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Clinical outcome and gene- and microRNA-expression profiling according to the Wilms tumor 1 (WT1) single nucleotide polymorphism rs16754 in adult de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study.

ABSTRACT: The alleles of the Wilms tumor 1 (WT1) polymorphism rs16754 harbor adenine (A) or guanine (G). Recently, rs16754 has been reported to affect the outcome of patients with cytogenetically normal acute myeloid leukemia. To validate this finding, we investigated pretreatment features and outcome associated with rs16754 in a large cohort of patients with cytogenetically normal acute myeloid leukemia.Four-hundred and thirty-three intensively treated and molecularly characterized cytogenetically normal patients with de novo acute myeloid leukemia (18-83 years old) were analyzed for rs16754. To gain biological insights, we studied the gene- and microRNA-expression profiles for associations with rs16754.Three-hundred and nine (71%) patients were homozygous for A (WT1(AA)), 112 (26%) were heterozygous (WT1(AG)) and 12 (3%) were homozygous for G (WT1(GG)). For comparison with previous studies, we grouped WT1(AG) and WT1(GG) patients and compared them with WT1(AA) patients divided into younger (<60 years) and older (?60 years) adults. We found no independent prognostic impact of WT1(AA). However, WT1(GG) patients, who were less often Caucasian than WT1(AG) (P=0.001) or WT1(AA) (P=0.008) patients, and had TET2 mutations more often than WT1(AG) (P=0.02) patients, had, among patients with FLT3-internal tandem duplication and/or NPM1 wild-type, better disease-free (P=0.02) and overall survival (P=0.04) than WT1(AA) and WT1(AG) patients combined. Unsupervised and supervised analyses of the gene- and microRNA-expression profiles suggested that there were no distinct expression patterns associated with any rs16754 genotype.We did not observe the previously reported adverse impact of WT1(AA) but found favorable outcomes associated with the homozygous WT1(GG). Considering its low frequency, confirmatory studies are necessary. The biological significance of rs16754 remains questionable as no distinct expression profiles were associated with the genotypes.

SUBMITTER: Becker H

PROVIDER: S-EPMC3186310 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Clinical outcome and gene- and microRNA-expression profiling according to the Wilms tumor 1 (WT1) single nucleotide polymorphism rs16754 in adult de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study.

Becker Heiko H Maharry Kati K Radmacher Michael D MD Mrózek Krzysztof K Metzeler Klaus H KH Whitman Susan P SP Schwind Sebastian S Kohlschmidt Jessica J Wu Yue-Zhong YZ Powell Bayard L BL Carter Thomas H TH Kolitz Jonathan E JE Wetzler Meir M Carroll Andrew J AJ Baer Maria R MR Moore Joseph O JO Caligiuri Michael A MA Larson Richard A RA Marcucci Guido G Bloomfield Clara D CD

Haematologica 20110609 10

<h4>Background</h4>The alleles of the Wilms tumor 1 (WT1) polymorphism rs16754 harbor adenine (A) or guanine (G). Recently, rs16754 has been reported to affect the outcome of patients with cytogenetically normal acute myeloid leukemia. To validate this finding, we investigated pretreatment features and outcome associated with rs16754 in a large cohort of patients with cytogenetically normal acute myeloid leukemia.<h4>Design and methods</h4>Four-hundred and thirty-three intensively treated and mo ...[more]

PMID: 21659357

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Project description:Rat sarcoma gene (RAS) holds great importance in pathogenesis of acute myeloid leukemia (AML). The activated mutations in Neuroblastoma rat sarcoma viral oncogene homolog (NRAS) and Kirsten rat sarcoma viral oncogene homolog (KRAS) confers proliferative and survival signals, deliberating numerous effects on overall survival and progression free survival in AML patients. In this study thirty one (31) blood samples of adult newly diagnosed AML patients were collected to identify possible incidence of mutations through amplification of KRAS (exon 1 and 2) and NRAS gene (exon 1 and 2) using polymerase chain reaction (PCR). Amplicons were then subjected to sequencing and were analyzed through Geneious Prime 2019. Five of thirty one (16.12%) patients had altered sites in either NRAS or KRAS. The NRAS mutations were observed in three AML patients (N = 3, 9.67%). A novel missense mutation NRAS-I36R (239 T > G) representing a substitution of single nucleotide basepair found in NRAS exon 1 while exon 2 was detected with heterozygous mutation NRAS-E63X (318G > T) and insertion (A), resulting in frameshift of the amino acid sequence and insertion of two nucleotide basepairs (TA) in two of the patients. KRAS mutations (N = 2, 6.45%) were found in exon 1 whereas no mutations in KRAS exon 2 were detected in our patient cohort. Mutation in KRAS Exon 1, KRAS-D30N (280G > A) was observed in two patients and one of them also had a novel heterozygous mutation KRAS-L16N (240G > C). In addition there was no statistically significant association of mutRAS gene of AML patients with several prognostic markers including age, gender, karyotyping, CD34 positivity, cytogenetic abnormalities, total leukocyte count, white blood cell count and French-American-British (FAB) classification. However, the presence of mutRAS gene were strongly associated (p = 0.001) with increased percentage of bone marrow blasts. The prevalence of mutations in correlation with clinical and hematological parameter is useful for risk stratification in AML patients.

Dataset Information

Clinical outcome and gene- and microRNA-expression profiling according to the Wilms tumor 1 (WT1) single nucleotide polymorphism rs16754 in adult de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study.

Publications

Clinical outcome and gene- and microRNA-expression profiling according to the Wilms tumor 1 (WT1) single nucleotide polymorphism rs16754 in adult de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study.

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