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DOI: 10.21294/1814-4861-2018-17-4-53-58 УДК: 618.19-006.6-056.7-053:575.113:575.24(47+57)
Для цитирования: Анисименко М.С., Пауль Г.А., Козяков А.Е., Гуткина Н.И., Бердюгина Д.А., Гаранин А.Ю., Буторина А.В., Горностаева Е.В., Хафизов К.Ф., Вяткин Ю.В., Штокало Д.Н., Коваленко С.П. Спектр мутаций гена BRCA1 у больных раком молочной железы в молодом возрасте в России. Сибирский онкологический журнал. 2018; 17 (4): 53-58. - doi: 10.21294/1814-4861-2018-17-4-53-58.
For citation: Anisimenko M.S., Paul G.A., Kozyakov A.E., Gutkina N.I., Berdyugina D.A., Garanin A.Yu., Butorina A.V., Gornostaeva E.V., Khafizov K.F., Vyatkin Yu.V., Shtokalo D.N., Kovalenko S.P. The spectrum of BRCA1 gene mutations in early onset breast cancer patients from Russia. Siberian Journal of Oncology. 2018; 17 (4): 53-58. - doi: 10.21294/1814-4861-2018-17-4-53-58.
СПЕКТР МУТАЦИЙ ГЕНА BRCA1 У БОЛЬНЫХ РАКОМ МОЛОЧНОЙ ЖЕЛЕЗЫ В МОЛОДОМ ВОЗРАСТЕ В РОССИИ
М.С. Анисименко12, Г.А. Пауль2, А.Е. Козяков3, Н.И. Гуткина1,
Д.А. Бердюгина12, А.Ю. Гаранин12, А.В. Буторина12, Е.В. Горностаева12,
К.Ф. Хафизов4, Ю.В. Вяткин5, Д.Н. Штокало56, С.П. Коваленко127
Федеральный исследовательский центр фундаментальной и трансляционной медицины, г Новосибирск, Россия1
Россия, 630117, г Новосибирск, ул. Тимакова, 21
Лаборатория генодиагностики ООО «Биолинк», г Новосибирск, Россия2 Россия, 630117, г Новосибирск, ул. Тимакова, 22 Новосибирский областной клинический онкологический диспансер, Новосибирск, Россия. E-mail: jocus@bk.ru3 Россия, 630108, г Новосибирск, ул. Плахотного, 23
Центральный научно-исследовательский институт эпидемиологии Роспотребнадзора, г Москва, Россия4
Россия, 111123, г. Москва, ул. Новогиреевская, 3а4
ООО «АкадемДжин», г. Новосибирск, Россия5
Россия, 630090, г Новосибирск, пр. академика Лаврентьева, 65
Институт систем информатики им. А.П. Ершова СО РАН, г. Новосибирск, Россия6
Россия, 630090, г Новосибирск, пр. Академика Лаврентьева, 66
Новосибирский государственный университет, г Новосибирск, Россия7
Россия, 630090, г Новосибирск, ул. Пирогова, 17
Аннотация
Цель исследования - оценить частоту встречаемости патогенных мутаций в BRCA1 гене у женщин с раком молочной железы, проживающих в России. Материал и методы. Проведён анализ полной кодирующей части гена BRCA1 у 445 больных раком молочной железы на ранней стадии (возраст больных до 40 лет), проживающих в Новосибирской области (Россия), с помощью метода таргетного секвенирования на платформе Ion Torrent. Результаты. Выявлено 40 (9 %) носительниц различных патогенных мутаций. У 35 (7,9 %) пациенток обнаружена мутация 5382insC, описанная ранее как «мутация-основателя» в славянской популяции. У 5 (1,1 %) пациенток были выявлены другие различные патогенные мутации, а именно C61G, 462delCC, E143X, 4153delA и IVS18 + 1G> T. Кроме того, 29 генетических вариантов с отсутствующей или неясной клинической значимостью были обнаружены в гене BRCA1 у 445 больных раком молочной железы на ранней стадии. Выводы. Получены данные о частоте генетических вариаций гена BRCA1 у больных раком молочной железы на ранней стадии, проживающих в Новосибирской области (Россия). Доля мутации 5382insC составляет 87,5 % от всех патогенных мутаций в гене BRCA1, обнаруженных у пациенток.
Ключевые слова: ген ВРОД1, мутация, рак молочной железы в молодом возрасте, наследственный рак, секвенирование следующего поколения, таргетное секвенирование.
1=7 Анисименко Максим Сергеевич, jocus@bk.ru СИБИРСКИЙ ОНКОЛОГИЧЕСКИЙ ЖУРНАЛ. 2018; 17(4): 53-58
THE spectrum OF BRCA1 GENE MuTATIONS IN EARLY ONSET breast CANCER PATIENTS FROM RuSSIA
M.S. Anisimenko12, G.A. Paul2, A.E. Kozyakov3, N.I. Gutkina1,
D.A. Berdyugina12, A.Yu. Garanin12, A.V. butorina12, E.V. Gornostaeva12,
K.F. Khafizov4, Yu.V. Vyatkin5, D.N. Shtokalo56, S.P. Kovalenko127
Federal Research Center of Fundamental and Translational Medicine, Novosibirsk, Russia1
2, Timakova Street, 630117-Novosibirsk, Russia. E-mail: jocus@bk.ru1
BioLink Ltd, Novosibirsk, Russia2
2, Timakova Street, 630117-Novosibirsk, Russia2
Novosibirsk Regional Oncological Clinic, Novosibirsk, Russia3
2, Plahotnogo Street, 630108-Novosibirsk, Russia3
Central Research Institute of Epidemiology, Moscow, Russia4
3a, Novogireevskaya Street, 111123-Moscow, Russia4
AcademGene LLC, Novosibirsk, Russia5
6, Academician Lavrentiev Ave., 630090-Novosibirsk, Russia5
A.P. Ershov Institute of Informatics Systems, Novosibirsk, Russia6
6, Akademika Lavrentieva Ave., 630090-Novosibirsk, Russia6
Novosibirsk State University, Novosibirsk, Russia7
1, Pirogova Street, 630090-Novosibirsk, Russia7
Abstract
Aim of the study. Aim of the study was to estimate the occurrence of pathogenic mutations in the BRCA1 gene in Russian breast cancer patients. Material and methods. Complete coding sequence of the BRCA1 gene of 445 early onset breast cancer patients (under 40 years) from Novosibirsk region (Russia) were analyzed by targeted Next Generation Sequencing (NGS) using Ion Torrent platform. Results. Forty (9%) carriers of various pathogenic mutations were revealed. Thirty five (7,9%) patients carried 5382insC mutation, described earlier as a founder mutation for Slavic population. Five (1.1%) patients carried various pathogenic mutations, namely C61G, 462delCC, E143X, 4153delA, and IVS18+1G>T. Besides, 29 genetic variants with no clinical significance or with unknown clinical significance were detected in BRCA1 gene among 445 early onset breast cancer patients. Conclusions. Data on the frequency of genetic variations in the BRCA1 gene among early onset breast cancer patients in the Novosibirsk Region (Russia) were obtained. Proportion of the 5382insC mutation is 87.5% of all pathogenic mutations in the BRCA1 gene found in patients.
Keywords: BRCA1 gene, mutation, early onset breast cancer, hereditary cancer, NGS, targeted sequencing.
found even in large (about 8000) population samples [8]. Early onset cancer patient's cohort contains increased proportion of hereditary cancer cases, so analysis of this group can provide information on the spectrum and frequencies of pathogenic mutations in population. This information can be of value for the guidelines for the analysis of mutations among Russian citizens. In this study, we analyzed a complete coding sequence of BRCA1 gene of 445 early onset breast cancer patients from Novosibirsk region with the aim to estimate the occurrence of pathologic mutations in the BRCA1 gene in Russia.
Material and Methods
Blood samples were collected from 445 breast cancer patients of the Novosibirsk Regional Oncology Clinic between April 2013 and June 2016. The age of the patients at the time of diagnosis was from 19 to 40 years.
DNA was isolated from the blood samples using RealBest extraction 100 Kit (Vector-Best, Russia). Analysis of the complete coding sequence of the
Introduction
Hereditary factors account for up to 10% of all breast cancer cases [1]. A significant part of the hereditary forms of breast cancer is caused by mutations in the BRCA1 and BRCA2 genes. The likelihood of a malignancy during the lifespan for BRCA1/2 mutation carriers is very high (up to 90%) [2].
Several studies demonstrated the prevalence of BRCA1 5382insC mutation among breast/ovarian cancer patients in Russia [3-5]. Frequency of 185delAG, C61G, and 4153delA mutations is significantly less compared to 5382insC, the frequency of other mutations in BRCA1 gene remains unexplored [6, 7]. However, there are no exact figures regarding frequency of BRCA1 mutation in Russian population and among cancer patients, these data can be useful for screening programs and/or for placing objectives on the mutation analysis guidelines. According to our previous results, population study can reveal only frequent mutations (as BRCA1 5382insC), only single cases of other frequent mutations can be
Table 1
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Genetic variants found in early onset breast cancer patients in the Novosibirsk region
Exon/ Intron
HGVS genomic (GRSh37 assembly)
Mutation type
Base change
Designation HGVS cDNA HGVS protein
dbSNP
Clinical importance (BIC)
Number
of homozygous carriers
Homozygous carriers frequency
Number of heterozygous carriers
Heterozygous carriers frequency
Allele frequency
Allele Allele
fre- frequency
quency (1000
(ExAC) genomes)
Ol Ol
In 2 41267S10G>A IVS C>T 1VS2-14C>T c.81-14C>T - rs80358006 Unknown 0 0 1 0.0022 0.0011 0.0005 -
Ex 5 41258504A>C Missense T>G C61G c.181T>G p.CysölGly rs28897672 Yes 0 0 1 0.0022 0.0011 0.00007 -
In 5 41258417T>A IVS A>T IVS5+56A>T c.212+56A>T - - - 0 0 1 0.0022 0.0011 - -
Ex 7 41256236_41256237delGG Frameshift delCC 462delCC c.343_344delCC p.Proll5Terfs - - 0 0 1 0.0022 0.0011 - -
Ex 7 41256153C>A Nonsense G>T E143X c.427G>T p.Glul43Ter rs80356991 Yes 0 0 1 0.0022 0.0011 0.0001 -
In 7 41251931G>A IVS C>T IVS7-34C>T C.442-340T - rs799923 No 11 0.0247 139 0.3124 0.1809 0.1738 0.0986
Ex S 41251S03T>C Missense A>G il 79C c.536A>G p. Tyrl 79Cys rs56187033 Unknown 0 0 3 0.0067 0.0034 0.0003 0.0002
In 8 4125177SdelC IVS delG IVS8+14delG c. 547+14_547+14delG - rs273902771 Unknown 0 0 1 0.0022 0.0011 0.0001 -
Ex 9 41249263G>A Synonymous C>T 7100T C.5910T p.Cysl97= rs 1799965 No 0 0 1 0.0022 0.0011 0.0015 0.0004
Ex 11 412464S1T>C Missense A>G Q356R c,1067A>G p.Gln356Arg rs 1799950 Unknown 2 0.0045 37 0.0831 0.0461 0.0441 0.0218
Ex 11 4124629ST>C Missense A>G N417S c. 1250A>G p.Asn417Ser rsS0357113 Unknown 0 0 1 0.0022 0.0011 - -
Ex 11 41246092A >G Missense T>C E4S6L c,1456T>C p.Phe486Leu rs55906931 Unknown 0 0 1 0.0022 0.0011 0.0003 0.0002
Ex 11 41245900T>G Missense A>C N550H c,1648A>C p.Asn550His rs56012641 Unknown 0 0 3 0.0067 0.0034 0.0003 0.0002
Ex 11 41245471C>T Missense G>A D693N c.2077G>A p.Asp693Asn rs4986850 No 0 0 32 0.0719 0.0360 0.0568 0.0335
Ex 11 41245466G>A Synonymous C>T 2201 C>T C.20820T p.Ser694= rs1799949 No 31 0.0697 193 0.4337 0.2865 0.3483 0.3365
Ex 11 41245237A>G Synonymous T>C 2430T>C c.2311T>C p.Leu771 = rs 16940 No 27 0.0607 221 0.4966 0.3090 0.3420 0.3353
Ex 11 41244952G>A Missense C>T RS66C c.2596C>T p.ArgS66Cys rs41286300 No 0 0 1 0.0022 0.0011 0.0001 -
Ex 11 41244936G>A Missense ot P871L C.26120T p.Pro871Leu rs 799917 No 26 0.0584 223 0.5011 0.3090 0.4100 0.4561
Ex 11 41244435T>C Missense A>G E103SG c.3113A>G p.Glul038Gly rsl6941 No 23 0.0517 152 0.3416 0.2225 0.3429 0.3357
Ex 11 412444290T Missense G>A S1040N c.3119G>A p.SerlQ40Asn rs4986852 Unknown 0 0 4 0.0090 0.0045 0.0132 0.0098
Ex 11 41244029A>C Missense T>G S1173R c.3519T>G p.Serll73Arg - - 0 0 1 0.0022 0.0011 - -
Ex 11 41244000T>C Missense A>G K1183R c.3548A>G p.Lysll83Arg rs16942 No 30 0.0674 174 0.3910 0.2629 0.3490 0.3526
Ex 11 41243513delT Frameshift delA 4153delA c.4035_4035delA p.Glul345=fs rs80357711 Yes 0 0 1 0.0022 0.0011 0.00004 -
Ex 11 41243509T>C Missense A>G R1347G c.4039A>G p.Argl347Gly rs28897689 Unknown 0 0 4 0.0090 0.0045 0.0040 0.0006
Ex 13 41234470A>G Synonymous T>C 4427T>C c.4308T>C p.Serl436= rsl060915 No 25 0.0562 214 0.4809 0.2966 0.3431 0.3363
Ex 15 4122648SOA Missense G>T SI 5121 c.4535G>T p.Serl512Ile rsl800744 No 0 0 1 0.0022 0.0011 0.0022 0.0006
Ex 16 41223094T>C Missense A>G S1613G c.4837A>G p.Serl613Gly rsl799966 No 25 0.0562 226 0.5079 0.3101 0.3496 0.3558
Ex 16 4122304SA>G Missense T>C Ml 62 ST c.4883T>C p.Metl 628Thr rs4986854 Unknown 0 0 5 0.0112 0.0056 0.0015 0.0026
Ex 16 412229 75C>T Missense G>A M1652I c.4956G>A p.Metl652Ile rsl 799967 Unknown 0 0 22 0.0494 0.0247 0.0176 0.0112
Ex 17 41219694C>A Missense G>T A1669S c.5005G>T p.Alal 669Ser rs80357087 Unknown 0 0 2 0.0045 0.0022 0.00005 -
In 17 41216021G>A IVS C>T IVS17-530T C.5075-530T - rs8176258 No 0 0 9 0.0202 0.0101 - 0.0110
In 18 412158900A IVS G>T IVS18+1G>T c.5152+lG>T - rs80358094 Yes 0 0 1 0.0022 0.0011 - -
In 18 412158250T IVS G>A IVS18+66G>A c.5152+66G>A - rs3092994 No 31 0.0697 149 0.3348 0.2371 - 0.3425
Ex 20 41209082_41209083insG Frameshift insC 5382insC c.5263_5264insC p.Glnl756Profs rs80357906 Yes 0 0 35 0.0787 0.0393 - -
In 20 4120S9910T IVS G>A IVS20+78G>A c.5277+78G>A rs80358107 Unknown 0 0 3 0.0067 0.0034 0.0002
Figure 1. Frequency of the BRCA1 5382insC mutation in early onset breast cancer patients, unselected breast cancer patients, and in general population of Novosibirsk city
7,9%
Early onset
cancer patients cancer patients Novosibirsk
BRCA1 gene (22 exons, 5592 bp) was performed by targeted sequencing on IonTorrent platform. All exons with adjacent intron regions (20-80 bp) were completely covered with 68 amplicons (140-190 bp). Primers were designed by using Ion AmpliSeq Designer and Primer 3 software. The primer pairs were combined into 3 pools. Three multiplex PCR reactions were used to amplify the 68 selected fragments. Multiplex reaction products were combined and purified using Agencourt AMPure XP magnetic beads (Beckman Coulter, USA). The amplicons were ligated with bar codes and A/P1 adapters. Then enrichment was carried out with the primer pair complementary to adapters A and P1. Concentration of the purified enriched amplicons was measured using Qubit dsDNA HS Assay kit on the Qubit 3.0 fluorimeter (Life Technologies, USA). The normalized DNA libraries were then amplified by emulsion PCR using Ion PGM Hi-Q OT2 kit and sequenced using Ion PGM instrument (Life Technologies, USA) according to the manufacturer's instructions.
Bioinformatic analysis of the raw data was based on PRINSEQ technique [9]. The nucleotide sequences obtained in the analysis were compared with the reference sequence of the human genome GRCh37/ hg19 using the BWA-MEM software version 0.7.5 [10]. The search for genetic variants was carried out using the SAM tools software version 0.1.19 [11].
Results and discussion
Analysis of 445 early onset breast cancer patients revealed 35 genetic variants in BRCA1 gene. Results of the study are presented in Table 1.
We detected 40 carriers (9%) of various pathogenic mutations, including 35 carriers (7.9%) of 5382insC mutation. BRCA1 5382 insC was described as founder mutation for Slavic population [5]. Five patients (1.1%) carried pathogenic mutations C61G, 462delCC, E143X, 4153delA, and IVS18+1G>T (each particular mutation was found in a single patient in a heterozygote state). All pathogenic mutations are depicted in bold in Table 1. According to our previous results, the frequency of the 5382insC mutation among residents
of Novosibirsk city is 0.25% [8], the frequency of this mutation among unselected breast cancer patients in the Novosibirsk region is 3.6% [12]. Figure 1 shows the frequency of the 5382insC mutation among unselected breast cancer patients and in the cohort of early onset breast cancer patients in comparison with the frequency of this mutation in general population.
Remarkably, allele frequency of 9 genetic variants is at least twice higher than the frequency provided in the database for general population (ExAC or/and 1000 genomes), these variants are marked in italics in Table 1.
The frequency of three genetic variants has not assigned in dbSNP yet and are not specified in Table 1. Two of these variants were undisclosed for the first time. Ermolenko N.A. et al. found the 462delCC (p.Pro115Terfs) mutation in Russian breast cancer patients [13].
The obtained data on BRCA1 mutation frequencies can be the basis for the guidelines for mutation analysis in various cohort of breast cancer patients (patients with family history, early onset breast cancer patients etc.). Indeed, our data indicate the absence of hot-spot mutation except BRCA1 5382insC, but a very strong prevalence of this mutation in early onset cancer patients (87.5 % of all found BRCA1 mutations). A frequency of the BRCA1 5382insC mutation among non-selected breast cancer patients in Russia was reported in several studies [4, 12, 14]. Similar frequency of the BRCA1 5382insC mutation was reported for Ukranian breast cancer patients [15].
In spite of the high frequency of the BRCA1 5382insC mutation among unselected cancer patients in Poland [16] the mutation occurrence is more than two times less than in Russia (1.9 %) and just slightly higher than the frequency of the mutation C61G (1.2 %). A frequency of BRCA1 5382insC mutation in Germany among unselected breast cancer patients is even less (1%) [17].
Thus, the frequency ofthe BRCA1 5382C mutation among unselected breast cancer patients from Europe is maximal in Russia (3.6-4 %), intermediate in Poland
клинические исследования
and Germany (1.9 % and 1.0 %, correspondingly) and quite rare in France [18] and in Spain [19].
So, this data leads to the logical considerations
regarding the workflow of the BRCA1 gene mutations
analysis specifically for Russia. The frequencies of
BRCA1 gene mutations in Russia dictates the need to
analyze BRCA1 5382insC mutation as the first step of
analysis and, if not found, to analyze a complete coding
region of BRCA1 gene. This workflow is in contrast
with the accepted idea to analyze 4-8 mutations
which were ever found in cancer patients with family
history. Moreover, due to the low cost and relative
simplicity analysis of the BRCA1 5382insC mutation
can be offered to all breast cancer patients with and
without family history since a number of publications
demonstrate a limited significance of family history in the present study.
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Conclusion
As a result of the study, data on the frequency of genetic variations in the BRCA1 gene among early onset breast cancer patients in the Novosibirsk Region were obtained. Important, that the proportion of the 5382insC mutation is 87.5 % of all pathogenic mutations in the BRCA1 gene found in patients. Frequency of the 4153delA mutation, which was previously characterized as a founder mutation for Russian breast/ovarian cancer patients is not higher than frequency of other pathogenic mutations found
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Received 29.06.18 Accepted 01.08.18
Funding
This study required no funding. Conflict of interest
The authors declare that they have no conflict of interest.
ABOUT THE AUTHORS
Maxim S. Anisimenko, Junior research fellow, Federal Research Center of Fundamental and Translational Medicine (Novosibirsk, Russia). E-mail: jocus@bk.ru. Researcher ID (WOS): I-3226-2017. Author ID (Scopus): 36514172600.
Galina A. Paul, MD, Head of laboratory, laboratory physician, BioLink Ltd (Novosibirsk, Russia). E-mail: galapaul@mail.ru. Author ID (Scopus): 56417221700.
Anton E. Kozyakov, Head of division, oncologist, Novosibirsk Regional Oncological Clinic (Novosibirsk, Russia). E-mail: dr-anton72@ mail.ru. Author ID (Scopus): 56418702200.
Nadezhda 1 Gutkina, PhD, Senior researcher, Federal Research Center of Fundamental and Translational Medicine (Novosibirsk, Russia). E-mail: gutkina.nadezhda@gmail.com. Author ID (Scopus): 6701374482.
Daria A. Berdyugina, Junior research fellow, Federal Research Center of Fundamental and Translational Medicine (Novosibirsk, Russia). E-mail: kostyakovada1993@yandex.ru.
Alexander Yu. Garanin, Laboratory assistant, Federal Research Center of Fundamental and Translational Medicine (Novosibirsk, Russia). E-mail: chemistry1992sasha@mail.ru.
Anna V. Butorina, Laboratory assistant, Federal Research Center of Fundamental and Translational Medicine (Novosibirsk, Russia). E-mail: anechkaustina1991@mail.ru.
Elena V. Gornostaeva, Junior research fellow, Federal Research Center of Fundamental and Translational Medicine (Novosibirsk, Russia). E-mail: phys.lena@gmail.com.
Kamil F. Khafizov, PhD, Head of scientific group, Central Research Institute of Epidemiology (Moscow, Russia). E-mail: kkhafizov@ gmail.com. Researcher ID (WOS): E-5368-2011. Author ID (Scopus): 26536043300. ORCID: 0000-0001-5524-0296. Yuri V. Vyatkin, Head of Department of Bioinformatic technologies, AcademGene LLC (Novosibirsk, Russia). E-mail: yuri@nprog. ru. Researcher ID (WOS): E-8027-2018. Author ID (Scopus): 55651086400. ORCID: 0000-0002-9056-8796.
Dmitry N. Shtokalo, PhD, Senior researcher, A.P.Ershov Institute of Informatics Systems (Novosibirsk, Russia). E-mail: shtokalod2@ gmail.com. Researcher ID (WOS): H-3351-2016. Author ID (Scopus): 14219725900. ORCID: 0000-0003-3716-2794. Sergei P. Kovalenko, PhD, Head of laboratory, Federal Research Center of Fundamental and Translational Medicine (Novosibirsk, Russia). E-mail: sp_kovalenko@yahoo.com. Author ID (Scopus): 7101988072.
СВЕДЕНИЯ ОБ АВТОРАХ
Анисименко Максим Сергеевич, младший научный сотрудник, Федеральный исследовательский центр фундаментальной и трансляционной медицины (г. Новосибирск, Россия). E-mail: jocus@bk.ru. SPIN-код: 7751-0277. Researcher ID (WOS): I-3226-2017. Author ID (Scopus): 36514172600.
Пауль Галина Александровна, кандидат медицинских наук, заведующий лабораторией, врач-лабораторный генетик, ООО «Биолинк» (г. Новосибирск, Россия). E-mail: galapaul@mail.ru. Author ID (Scopus): 56417221700.
Козяков Антон Евгеньевич, заведующий отделением, врач-онколог, Новосибирский областной клинический онкологический диспансер (г. Новосибирск, Россия). E-mail: dr-anton72@mail.ru. SPIN-код: 9596-0420. Author ID (Scopus): 56418702200. Гуткина Надежда Игоревна, кандидат биологических наук, старший научный сотрудник, Федеральный исследовательский центр фундаментальной и трансляционной медицины (г. Новосибирск, Россия). E-mail: gutkina.nadezhda@gmail.com. SPIN-код: 6170-9570. Author ID (Scopus): 6701374482.
Бердюгина Дарья Алексеевна, младший научный сотрудник, Федеральный исследовательский центр фундаментальной и трансляционной медицины (г. Новосибирск, Россия). E-mail: kostyakovada1993@yandex.ru. SPIN-код: 4870-4030. Гаранин Александр Юрьевич, лаборант, Федеральный исследовательский центр фундаментальной и трансляционной медицины (г. Новосибирск, Россия). E-mail: chemistry1992sasha@mail.ru.
Буторина Анна Владимировна, лаборант, Федеральный исследовательский центр фундаментальной и трансляционной медицины (г. Новосибирск, Россия). E-mail: anechkaustina1991@mail.ru.
Горностаева Елена Викторовна, младший научный сотрудник, Федеральный исследовательский центр фундаментальной и трансляционной медицины (г. Новосибирск, Россия). E-mail: phys.lena@gmail.com.
Хафизов Камиль Фаридович, кандидат биологических наук, руководитель научной группы, Центральный научно-исследовательский институт эпидемиологии Роспотребнадзора (г. Москва, Россия). E-mail: kkhafizov@gmail.com. SPIN-код: 9082-5749. Researcher ID (WOS): E-5368-2011. Author ID (Scopus): 26536043300. ORCID: 0000-0001-5524-0296. Вяткин Юрий Викторович, руководитель отдела биоинформационных технологий, ООО «АкадемДжин» (г. Новосибирск, Россия). E-mail: yuri@nprog.ru. Researcher ID (WOS): E-8027-2018. Author ID (Scopus): 55651086400. ORCID: 0000-0002-9056-8796. Штокало Дмитрий Николаевич, кандидат физико-математических наук, старший научный сотрудник, Институт систем информатики им. А.П. Ершова СО РАН (г. Новосибирск, Россия). E-mail: shtokalod2@gmail.com. SPIN-код: 2745-4217. Researcher ID (WOS): H-3351-2016. Author ID (Scopus): 14219725900. ORCID: 0000-0003-3716-2794.
Коваленко Сергей Петрович, доктор биологический наук, заведующий лабораторией, Федеральный исследовательский центр фундаментальной и трансляционной медицины (г. Новосибирск, Россия). E-mail: sp_kovalenko@yahoo.com. SPIN-код: 22726747. Author ID (Scopus): 7101988072.
Финансирование
Авторы данной статьи подтвердили отсутствие финансовой поддержки. Конфликт интересов
Авторы объявляют, что у них нет конфликта интересов.
Поступила 29.06.18 Принята в печать 01.08.18
