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Genetic polymorphisms of histone methyltransferase SETD2 predicts prognosis and chemotherapy response in Chinese acute myeloid leukemia patients.

ABSTRACT: BACKGROUND:SETD2, the single mediator of trimethylation of histone 3 at position lysine 36, has been reported associated with initiation progression and chemotherapy resistance in acute myeloid leukemia (AML). Whether polymorphisms of SETD2 affect prognosis and chemotherapy response of AML remains elusive. METHODS:Three tag single-nucleotide polymorphisms (tagSNPs) of SETD2 were genotyped in 579 AML patients by using Sequenom Massarray system. Association of the SNPs with complete remission (CR) rate after Ara-C based induction therapy, overall survival (OS) and relapse-free survival (RFS) were analyzed. RESULT:Survival analysis indicated that SETD2 rs76208147 TT genotype was significantly associated with poor prognosis of AML (TT vs. CC?+?CT hazard ratio: HR?=?1.838, 95% confidence interval (CI) 1.005-3.360, p?=?0.048). After adjusting for the known prognostic factors including risk stratification, age, allo-SCT, WBC count and LDH count, rs76208147 TT genotype was still associated with OS in the multivariate analysis (TT vs. CC?+?CT HR?=?1.923, 95% CI 1.007-3.675, p?=?0.048). In addition, after adjusting by other clinical features, patients with rs4082155? allele G carries showed higher rate of complete remission which indicated by CR rate (AG?+?GG vs. AA odd ratio (OR)?=?0.544, 95% CI 0.338-0.876, p?=?0.012). CONCLUSIONS:SETD2 genetic polymorphism is associated with AML prognosis and chemotherapy outcome, suggesting the possibility for development in AML diagnostics and therapeutics towards SETD2.

SUBMITTER: Wang S

PROVIDER: S-EPMC6437967 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Genetic polymorphisms of histone methyltransferase SETD2 predicts prognosis and chemotherapy response in Chinese acute myeloid leukemia patients.

Wang Suwei S Yuan Xiaoqing X Liu Yazhen Y Zhu Kewei K Chen Peng P Yan Han H Zhang Daoyu D Li Xi X Zeng Hui H Zhao Xielan X Chen Xiaoping X Zhou Gan G Cao Shan S

Journal of translational medicine 20190328 1

<h4>Background</h4>SETD2, the single mediator of trimethylation of histone 3 at position lysine 36, has been reported associated with initiation progression and chemotherapy resistance in acute myeloid leukemia (AML). Whether polymorphisms of SETD2 affect prognosis and chemotherapy response of AML remains elusive.<h4>Methods</h4>Three tag single-nucleotide polymorphisms (tagSNPs) of SETD2 were genotyped in 579 AML patients by using Sequenom Massarray system. Association of the SNPs with complete ...[more]

PMID: 30922329

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Project description:BackgroundAcute myeloid leukemia (AML) is a highly heterogenous disease with varying clinical outcomes among patients. Epithelial-mesenchymal transition (EMT) is an important mechanism underlying cancer metastasis and chemotherapy resistance. However, few EMT-based signatures have been established to predict AML prognosis and treatment efficacy.MethodsBy conducting comparative RNA-seq analysis, we discovered the differential expression of EMT genes between AML patients with relapse and those without relapse. Based on the prognostic analysis of the differentially expressed EMT genes, a metastasis-related EMT signature (MEMTs) was constructed. An analysis was conducted on both TARGET and TCGA cohorts to explore the possible association between MEMTs and prognosis in AML. Three separate chemotherapy treatment cohorts were utilized to assess the predictive efficacy of MEMTs for chemotherapy response. In addition, the potential correlation between MEMTs and the tumor microenvironment was also investigated. Finally, random forest analysis and functional experiments were conducted to verify the key MEMTs gene associated with AML metastasis.ResultsBased on expression and prognostic analysis, we constructed MEMTs that include three EMT genes (CDH2, LOX, and COL3A1). Our findings suggested that the MEMTs could act as a prognostic factor for AML patients, and furthermore, it proved to be a predictor of their response to chemotherapy. Specifically, high MEMTs was associated with worse prognosis and poor response to chemotherapy, while low MEMTs was linked to better prognosis and higher response rates. Random forest and functional experiments demonstrate that CDH2 is a key gene promoting leukemia cell metastasis among the three MEMTs genes.ConclusionThe identification of MEMTs could potentially act as a predictor for the prognosis and the response to chemotherapy in AML patients. Individual tumor evaluation based on MEMTs could provide personalized treatment options for AML patients in the future.

Dataset Information

Genetic polymorphisms of histone methyltransferase SETD2 predicts prognosis and chemotherapy response in Chinese acute myeloid leukemia patients.

Publications

Genetic polymorphisms of histone methyltransferase SETD2 predicts prognosis and chemotherapy response in Chinese acute myeloid leukemia patients.

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