CI, 0.27 to 0.74; P = .002) in multivariate analysis. The favorable effect of SNP rs16754 was stronger in NPM1/FLT3-ITD (internal tandem duplication of the FLT3 gene) high-risk patients compared with NPM1/FLT3-ITD low-risk patients. Favorable prognosis could not be identified by any other known low-risk marker in half the patients with at least one minor allele (13% of all patients). No difference for complete remission rate, RFS, or OS was found between patients with or without acquired WT1 mutations. Conclusion WT1 SNP rs16754 may be a novel independent favorable-risk marker in CN-AML patients that might improve risk and treatment stratification.

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