scholarly journals A genome-wide single-nucleotide polymorphism-array can improve the prognostic stratification of the core binding factor acute myeloid leukemia

2012 ◽  
Vol 87 (10) ◽  
pp. 961-968 ◽  
Author(s):  
Jungwon Huh ◽  
Hee-Je Kim ◽  
Chul Won Jung ◽  
Hee-Jin Kim ◽  
Sun-Hee Kim ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Single Nucleotide Polymorphism Array ◽  
Nucleotide Polymorphism ◽  
Core Binding Factor ◽  
Single Nucleotide ◽  
The Core ◽  
Genome Wide ◽  
A Genome ◽  
Binding Factor ◽  
Prognostic Stratification

scholarly journals High-resolution genomic profiling of adult and pediatric core-binding factor acute myeloid leukemia reveals new recurrent genomic alterations

Blood ◽  
2012 ◽  
Vol 119 (10) ◽  
pp. e67-e75 ◽  
Author(s):  
Michael W. M. Kühn ◽  
Ina Radtke ◽  
Lars Bullinger ◽  
Salil Goorha ◽  
Jinjun Cheng ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Single Nucleotide Polymorphism Array ◽  
Nucleotide Polymorphism ◽  
Array Analysis ◽  
Core Binding Factor ◽  
Single Nucleotide ◽  
Binding Factor ◽  
Acute Myeloid

Abstract To identify cooperating lesions in core-binding factor acute myeloid leukemia, we performed single-nucleotide polymorphism-array analysis on 300 diagnostic and 41 relapse adult and pediatric leukemia samples. We identified a mean of 1.28 copy number alterations per case at diagnosis in both patient populations. Recurrent minimally deleted regions (MDRs) were identified at 7q36.1 (7.7%), 9q21.32 (5%), 11p13 (2.3%), and 17q11.2 (2%). Approximately one-half of the 7q deletions were detectable only by single-nucleotide polymorphism-array analysis because of their limited size. Sequence analysis of MLL3, contained within the 7q36.1 MDR, in 46 diagnostic samples revealed one truncating mutation in a leukemia lacking a 7q deletion. Recurrent focal gains were identified at 8q24.21 (4.7%) and 11q25 (1.7%), both containing a single noncoding RNA. Recurrent regions of copy-neutral loss-of-heterozygosity were identified at 1p (1%), 4q (0.7%), and 19p (0.7%), with known mutated cancer genes present in the minimally altered region of 1p (NRAS) and 4q (TET2). Analysis of relapse samples identified recurrent MDRs at 3q13.31 (12.2%), 5q (4.9%), and 17p (4.9%), with the 3q13.31 region containing only LSAMP, a putative tumor suppressor. Determining the role of these lesions in leukemogenesis and drug resistance should provide important insights into core-binding factor acute myeloid leukemia.

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.

Whole Genome Association Study in Acute Myeloid Leukemia with a Normal Karyotype, Using a Single-Nucleotide Polymorphism (SNP) Analysis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4253-4253
Author(s):  
Yongjun Cha ◽  
Kwang-Sung Ahn ◽  
Juwon Park ◽  
Byung-Su Kim ◽  
Soo-Mee Bang ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Snp Analysis ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Genome Wide ◽  
A Genome ◽  
Significant Difference ◽  
Acute Myeloid

Abstract As a result of numerous genetic aberrations, acute myeloid leukemia (AML) present with very heterogeneous clinical features. Moreover, structural and numerical chromosome aberrations currently comprise the most important basis for predicting these heterogeneous outcomes. However, 30 to 50 percent of AML patients have cytogenetically normal karyotypes. Though submicroscopic genetic alterations (such as NPM1, CEBPA, MLL-PTD) are increasingly being used for clinical purposes, additional markers with prognostic or predictive value are still lacking in this group. In this study, we performed a genome-wide, single-nucleotide polymorphism (SNP) study in order to identify novel genomic regions of interest in normal karyotype AML. 54 untreated AML patients with normal karyotypes were analyzed with an Illumina infinium 317K SNP chip assay. SNP genotype call rate was 99.8 percent, resulting in a resolution of 1 SNP/Mb. In a genome-wide SNP analysis, 317 SNP loci, having a significant difference between AML and normal control, were found. In addition, about 300 loci were also identified, showing a significant difference between patients who achieved CR and those who did not. Some of these were found to be related with drug metabolism and MDR family. Also we used the SNP assay to screen a loss of heterozygosity (LOH), suggesting possible involvement of tumor suppressor genes. In summary, 38 LOH regions larger than 1Mb were observed in 23 cases (43%) among 54 AML patients having normal karyotypes. Most (55%) of them were copy-neutral events and the most frequently identified alterations were located at 3p, 8p, 13q and 22q. 11 (29%) out of 38 LOH regions had overlapping parts among them. Some LOHs were correlated with response to chemotherapy. Various genetic changes were discovered by use of an SNP-based chip array in normal karyotype AML patients. Moreover, some of these were related with CR acquisition and drug metabolism. These results can be used to differentiate normal karyotype AML and warrant further study.

Genome-Wide Single-Nucleotide Polymorphism-Array Can Improve Prognostic Stratification of Core Binding Factor Acute Myeloid Leukemia, Especially in the Subgroup with Inv(16)/t(16;16) or without D816 C-KIT Mutation,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3515-3515
Author(s):  
Jungwon Huh ◽  
Heeje Kim ◽  
Woo-Sung Min ◽  
Chul Won Jung ◽  
Hee-Jin Kim ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Prognostic Value ◽  
Nucleotide Polymorphism ◽  
Core Binding Factor ◽  
Single Nucleotide ◽  
Kit Mutation ◽  
Genome Wide ◽  
Binding Factor ◽  
Kit Gene

Abstract Abstract 3515 Background: The core binding factor (CBF) AML can be achieved long-term remission with high dose cytarabine-based chemotherapy alone. However, those with C-KIT gene mutation (esp. D816 C-KIT mutation) showed worse treatment outcomes compared to those with wild type C-KIT gene. The remaining cases without D816 C-KIT mutation is around 75% of CBF AML, which implies requirement of more sophisticated dissection of the patients according to their prognosis. Single nucleotide polymorphism (SNP) array (SNP-A) could detect cryptic abnormal genomic lesions, not identified by metaphase cytogenetics(MC). In this study, we analyzed the prognostic value of SNP-A based karyotyping combined with MC and its association with C-KIT mutation to facilitate further stratification of CBF AML patients. Methods and Materials: A total of 98 CBF AML patients were included and of whom, 63 (64%) and 35 patients (36%) were t(8;21) and inv(16)/t(16;16), respectively. Genome-Wide Human SNP 6.0 Array (Affymetrix, CA, USA) was performed using DNAs from marrow samples taken at diagnosis. Results: A total of 40 abnormal genomic lesions in 25 patients (26%) were detected by SNP-A karyotyping analysis, with a mean of 1.6 lesions per affected case (median size 33.6 Mb; range 0.4–145.9 Mb), including 3 CN-LOH lesions, 17 gain lesions, and 20 loss lesions. Survival of the patients with abnormal lesion(s) detected by SNP-A or/and MC was worse than those without any lesions in terms of 2 years' overall survival (OS; 57.5% vs 76.4%, p=0.028), event-free (EFS; 45.7% vs 66.2%, p=0.072) and leukemia free survival (LFS; 49.0% vs 77.4%, p=0.015). In contrast, MC alone could not stratify patients according to their long-term prognosis. Especially, in the subgroup with inv(16)/t(16;16), survival of patients with abnormal SNP-A/MC lesion showed worse than that of those without lesion (40.9±12.7% vs 80.2±10.4% at 2 yrs, p=0.040), but not in the subgroup with t(8;21) (66.85±9.1% vs 74.4±7.8% at 2 yrs, p=0.240). As for the subgroup with D816 C-KIT mutation, there were no differences of OS (p=0.417), EFS (p=0.380) and LFS (p=0.218) according to the presence of abnormal lesions detected by either SNP-A or MC. However, in the subgroup without D816 C-KIT mutation, those with abnormal lesions detected by either SNP-A or MC showed worse survival compared to those without abnormal lesions with respect to OS (61.6±8.7% vs 82.7±5.6% at 2 yrs, p=0.038). Multivariate analysis confirmed prognostic impact of abnormal SNP/MC lesions on OS (HR 2.743, p=0.020), EFS (HR 2.434, p=0.025), and LFS (HR 3.350, p=0.012). Conclusion: This study suggests that combined use of SNP-A with MC in the initial evaluation of CBF AML can provide an important prognostic value, especially in the inv(16)/t(16;16) subgroup or in the patients without having D816 C-KIT mutation. Disclosures: No relevant conflicts of interest to declare.

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