Dataset Information

Phe354Leu Polymorphism of LKB1 Is a Potential Prognostic Factor for Cytogenetically Normal Acute Myeloid Leukemia.

ABSTRACT: BACKGROUND/AIM:Liver kinase B1 (LKB1) is a major activator of the AMP-dependent kinase/mammalian target of rapamycin pathway. The prevalence and the specificity of LKB1 gene mutation in acute myeloid leukemia (AML) have not been well established. This study aimed to examine mutation of LKB1 in AML and its clinical and pathological implications. PATIENTS AND METHODS:Eighty-five patients newly diagnosed with cytogenetically normal AML were analyzed using polymerase chain reaction followed by direct sequencing. RESULTS:A silent mutation (837C>T) of LKB1 was detected in one patient and a pathogenic polymorphism Phe354Leu which diminishes LKB1 ability to maintain cell polarity was detected in six (7%) patients. The Phe354Leu polymorphism occurred concurrently with mutations of nucleophosmin 1 (NPM1), fms-related tyrosine kinase 3 (FLT3) and CCAAT/enhancer binding protein alpha (CEBPA), but not with metabolism-related genes, isocitrate dehydrogenase [nicotinamide adenine dinucleotide phosphate (+)]1 (IDH1) and IDH2. Patients with Phe354Leu polymorphism diagnosed at younger ages had a worse overall survival. CONCLUSION:LKB1 may be involved in the leukemogenesis and progression of cytogenetically normal AML.

SUBMITTER: Yang MY

PROVIDER: S-EPMC5656856 | biostudies-literature | 2017 Sep-Oct

REPOSITORIES: biostudies-literature

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Phe354Leu Polymorphism of <i>LKB1</i> Is a Potential Prognostic Factor for Cytogenetically Normal Acute Myeloid Leukemia.

Yang Ming-Yu MY Hsiao Hui-Hua HH Liu Yi-Chang YC Hsu Cheng-Ming CM Lin Sheng-Fung SF Lin Pai-Mei PM

In vivo (Athens, Greece) 20170901 5

<h4>Background/aim</h4>Liver kinase B1 (LKB1) is a major activator of the AMP-dependent kinase/mammalian target of rapamycin pathway. The prevalence and the specificity of LKB1 gene mutation in acute myeloid leukemia (AML) have not been well established. This study aimed to examine mutation of LKB1 in AML and its clinical and pathological implications.<h4>Patients and methods</h4>Eighty-five patients newly diagnosed with cytogenetically normal AML were analyzed using polymerase chain reaction fo ...[more]

PMID: 28882949

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Project description:BACKGROUND:Aberrant DNA methylation is known to occur in patients with acute myeloid leukemia (AML), whereas methylation signatures and prognostic markers have been proposed. The objective of the current study was to evaluate all CpG sites of the genome and identify prognostic methylation markers for overall survival in patients with AML with normal karyotype (AML-NK). METHODS:AML-NK samples from 7 SWOG trials were analyzed using a novel genome-wide approach called "CHARMcox" (comprehensive high-throughput array-based relative methylation analysis combined with the Cox proportional hazards model) controlling for known clinical covariates. CHARMcox was applied to a phase 1 discovery cohort (72 patients) to identify survival-associated methylation regions (SAMRs). Subsequently, using bisulfite pyrosequencing, SAMRs were studied in phase 2 model-building (65 patients) and phase 3 validation (65 patients) cohorts. An independent external cohort from The Cancer Genome Atlas (TCGA) AML study (LAML) was used for further validation (93 patients). RESULTS:Two SAMRs, located at the CpG island shores of leucine zipper tumor suppressor 2 (LZTS2) and nuclear receptor subfamily 6 group a member 1 (NR6A1), respectively, were identified. Multivariable analyses demonstrated that hypomethylation of either LZTS2 or NR6A1 was associated with worse overall survival in the SWOG cohort (P<.001). The prognosis was validated in patients with AML-NK from the TCGA-LAML cohort. Methylation values below the median at both markers predicted worse overall survival (SWOG: hazard ratio, 1.89 [P<.001]; and TCGA-LAML: hazard ratio, 2.08 [P=.006]). The C-statistic was 0.71 for both cohorts, and the impact was independent of the Fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) status. CONCLUSIONS:The 2 methylation markers, measurable by clinically applicable assays such as bisulfite pyrosequencing, are promising for risk stratification among patients with AML-NK. Cancer 2017;123:2472-81. © 2017 American Cancer Society.

Dataset Information

Phe354Leu Polymorphism of LKB1 Is a Potential Prognostic Factor for Cytogenetically Normal Acute Myeloid Leukemia.

Publications

Phe354Leu Polymorphism of <i>LKB1</i> Is a Potential Prognostic Factor for Cytogenetically Normal Acute Myeloid Leukemia.

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