Alexey I. Kalinkin

Research Centre for Medical Genetics

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Co-Authors

V. V. Strelnikov

Research Centre for Medical Genetics

АС

А. С. Танас

Research Centre for Medical Genetics

Ekaterina Kuznetsova

Sechenov University

ВС

В.О. Сигин

Research Centre for Medical Genetics

Zaletaev Dv

Research Centre for Medical Genetics

МВ

М. В. Немцова

Sechenov University

E. Ignatova

Sarah Cannon Research Institute

НВ

Н. В. Литвяков

Tomsk National Research Medical Center

Irina V. Bure

Russian Medical Academy of Continuous Professional Education

ИВ

И.И. Виноградов

Ryazan State Medical University named after Academician I.P. Pavlov

Cooperative Institutions

Sechenov University

Ministry of Health of the Russian Federation

Research Centre for Medical Genetics

Russian Academy of Sciences

Russian Medical Academy of Continuous Professional Education

Russian Cancer Research Center NN Blokhin

Research Institute of Medical Genetics of Russian Academy of Medical Sciences

Pirogov Russian National Research Medical University

Academy of Medical Sciences

Federal Medical-Biological Agency

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Analysis of miRNA Expression in Patients with Rheumatoid Arthritis during Olokizumab Treatment

Journal of Personalized Medicine (2020)

Irina V. Bure D. S. Mikhaylenko Ekaterina Kuznetsova Ekaterina A. Alekseeva Kristina I. Bondareva

Rheumatoid arthritis (RA) is the most common autoimmune disease worldwide. Epigenetic alternations of microRNAs (miRNAs) can contribute to its pathogenesis and progression. As the first line therapy with DMARDs is not always successful, other drugs and therapeutic targets should be applied. This study aims to measure the expression level of plasma miRNAs in RA patients treated with olokizumab and to evaluate their potential as prognostic biomarkers. The expression of 9 miRNAs was quantified in 103 RA patients before treatment and at weeks 12 and 24 of olokizumab therapy by reverse transcription-polymerase chain reaction (RT-PCR) assay and analyzed in groups of responders and non-responders. Almost all miRNAs changed their expression during therapy. The ROC curve analysis of the most prominent of them together with consequent univariate and multivariate regression analysis revealed statistically significant associations with the olokizumab therapy efficiency scores for miR-26b, miR-29, miR-451, and miR-522. Therefore, these miRNAs might be a potential therapeutic response biomarker.

Pathogenesis

10.3390/jpm10040205

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Citations (10)

Genome-Wide Methylotyping Resolves Breast Cancer Epigenetic Heterogeneity and Suggests Novel Therapeutic Perspectives

Epigenomics (2019)

А. С. Танас В.О. Сигин Alexey I. Kalinkin Н. В. Литвяков Е. М. Slonimskaya

Aim: To provide a breast cancer (BC) methylotype classification by genome-wide CpG islands bisulfite DNA sequencing. Materials & methods: XmaI-reduced representation bisulfite sequencing DNA methylation sequencing method was used to profile DNA methylation of 110 BC samples and 6 normal breast samples. Intrinsic DNA methylation BC subtypes were elicited by unsupervised hierarchical cluster analysis, and cluster-specific differentially methylated genes were identified. Results & conclusion: Overall, six distinct BC methylotypes were identified. BC cell lines constitute a separate group extremely highly methylated at the CpG islands. In turn, primary BC samples segregate into two major subtypes, highly and moderately methylated. Highly and moderately methylated superclusters, each incorporate three distinct epigenomic BC clusters with specific features, suggesting novel perspectives for personalized therapy.

Epigenomics

Methylated DNA immunoprecipitation

CpG site

Bisulfite sequencing

Illumina Methylation Assay

Differentially methylated regions

Bisulfite

10.2217/epi-2018-0213

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Citations (32)

17P Cyclophosphamide influence on survival probability of breast cancer patients depending on leukotriene receptor LTB4R gene expression level

Annals of Oncology (2020)

Alexey I. Kalinkin В.О. Сигин А. С. Танас V. V. Strelnikov

Log-rank test

10.1016/j.annonc.2020.08.2176

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Design of Marker Panels for Prediction of Neoadjuvant Chemotherapy Response of Triple-Negative Breast Tumors Based on the Results of Genome-Wide DNA Methylation Screening

Russian Journal of Genetics (2022)

Alexey I. Kalinkin В.О. Сигин E. Ignatova М. А. Фролова Ekaterina Kuznetsova

Human genetics

10.1134/s1022795422070080

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Genetic screening of Russian Usher syndrome patients toward selection for gene therapy

Ophthalmic Genetics (2018)

Marianna E. Ivanova В. Н. Трубилин Dmitry S. Atarshchikov Andrey M. Demchinsky V. V. Strelnikov

Background: Usher syndrome (USH) is heterogeneous in nature and requires genetic test for diagnosis and management. Mutations in USH associated genes are reported in some populations except Russians. Here, we first time represented the mutation spectrum of a Russian USH cohort.Methods: Twenty-eight patients with USH were selected from 3214 patients from Deaf-Blind Support Foundation "Con-nection" during 2014–2016 following the observational study NCT03319524. Complete ophthalmologic, ENT, and vestibular medical tests were done for clinical characterization. NGS, MLPA, and Sanger sequencing were considered for genetic analysis.Results: Around 53.57% and 39.28% patients had USH1 and USH2, respectively; 17.85% cases (n = 5/28) had no known mutation. Eleven (73.33%) subjects showed variations in USH1 associated genes MYO7A (72.72%), CDH23 (9.09%), PCDH15 (9.09%), and USH1C (9.09%). Eleven mutations are detected in MYO7A where 54.54% are novel. MYO7A: p.Q18* was most frequent (27.27%) mutation and is associated with early manifestation and most severe clinical picture. Two novel mutations (p.E1301* and c.158-?_318+?del) are detected in PCDH15 gene. Around 90.90% patients suspected to be USH2 are confirmed by genetic testing. Eleven mutations detected in the USH2A gene, where 27.27% were novel. Most common USH2A mutation is p.W3955* (50%) followed by p.E767fs, p.R1653*, and c.8682-9A> G (20% each).Conclusion: The Russian USH cohort shows both novel and known USH mutations. Clinically the prevalence of USH2 is low (39.28%) and the frequency of MYO7A mutations responsible for USH1B is very high (63.63%, N = 7/11) compared to other cohorts. These seven patients carrying MYO7A mutations are preliminarily eligible for the UshStat® gene therapy.

Usher syndrome

Sanger sequencing

10.1080/13816810.2018.1532527

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Identification of prognostically significant DNA methylation signatures in patients with various breast cancer types

Bulletin of Russian State Medical University (2022)

Alexey I. Kalinkin V. O. Sigin MV Nemtsova В В Стрельников

Breast cancer (BC) is the most frequently diagnosed cancer and one of the major causes of female mortality. The development of prognostic models based on multiomics data is the main goal of precision oncology. Aberrant DNA methylation in BC is a diagnostic marker of carcinogenesis. Despite the existing factors of BC prognosis, introduction of methylation markers would make it possible to obtain more accurate prognostic scores. The study was aimed to assess DNA methylation signatures in various BC subtypes for clinical endpoints and patients' clinicopathological characteristics. The data on methylation of CpG dinucleotides (probes) and clinical characteristics of BC samples were obtained from The Cancer Genome Atlas Breast Cancer database. CpG dinucleotides associated with the selected endpoints were chosen by univariate Cox regression method. The LASSO method was used to search for stable probes, while further signature construction and testing of the clinical characteristics independence were performed using multivariate Cox regression. The dignostic and prognostic potential of the signatures was assessed using ROC analysis and Kaplan–Meier curves. It has been shown that the signatures of selected probes have a significant diagnostic (AUC 0.76–1) and prognostic (p < 0.05) potential. This approach has made it possible to identify 47 genes associated with good and poor prognosis, among these five genes have been described earlier. If the genome-wide DNA analysis results are available, the research approach applied can be used to study molecular pathogenesis of BC and other disorders.

CpG site

Univariate

10.24075/brsmu.2022.056

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Mutations in Epigenetic Regulation Genes in Gastric Cancer

Cancers (2021)

М. В. Немцова Alexey I. Kalinkin Ekaterina Kuznetsova Irina V. Bure Ekaterina A. Alekseeva

We have performed mutational profiling of 25 genes involved in epigenetic processes on 135 gastric cancer (GC) samples. In total, we identified 79 somatic mutations in 49/135 (36%) samples. The minority (n = 8) of mutations was identified in DNA methylation/demethylation genes, while the majority (n = 41), in histone modifier genes, among which mutations were most commonly found in KMT2D and KMT2C. Somatic mutations in KMT2D, KMT2C, ARID1A and CHD7 were mutually exclusive (p = 0.038). Mutations in ARID1A were associated with distant metastases (p = 0.03). The overall survival of patients in the group with metastases and in the group with tumors with signet ring cells was significantly reduced in the presence of mutations in epigenetic regulation genes (p = 0.036 and p = 0.041, respectively). Separately, somatic mutations in chromatin remodeling genes correlate with low survival rate of patients without distant metastasis (p = 0.045) and in the presence of signet ring cells (p = 0.0014). Our results suggest that mutations in epigenetic regulation genes may be valuable clinical markers and deserve further exploration in independent cohorts.

ARID1A

Cancer Epigenetics

10.3390/cancers13184586

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Метилирование гена LTB4R как маркёра потенциальной чувствительности трижды негативного рака молочной железы к ингибиторам лейкотриеновых рецепторов

Фармакогенетика и Фармакогеномика (2018)

Alexey I. Kalinkin В.О. Сигин V. V. Strelnikov E. Ignatova Т. В. Кекеева

The problem of translation of modern achievements of personalized medicine into everyday clinical practice is actively discussed, but far from being resolved. The authors presented the clinical case of adverse course of juvenile myoclonic epilepsy in a 63-year-old woman. The authors emphasized that after the correction of antiepileptic therapy, taking into account the position of personalized medicine, not only achieved pharmacoinduced remission of epileptic seizures, but also significantly improved the quality of life of the patient.

Clinical Practice

10.24411/2588-0527-2018-10008

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HRD Testing of Ovarian Cancer in Routine Practice: What Are We Dealing With?

International Journal of Molecular Sciences (2023)

Т. В. Кекеева Yu Yu Andreeva А. С. Танас Alexey I. Kalinkin С. В. Хохлова

Assessment of homologous recombination deficiency (HRD) status is now essential for ovarian cancer patient management. The aim of our study was to analyze the influence of ethnic variations, tumor purity, and neoadjuvant chemotherapy (CT) on the determination of HRD scores as well as to evaluate feasibility of HRD testing with the Amoy HRD Focus Assay in routine clinical practice. The HRD status, including the BRCA status and genomic scar score (GSS), was analyzed in 452 ovarian cancer specimens. The successful rate of HRD testing was 86% (388/452). The BRCA mutational rate was 29% (114/388); 252 samples (65%) were classified as HRD-positive. Our data demonstrate the feasibility of internal HRD testing by the AmoyDx HRD Focus Panel for high-grade serous ovarian cancer (HGSOC), showing results similar to other methods. The HRD rate in the Russian population is very similar to those of other European populations, as is the BRCA mutation frequency. The most substantial contribution to HRD level diversity is testing criteria depending on intrahospital arrangements. The analysis shows that biallelic BRCA alterations had higher GSS compared with those with monoallelic inactivation, consistent with positive HRD status. The study indicates that grades 1-2 of the pathological response caused by chemotherapy affect HRD scores and suggests controlling for tumor purity of 40% or more as a critical factor for GSS measurement.

10.3390/ijms241310497

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Results of expression microarray analysis of tumor tissue from patients with colorectal cancer

Experimental and Clinical Gastroenterology (2024)

Е. П. Куликов Sergey A. Mertsalov V. V. Strelnikov Alexey I. Kalinkin Evgeniya I. Shumskaya

The aim of the study was to evaluate the expression profile and search for markers of progression in tumor tissue in colorectal cancer. Materials and Methods - Tumor tissue samples obtained from videocolonoscopy in patients with verified colorectal cancer served as the material for the study. A total of 37 specimens were involved in the study. Of these, there were 14 samples with a “favorable” prognosis and 23 with an “unfavorable” prognosis. The quality and quantity of ribonucleic acid in the eluted solution were evaluated using an IMPLEN nanospectrophotometer (Germany). A SurePrint G3 HumanGeneExpv3 ArrayKit microarray kit (Agilent, USA) was used to assess gene expression. Microarrays were scanned on an InnoScan 1100 AL (USA) with subsequent image processing using Mapix Software (USA). For the procedure of searching for differentially expressed genes, we used the Moderated t-statistics method, which is implemented in the limma package. Results - Based on the scatter plot, the most divergent genes in samples with and without progression were selected. The following markers were selected: Marker9 (GZMB), Marker5 (CXCL11), Marker3 (SYNE4), Marker20 (MIR4432HG), Marker19 (ZDHHC11), Marker11 (COL17A1), Marker13 (ZDHHC11B), Marker17 (AGR3). Low-expressing genes mainly affected DNA replication and cell cycle pathways, whereas high-expressing genes affected metabolic pathways. Conclusions - We found an association of long-term outcomes with the expression of the gene combination ZDHHC11, MIR4432HG, and GZMB. Further study of this gene combination and increased sampling will allow the construction of a test system for predicting the course and response to treatment of patients with colorectal cancer.

Tissue microarray

10.31146/1682-8658-ecg-227-7-68-74

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