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Frequent variations in cancer-related genes may play prognostic role in treatment of patients with chronic myeloid leukemia.

ABSTRACT: BACKGROUND:Genome variability of host genome and cancer cells play critical role in diversity of response to existing therapies and overall success in treating oncological diseases. In chronic myeloid leukemia targeted therapy with tyrosine kinase inhibitors demonstrates high efficacy in most of the patients. However about 15 % of patients demonstrate primary resistance to standard therapy. Whole exome sequencing is a good tool for unbiased search of genetic variations important for prognosis of survival and therapy efficacy in many cancers. We apply this approach to CML patients with optimal response and failure of tyrosine kinase therapy. RESULTS:We analyzed exome variations between optimal responders and failures and found 7 variants in cancer-related genes with different genotypes in two groups of patients. Five of them were found in optimal responders: rs11579366, rs1990236, rs176037, rs10653661, rs3803264 and two in failures: rs3099950, rs9471966. These variants were found in genes associated with cancers (ANKRD35, DNAH9, MAGEC1, TOX3) or participating in cancer-related signaling pathways (THSD1, MORN2, PTCRA). CONCLUSION:We found gene variants which may become early predictors of the therapy outcome and allow development of new early prognostic tests for estimation of therapy efficacy in CML patients. Normal genetic variation may influence therapy efficacy during targeted treatment of cancers.

SUBMITTER: Lavrov AV

PROVIDER: S-EPMC4895599 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Frequent variations in cancer-related genes may play prognostic role in treatment of patients with chronic myeloid leukemia.

Lavrov Alexander V AV Chelysheva Ekaterina Y EY Smirnikhina Svetlana A SA Shukhov Oleg A OA Turkina Anna G AG Adilgereeva Elmira P EP Kutsev Sergey I SI

BMC genetics 20160127

<h4>Background</h4>Genome variability of host genome and cancer cells play critical role in diversity of response to existing therapies and overall success in treating oncological diseases. In chronic myeloid leukemia targeted therapy with tyrosine kinase inhibitors demonstrates high efficacy in most of the patients. However about 15 % of patients demonstrate primary resistance to standard therapy. Whole exome sequencing is a good tool for unbiased search of genetic variations important for prog ...[more]

PMID: 26822197

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Project description:BackgroundChemotactic cytokines play a crucial role in the development of acute myeloid leukemia (AML). Thus, investigating the mechanisms of chemotactic cytokine-related genes (CCRGs) in AML is of paramount importance.MethodsUsing the TCGA-AML, GSE114868, and GSE12417 datasets, differential expression analysis identified differentially expressed CCRGs (DE-CCRGs). These genes were screened by overlapping differentially expressed genes (DEGs) between AML and control groups with CCRGs. Subsequently, functional enrichment analysis and the construction of a protein-protein interaction (PPI) network were conducted to explore the functions of the DE-CCRGs. Univariate Cox regression, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses identified relevant prognostic genes and developed a prognostic model. Survival analysis of the prognostic gene was performed, followed by functional similarity analysis, immune analysis, enrichment analysis, and drug prediction analysis.ResultsDifferential expression analysis revealed 6,743 DEGs, of which 29 DE-CCRGs were selected for this study. Functional enrichment analysis indicated that DE-CCRGs were primarily involved in chemotactic cytokine-related functions and pathways. Six prognostic genes (CXCR3, CXCR2, CXCR6, CCL20, CCL4, and CCR2) were identified and incorporated into the risk model. The model's performance was validated using the GSE12417 dataset. Survival analysis showed significant differences in AML overall survival (OS) between prognostic gene high and low expression groups, indicating that prognostic gene might be significantly associated with patient survival. Additionally, nine different immune cells were identified between the two risk groups. Correlation analysis revealed that CCR2 had the most significant positive correlation with monocytes and the most significant negative correlation with resting mast cells. The tumor immune dysfunction and exclusion score was lower in the high-risk group.ConclusionCXCR3, CXCR2, CXCR6, CCL20, CCL4, and CCR2 were identified as prognostic genes correlated to AML and the tumor immune microenvironment. These findings offerred novel insights into the prevention and treatment of AML.

Project description:A previous study has demonstrated a significant decrease in the TCR? gene expression level in chronic myeloid leukemia (CML); thus, we further investigated the expression of TCR?-regulating factors, the distribution of the TCR? 3' untranslated region (3'-UTR) splice variants, and the expression level and correlation of the alternative splicing factor/splicing factor 2 (ASF/SF-2), Fc?RI? and ZAP-70 genes. TCR? 3'-UTR splice variants were identified in peripheral blood mononuclear cells (PBMCs) from 14 healthy individuals, 40 patients with CML and 22 patients with CML in complete remission (CML-CR) by RT-PCR. The expression level of the TCR?, Fc?RI?, ASF/SF-2 and ZAP-70 genes was analyzed by real-time quantitative PCR. While the expression of TCR? gene in the CML group was significantly lower than that in the healthy individual and CML-CR groups, a significantly higher expression of the FceRI? and ASF/SF-2 genes was found in the CML group. Two types of splicing forms were detected in all of the healthy individual CML-CR cases: wild type (WT) TCR? 3'-UTR and alternatively splieced (AS) TCR? 3'-UTR which have been alternatively splieced in the WT TCR? 3'-UTR . However, 35% of the CML cases contained only the wild type TCR? 3'-UTR isoform. Based on the TCR? 3'-UTR isoform expression characteristic, we divided the patients with CML into two subgroups: the WT+AS- CML group, containing patients that express only the wild type TCR? 3'-UTR, and the WT+AS+ CML group, which contained patients that expressed two TCR? 3'-UTR isoforms. A significantly different ASF/SF-2 and Fc?RI? gene expression pattern was found between the WT+AS- and WT+AS+CML groups. We concluded that defective TCR? expression may be characterized in the WT+AS-and WT+AS+CML subgroups by the different gene expression pattern. The overexpression of ASF/SF2, which alternatively splices the TCR? 3'-UTR, is thought to participate in feedback regulation. The characteristics of TCR? 3'-UTR alternative splicing may be a novel immunological marker for the evaluation of the CML immune status.

Project description:Accurate prognostic stratification of patients can provide guidance for personalized therapy. Many prognostic models for acute myeloid leukemia (AML) have been reported, but most have considerable inaccuracies due to contained variables with insufficient capacity of predicting survival and lack of adequate verification. Here, 235 genes strongly related to survival in AML were systematically identified through univariate Cox regression analysis of eight independent AML datasets. Pathway enrichment analysis of these 235 genes revealed that the IL-2/STAT5 signaling pathway was the most highly enriched. Through Cox proportional-hazards regression model and stepwise algorithm, we constructed a six-gene STAT5-associated signature based on the most robustly survival-related genes related to the IL-2/STAT5 signaling pathway. Good prognostic performance was observed in the training cohort (GSE37642-GPL96), and the signature was validated in seven other validation cohorts. As an independent prognostic factor, the STAT5-associated signature was positively correlated with patient age and ELN2017 risk levels. An integrated score based on these three prognostic factors had higher prognostic accuracy than the ELN2017 risk category. Characterization of immune cell infiltration indicated that impaired B-cell adaptive immunity, immunosuppressive effects, serious infection, and weakened anti-inflammatory function tended to accompany high-risk patients. Analysis of in-house clinical samples revealed that the STAT5-assocaited signature risk scores of AML patients were significantly higher than those of healthy people. Five chemotherapeutic drugs that were effective in these high-risk patients were screened in silico. Among the five drugs, MS.275, a known HDAC inhibitor, selectively suppressed the proliferation of cancer cells with high STAT5 phosphorylation levels in vitro. Taken together, the data indicate that the STAT5-associated signature is a reliable prognostic model that can be used to optimize prognostic stratification and guide personalized AML treatments.

Project description:IntroductionAcute myeloid leukemia (AML) is an aggressive blood cancer with high heterogeneity and poor prognosis. Although the metabolic reprogramming of nicotinamide adenine dinucleotide (NAD) has been reported to play a pivotal role in the pathogenesis of acute myeloid leukemia (AML), the prognostic value of NAD metabolism and its correlation with the immune microenvironment in AML remains unclear.MethodsWe utilized our large-scale RNA-seq data on 655 patients with AML and the NAD metabolism-related genes to establish a prognostic NAD metabolism score based on the sparse regression analysis. The signature was validated across three independent datasets including a total of 1,215 AML patients. ssGSEA and ESTIMATE algorithms were employed to dissect the tumor immune microenvironment. Ex vivo drug screening and in vitro experimental validation were performed to identify potential therapeutic approaches for the high-risk patients. In vitro knockdown and functional experiments were employed to investigate the role of SLC25A51, a mitochondrial NAD+ transporter gene implicated in the signature.ResultsAn 8-gene NAD metabolism signature (NADM8) was generated and demonstrated a robust prognostic value in more than 1,800 patients with AML. High NADM8 score could efficiently discriminate AML patients with adverse clinical characteristics and genetic lesions and serve as an independent factor predicting a poor prognosis. Immune microenvironment analysis revealed significant enrichment of distinct tumor-infiltrating immune cells and activation of immune checkpoints in patients with high NADM8 scores, acting as a potential biomarker for immune response evaluation in AML. Furthermore, ex vivo drug screening and in vitro experimental validation in a panel of 9 AML cell lines demonstrated that the patients with high NADM8 scores were more sensitive to the PI3K inhibitor, GDC-0914. Finally, functional experiments also substantiated the critical pathogenic role of the SLC25A51 in AML, which could be a promising therapeutic target.ConclusionOur study demonstrated that NAD metabolism-related signature can facilitate risk stratification and prognosis prediction in AML and guide therapeutic decisions including both immunotherapy and targeted therapies.

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Frequent variations in cancer-related genes may play prognostic role in treatment of patients with chronic myeloid leukemia.

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Frequent variations in cancer-related genes may play prognostic role in treatment of patients with chronic myeloid leukemia.

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