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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: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:BackgroundAs a severe hematological malignancy in adults, acute myeloid leukemia (AML) is characterized by high heterogeneity and complexity. Emerging evidence highlights the importance of the tumor immune microenvironment and lipid metabolism in cancer progression. In this study, we comprehensively evaluated the expression profiles of genes related to lipid metabolism and immune modifications to develop a prognostic risk signature for AML.MethodsFirst, we extracted the mRNA expression profiles of bone marrow samples from an AML cohort from The Cancer Genome Atlas database and employed Cox regression analysis to select prognostic hub genes associated with lipid metabolism and immunity. We then constructed a prognostic signature with hub genes significantly related to survival and validated the stability and robustness of the prognostic signature using three external datasets. Gene Set Enrichment Analysis was implemented to explore the underlying biological pathways related to the risk signature. Finally, the correlation between signature, immunity, and drug sensitivity was explored.ResultsEight genes were identified from the analysis and verified in the clinical samples, including APOBEC3C, MSMO1, ATP13A2, SMPDL3B, PLA2G4A, TNFSF15, IL2RA, and HGF, to develop a risk-scoring model that effectively stratified patients with AML into low- and high-risk groups, demonstrating significant differences in survival time. The risk signature was negatively related to immune cell infiltration. Samples with AML in the low-risk group, as defined by the risk signature, were more likely to be responsive to immunotherapy, whereas those at high risk responded better to specific targeted drugs.ConclusionsThis study reveals the significant role of lipid metabolism- and immune-related genes in prognosis and demonstrated the utility of these signature genes as reliable bioinformatic indicators for predicting survival in patients with AML. The risk-scoring model based on these prognostic signature genes holds promise as a valuable tool for individualized treatment decision-making, providing valuable insights for improving patient prognosis and treatment outcomes in AML.

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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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