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Frequent Variations in Cancer-Related Genes May Play Prognostic Role in Treatment of Patients with Chronic Myeloid Leukemia Alexander V

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Frequent Variations in Cancer-Related Genes May Play Prognostic Role in Treatment of Patients with Chronic Myeloid Leukemia Alexander V Lavrov et al. BMC Genetics 2016, 17(Suppl 1):14 DOI 10.1186/s12863-015-0308-7 RESEARCH Open Access Frequent variations in cancer-related genes may play prognostic role in treatment of patients with chronic myeloid leukemia Alexander V. Lavrov1,2*, Ekaterina Y. Chelysheva3, Svetlana A. Smirnikhina1, Oleg A. Shukhov3, Anna G. Turkina3, Elmira P. Adilgereeva1 and Sergey I. Kutsev1,2 From The 7th International Young Scientists School “Systems Biology and Bioinformatics” (SBB’2015) Novosibirsk, Russia. 22-25 June 2015 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. Keywords: Genetic variation, Chronic myeloid leukemia, TKI resistance, Whole exome sequencing, Biomarkers, Prognostic factors Background result of this translocation two genes are fused: ABL Chronic myeloid leukemia (CML) accounts for about 10 % (chromosome 9) and BCR (chromosome 22) [1]. BCR/ABL of all leukemias. The primary mutation in blood stem cell is gene produces atypical tyrosine kinase – BCR/ABL which induced by the translocation between chromosomes 9 and activates MAPK pathway and induces cell proliferation, 22 leading to the formation of the so-called Philadelphia blocks apoptosis and leads to genome instability resulting chromosome (Ph+) – an aberrant chromosome 22. As a in further development of the disease. Till late 1990s the prognosis for the patients with CML * Correspondence: [email protected] was poor. The disease progressed gradually to the acceler- 1Laboratory of Mutagenesis, Federal State Budgetary Institution “Research ated phase, blast crisis and finally death. Invention of BCR/ ” Centre for Medical Genetics , Moskvorechie, 1, Moscow 115478, Russia ABLtyrosinekinaseinhibitor(TKI)madethediseasewell 2Department of Molecular and Cellular Genetics, State Budgetary Educational Institution of Higher Professional Education “Russian National Research controlled and dramatically improved patient’s survival. Medical University named after N.I. Pirogov” of Ministry of Health of the The first TKI – imatinib – has become the standard Russian Federation, Moscow, Russia therapy of CML since its FDA approval in 2001. Patient’s Full list of author information is available at the end of the article © 2016 Lavrov et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lavrov et al. BMC Genetics 2016, 17(Suppl 1):14 Page 36 of 48 survival considerably improved from 7.5 years after diagno- European Nucleotide Archive (http://www.ebi.ac.uk/ena/ sis before imatinib invention to 17.5 years now-a-days [2]. data/view/PRJEB9857). There were about 5300 unique However some patients still remain resistant to TKI therapy. variants in each sample. All 116,508 variants were merged The rate of primary resistance is in the range of 5–20 % [3, in one table for further annotation and analysis. Variants 4]. According to ELN recommendations 2013 [5] CML were found in 17,741 genes. In each gene we found from patients on TKI therapy are assigned to optimal responders, at least one variant in one or more samples up to 345 vari- failures and “warning” group. Optimal responders may con- ants (MUC16). The full list of genes with number of found tinue the same treatment, failures need treatment changes, variants is available in Additional file 2: Table S2. Pathway “warning” group needs careful observation with the readi- enrichment analysis using Gorilla (ver. Mar 28, 2015) [8] ness to change treatment options. Currently available prog- revealed possibly damaged by SNVs cellular pathways: nostic scores – Sokal and EUTOS may help to predict antigen processing and presentation of endogenous pep- patients with worse clinical outcome on TKIs although some tide antigen via MHC class I via ER pathway, TAP- − studies failed to demonstrate predictive value of EUTOS independent (p =1.8×10 7), interferon-gamma-mediated − score for different clinical outcomes including long-term signaling pathway (p =9.6×10 8) and O-glycan processing − overall survival rate [6, 7]. Therefore additional clinically (p =1.9×10 13); functions: peptide antigen binding (p = − − relevant prognostic markers for CML patients are extremely 1.8 × 10 10), MHC class II receptor activity (p =2.1×10 7); − important. High genetic variability of cancer cells in CML is and structures: MHC protein complex (p =3.7×10 11), difficult for analysis and selection of prognostic markers. integral component of lumenal side of endoplasmic − In this work we perform whole exome sequencing reticulum membrane (p =5.2×10 11), Golgi lumen (p = − (WES) of newly diagnosed CML patients and analyze 5×10 13) and ER to Golgi transport vesicle membrane − exomic variations which can serve as early predictive (p =7.7×10 10). The full list of the enrichment ana- markers of the high and low efficacy of TKI therapy. lysis results is available in Additional file 1: Table S3. Results Characteristics of the patients Variant analysis Twenty three patients were available with follow-up data at We were looking for variants which were present in all 6 months after beginning TKI treatment (11 males and 12 samples of one group and absent in all samples from the females; mean age – 42.4 years). Two patients (8.7 %) were opposite group. We performed such a filtering for optimal classified as failures, 7 patients (30.4 %) were assigned to responders and for the failures separately. In leukemic cells warning group and other 14 patients demonstrated optimal of all four optimal responder we found 11 333 variants in response according to ELN recommendations 2013. Blood total. These variants included both homozygous and het- samples from 8 patients were taken for further analysis: 4 erozygous SNPs. 152 of them were not present in either of optimal responders and 4 patients with TKI inefficacy (2 leukemic samples from patients with failure of the failures and 2 patients from the warning group). Frontline response. We further filtered missense and splice-site vari- therapy was imatinib in 3 optimal responders and 3 non ants and also variants in regulatory regions and we got only responders, and nilotinib in 1 responder and 1 non 27 variants. By manual verification of sequenced reads in responder.Twofailureswereswitchedtonilotiniband IGV browser [9, 10] we confirmed 21 variant. Based on dasatinib after 2.5 and 4 months of imatinib therapy. The GeneCards descriptions (available in October, 2014) we se- detailed description of the patients included in the study is lected 11 variants in genes known to be associated with available in the Additional file 1: Table S1. Blood samples cancers (ANKRD35 – rs11579366, ATP7B – rs732774, were drawn before starting TKI therapy when vast majority COSM147691, IGHV4-31 – rs61995642, ANPEP – rs25651, of nucleated blood cells were leukemic. Paired blood sam- DNAH9 – rs1990236, CCDC165 – rs632423, MAGEC1 – ples were drawn from 3 optimal responders after 6 months rs176037) or cancer-associated pathways like MAPK of TKI therapy during relapse for analysis of normal (FCRL3 – rs7522061, LRP2 – rs2229263, KLB – rs4975017) exomes. All 11 blood samples were sequenced. or cellular processes frequently deteriorated in cancer like DNA integrity control (FANCD2 – rs3864017). We selected Whole exome sequencing 3variants(ANKRD35 – rs11579366, DNAH9 – rs1990236, In total about 55 millions of nucleotides in targeted se- MAGEC1 – rs176037) positive for either SIFT [11] or Poly- quences were covered in average 20×. Sequences were Phen [12] score to validate them with Sanger sequencing. aligned to hg19. Ion Torrent Variant Caller plugin was We also selected additional variant previously not de- used to call variants. In each of 11 samples we found scribed in dbSNP135
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