vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ17.314vavilov-1281Research ArticleСИСТЕМНАЯ БИОЛОГИЯ И БИОМЕДИЦИНАSYSTEMS BIOLOGY AND BIOMEDICINEОсобенности экспрессионного профиля больных злокачественной меланомой в зависимости от ответа на иммунотерапиюDifferences in expression profiles in malingant melanoma patients according to immunotherapy responseЛукьяноваЕ. Н.LukyanovaE. N.

Москва.

Moscow.

ФедороваМ. С.FedorovaM. S.

Москва.

Moscow.

ПудоваЕ. А.PudovaE. A.

Москва.

Moscow.

НаседкинаТ. В.NasedkinaT. V.

Москва.

Moscow.

СтепановаЕ. В.StepanovaE. V.

Москва.

Moscow.

НюшкоК. М.NyushkoK. M.

Москва.

Moscow.

ПоповА. Ю.PopovA. Y.

Москва.

Moscow.

 КоробанН. В.KorobanN. V.

Москва.

Moscow.

ДмитриевА. А.DmitrievA. A.

Москва.

Moscow.

КиселеваМ. В.KiselevaM. V.

Москва.

Moscow.

ЛипатоваА. В.LipatovaA. V.

Москва.

Moscow.

ЗаседателевА. С.ZasedatelevA. S.

Москва.

Moscow.

КудрявцеваА. В.KudryavtsevaA. V.

Москва.

Moscow.

rhizamoeba@mail.ruИнститут молекулярной биологии им. В.А. Энгельгардта Российской академии наук.РоссияEngelhardt Institute of Molecular Biology RAS.Russian FederationИнститут молекулярной биологии им. В.А. Энгельгардта Российской академии наук; Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина Министерства здравоохранения Российской Федерации.РоссияEngelhardt Institute of Molecular Biology RAS; Blokhin National Cancer Research Center, Ministry of Health of the Russian Federation.Russian FederationНациональный медицинский исследовательский центр онкологии им. Н.Н. Блохина Министерства здравоохранения Российской Федерации.РоссияBlokhin National Cancer Research Center, Ministry of Health of the Russian Federation.Russian FederationНациональный медицинский исследовательский центр радиологии Министерства здравоохранения Российской Федерации.РоссияNational Medical Research Radiological Center, Ministry of Health of the Russian Federation.Russian FederationГородская клиническая больница им. Д.Д. Плетнева Департамента здравоохранения города Москвы.РоссияPletnev State Hospital, Department of Health of the Moscow.Russian FederationИнститут молекулярной биологии им. В.А. Энгельгардта Российской академии наук; Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина Министерства здравоохранения Российской Федерации.РоссияEngelhardt Institute of Molecular Biology RAS; Blokhin National Cancer Research Center, Ministry of Health of the Russian Federation.Russian FederationИнститут молекулярной биологии им. В.А. Энгельгардта Российской академии наук; Национальный медицинский исследовательский центр радиологии Министерства здравоохранения Российской Федерации.РоссияEngelhardt Institute of Molecular Biology RAS; National Medical Research Radiological Center, Ministry of Health of the Russian Federation.Russian Federation201721012018218925931Copyright © Лукьянова Е.Н., Федорова М.С., Пудова Е.А., Наседкина Т.В., Степанова Е.В., Нюшко К.М., Попов А.Ю.,  Коробан Н.В., Дмитриев А.А., Киселева М.В., Липатова А.В., Заседателев А.С., Кудрявцева А.В., 20182018Лукьянова Е.Н., Федорова М.С., Пудова Е.А., Наседкина Т.В., Степанова Е.В., Нюшко К.М., Попов А.Ю.,  Коробан Н.В., Дмитриев А.А., Киселева М.В., Липатова А.В., Заседателев А.С., Кудрявцева А.В.Lukyanova E.N., Fedorova M.S., Pudova E.A., Nasedkina T.V., Stepanova E.V., Nyushko K.M., Popov A.Y., Koroban N.V., Dmitriev A.A., Kiseleva M.V., Lipatova A.V., Zasedatelev A.S., Kudryavtseva A.V.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/1281

Одним из важнейших направлений современной молекулярной генетики и биомедицины является поиск предиктивных маркеров, помогающих выбрать наиболее эффективный способ лечения и препарат, а также индивидуально подобрать его дозировку. Особенно перспективными считаются те маркеры, которые могут обеспечить возможность применения неинвазивной, так называемой жидкостной биопсии. Этот метод позволяет оценить состояние опухоли по анализу естественных жидкостей организма, таких как кровь, моча или слюна. Подобные исследования наиболее удобны в случаях, когда необходимо проводить мониторинг эффективности терапии, чтобы вовремя зафиксировать момент возникнове ния резистентности опухолевых клеток, начало рецидива и перей ти на следующую линию терапии. При лечении агрессивных и быстро метастазирующих злокачественных новообразований, таких как меланома, наличие достоверных маркеров, позволяющих быстро и точно определить тактику лечения, особенно  важно. В последнее время появляется все больше исследований, посвященных поиску предиктивных маркеров эффективности иммунотерапии. Меланома характеризуется высокой иммуногенностью, в связи с чем она стала модельным объектом для исследования и внедрения новых подходов иммунотерапии. В настоящей работе проведено сравнение двух групп больных метастатической меланомой кожи с различным ответом на иммунотерапию блокаторами иммунных контрольных точек с целью идентифицировать новые предиктивные экспрессионные биомаркеры среди микро­ и матричных РНК, а также определить гены, ответственные за возникновение объективного ответа на терапию у пациентов. В исследовании выявлено несколько микроРНК со значительным изменением содержания в опухолевой ткани пациентов, по­разному отвечающих на иммуно терапию. Обнаружены также различия на уровне экспрессии их генов­мишеней, которые позволят более детально проанализировать молекулярные механизмы, определяющие чувствительность или резистентность клеток злокачественной меланомы к действию иммунотерапии. На основе полученных результатов предложены экспрессионные маркеры (мРНК и микроРНК), кото рые после дальнейшей апробации могут быть использованы как предикторы ответа опухолей злокачественной меланомы к иммунотерапии.

One of the most important branch of modern molecular genetics and biomedicine is the search for predictive markers that help choose the most effective way of treatment, drug and also determine its individual dosage. Among the markers, those that can provide the possibility of using a non­invasive, so­called “liquid biopsy” are considered particularly promising. This method allows the condition of the tumor to be assessed by analyzing the body’s natural fluids, such as blood, urine or saliva. Such studies are most convenient in those cases when it is necessary to monitor the effectiveness of therapy in order to record the time of the onset of resistance of tumor cells, the onset of relapse and to move on to the next line of therapy. In the treatment of aggressive and rapidly became metastatic malignant tumors, such as melanoma, the presence of reliable markers that allow quick and accurate determination of treatment tactics is especially important. Nowadays, there is an increasing number of studies devoted to the search for predictive markers of the effectiveness of immunotherapy. Melanoma is one of the most immunogenic tumors and, as a result, has become a model object for research into and introduction of new approaches to immunotherapy. In this study, we compared two groups of patients with metastatic skin melanoma, with different responses to immunotherapy with blockers of immune control points, to identify new predictive expression biomarkers among microRNAs and mRNAs, and to identify the genes responsible for the occurrence of an objective response to therapy. As a result, the study detected several microRNAs with a significant change in expression level within the tumor tissue of patients responding differently to immunotherapy. Differences in the level of expression of their target genes have also been found, that will allow a more detailed analysis of the molecular mechanisms that determine the sensitivity or resistance of malignant melanoma cells to the immunotherapy. Based on the obtained data, we have proposed expression markers (mRNAs and microRNAs) that can be used as predictors of malignant melanoma tumors to immunotherapy.

меланомаиммунотерапияпредиктивные маркерыпрофилирование микроРНКвысокопроизводительное секвенированиетранскриптомный анализрегуляция экспрессии геновmelanomaimmunotherapypredictive biomarkersNGSmiRNA profilingtranscriptomic analysisregulation of gene expressionReferencesAiba Y., Yamazaki T., Okada T., Gotoh K., Sanjo H., Ogata M., Kurosaki T. BANK negatively regulates Akt activation and subsequent B cell responses. Immunity. 2006;24(3):259-268. DOI 10.1016/j.immuni.2006.01.002.Aiba Y., Yamazaki T., Okada T., Gotoh K., Sanjo H., Ogata M., Kurosaki T. BANK negatively regulates Akt activation and subsequent B cell responses. Immunity. 2006;24(3):259-268. DOI 10.1016/j.immuni.2006.01.002.Alexandrov L.B., Nik-Zainal S., Wedge D.C., Aparicio S.A., Behjati S., Biankin A.V., Bignell G.R., Bolli N., Borg A., Børresen-Dale A.L., Boyault S., Burkhardt B., Butler A.P., Caldas C., Davies H.R., Desmedt C., Eils R., Eyfjörd J.E., Foekens J.A., Greaves M., Hosoda F., Hutter B., Ilicic T., Imbeaud S., Imielinski M., Jäger N., Jones D.T., Jones D., Knappskog S., Kool M., Lakhani S.R., López-Otín C., Martin S., Munshi N.C., Nakamura H., Northcott P.A., Pajic M., Papaemmanuil E., Paradiso A., Pearson J.V., Puente X.S., Raine K., Ramakrishna M., Richardson A.L., Richter J., Rosenstiel P., Schlesner M., Schumacher T.N., Span P.N., Teague J.W., Totoki Y., Tutt A.N., Valdés-Mas R., van Buuren M.M., van ‘t Veer L., Vincent-Salomon A., Waddell N., Yates L.R. Australian Pancreatic Cancer Genome Initiative; ICGC Breast Cancer Consortium; ICGC MMML-Seq Consortium; ICGC PedBrain, Zucman-Rossi J., Futreal P.A., McDermott U., Lichter P., Meyerson M., Grimmond S.M., Siebert R., Campo E., Shibata T., Pfister S.M., Campbell P.J., Stratton M.R. Signatures of mutational processes in human cancer. Nature. 2013;22;500(7463):415-421. DOI 10.1038/nature12477.Alexandrov L.B., Nik-Zainal S., Wedge D.C., Aparicio S.A., Behjati S., Biankin A.V., Bignell G.R., Bolli N., Borg A., Børresen-Dale A.L., Boyault S., Burkhardt B., Butler A.P., Caldas C., Davies H.R., Desmedt C., Eils R., Eyfjörd J.E., Foekens J.A., Greaves M., Hosoda F., Hutter B., Ilicic T., Imbeaud S., Imielinski M., Jäger N., Jones D.T., Jones D., Knappskog S., Kool M., Lakhani S.R., López-Otín C., Martin S., Munshi N.C., Nakamura H., Northcott P.A., Pajic M., Papaemmanuil E., Paradiso A., Pearson J.V., Puente X.S., Raine K., Ramakrishna M., Richardson A.L., Richter J., Rosenstiel P., Schlesner M., Schumacher T.N., Span P.N., Teague J.W., Totoki Y., Tutt A.N., Valdés-Mas R., van Buuren M.M., van ‘t Veer L., Vincent-Salomon A., Waddell N., Yates L.R. Australian Pancreatic Cancer Genome Initiative; ICGC Breast Cancer Consortium; ICGC MMML-Seq Consortium; ICGC PedBrain, Zucman-Rossi J., Futreal P.A., McDermott U., Lichter P., Meyerson M., Grimmond S.M., Siebert R., Campo E., Shibata T., Pfister S.M., Campbell P.J., Stratton M.R. Signatures of mutational processes in human cancer. Nature. 2013;22;500(7463):415-421. DOI 10.1038/nature12477.Benkusky N.A., Farrell E.F., Valdivia H.H. Ryanodine receptor channelopathies. Biochem. Biophys. Res. Commun. 2004;322(4):12801285. DOI 10.1016/j.bbrc.2004.08.033.Benkusky N.A., Farrell E.F., Valdivia H.H. Ryanodine receptor channelopathies. Biochem. Biophys. Res. Commun. 2004;322(4):12801285. DOI 10.1016/j.bbrc.2004.08.033.Bouchalova K., Cizkova M., Cwiertka K., Trojanec R., Hajduch M. Triple negative breast cancer – current status and prospective targeted treatment based on HER1 (EGFR), TOP2A and C-MYC gene assessment. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech. Repub. 2009;153(1):13-17.Bouchalova K., Cizkova M., Cwiertka K., Trojanec R., Hajduch M. Triple negative breast cancer – current status and prospective targeted treatment based on HER1 (EGFR), TOP2A and C-MYC gene assessment. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech. Repub. 2009;153(1):13-17.Davoli T., Uno H., Wooten E.C., Elledge S.J. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science. 2017;355(6322). DOI 10.1126/science.aaf8399.Davoli T., Uno H., Wooten E.C., Elledge S.J. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science. 2017;355(6322). DOI 10.1126/science.aaf8399.Duffy D.L., Zhao Z.Z., Sturm R.A., Hayward N.K., Martin N.G., Montgomery G.W. Multiple pigmentation gene polymorphisms account for a substantial proportion of risk of cutaneous malignant melanoma. J. Invest. Dermatol. 2010;130(2):520-528. Epub 2009; Aug 27. DOI 10.1038/jid.2009.258.Duffy D.L., Zhao Z.Z., Sturm R.A., Hayward N.K., Martin N.G., Montgomery G.W. Multiple pigmentation gene polymorphisms account for a substantial proportion of risk of cutaneous malignant melanoma. J. Invest. Dermatol. 2010;130(2):520-528. Epub 2009; Aug 27. DOI 10.1038/jid.2009.258.Gellatly S.A., Kalujnaia S., Cramb G. Cloning, tissue distribution and sub-cellular localisation of phospholipase C X-domain containing protein (PLCXD) isoforms. Biochem. Biophys. Res. Commun. 2012; 424(4):651-656. Epub 2012; Jun 22. DOI 10.1016/j.bbrc.012.06.079.Gellatly S.A., Kalujnaia S., Cramb G. Cloning, tissue distribution and sub-cellular localisation of phospholipase C X-domain containing protein (PLCXD) isoforms. Biochem. Biophys. Res. Commun. 2012; 424(4):651-656. Epub 2012; Jun 22. DOI 10.1016/j.bbrc.012.06.079.Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. DOI 10.1016/j.cell.2011.02.013.Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. DOI 10.1016/j.cell.2011.02.013.Hawkes J.E., Cassidy P.B., Manga P., Boissy R.E., Goldgar D., CannonAlbright L., Florell S.R., Leachman S.A. Report of a novel OCA2 gene mutation and an investigation of OCA2 variants on melanoma risk in a familial melanoma pedigree. J. Dermatol. Sci. 2013;69(1):307. Epub 2012; Oct 13. DOI 10.1016/j.jdermsci.2012.09.016.Hawkes J.E., Cassidy P.B., Manga P., Boissy R.E., Goldgar D., CannonAlbright L., Florell S.R., Leachman S.A. Report of a novel OCA2 gene mutation and an investigation of OCA2 variants on melanoma risk in a familial melanoma pedigree. J. Dermatol. Sci. 2013;69(1):307. Epub 2012; Oct 13. DOI 10.1016/j.jdermsci.2012.09.016.Hodi F.S., O’Day S.J., McDermott D.F., Weber R.W., Sosman J.A., Haanen J.B., Gonzalez R., Robert C., Schadendorf D., Hassel J.C., Akerley W., van den Eertwegh A.J., Lutzky J., Lorigan P., Vaubel J.M., Linette G.P., Hogg D., Ottensmeier C.H., Lebbé C., Peschel C., Quirt I., Clark J.I., Wolchok J.D., Weber J.S., Tian J., Yellin M.J., Nichol G.M., Hoos A., Urba W.J. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010; 363(8):711-723. Epub 2010; Jun 5. DOI 10.1056/NEJMoa1003466.Hodi F.S., O’Day S.J., McDermott D.F., Weber R.W., Sosman J.A., Haanen J.B., Gonzalez R., Robert C., Schadendorf D., Hassel J.C., Akerley W., van den Eertwegh A.J., Lutzky J., Lorigan P., Vaubel J.M., Linette G.P., Hogg D., Ottensmeier C.H., Lebbé C., Peschel C., Quirt I., Clark J.I., Wolchok J.D., Weber J.S., Tian J., Yellin M.J., Nichol G.M., Hoos A., Urba W.J. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010; 363(8):711-723. Epub 2010; Jun 5. DOI 10.1056/NEJMoa1003466.Huang S.K., Hoon D.S. Liquid biopsy utility for the surveillance of cutaneous malignant melanoma patients. Mol. Oncol. 2016;10(3):450463. Epub 2015; Dec 17. DOI 10.1016/j.molonc.2015.12.008.Huang S.K., Hoon D.S. Liquid biopsy utility for the surveillance of cutaneous malignant melanoma patients. Mol. Oncol. 2016;10(3):450463. Epub 2015; Dec 17. DOI 10.1016/j.molonc.2015.12.008.Katan M. New insights into the families of PLC enzymes: looking back and going forward. Biochem. J. 2005;391(3):e7-9. DOI 10.1042/BJ20051506.Katan M. New insights into the families of PLC enzymes: looking back and going forward. Biochem. J. 2005;391(3):e7-9. DOI 10.1042/BJ20051506.Kozyrev S.V., Abelson A.K., Wojcik J., Zaghlool A., Linga Reddy M.V., Sanchez E., Gunnarsson I., Svenungsson E., Sturfelt G., Jönsen A., Truedsson L., Pons-Estel B.A., Witte T., D’Alfonso S., Barizzone N., Danieli M.G., Gutierrez C., Suarez A., Junker P., Laustrup H., González-Escribano M.F., Martin J., Abderrahim H., Alarcón-Riquelme M.E. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat. Genet. 2008;40(2):211-216. DOI 10.1038/ng.79.Kozyrev S.V., Abelson A.K., Wojcik J., Zaghlool A., Linga Reddy M.V., Sanchez E., Gunnarsson I., Svenungsson E., Sturfelt G., Jönsen A., Truedsson L., Pons-Estel B.A., Witte T., D’Alfonso S., Barizzone N., Danieli M.G., Gutierrez C., Suarez A., Junker P., Laustrup H., González-Escribano M.F., Martin J., Abderrahim H., Alarcón-Riquelme M.E. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat. Genet. 2008;40(2):211-216. DOI 10.1038/ng.79.Krawczyk P., Kowalski D.M., Ramlau R., Kalinka-Warzocha E., Winiarczyk K., Stencel K., Powrózek T., Reszka K., Wojas-Krawczyk K., Bryl M., Wójcik-Superczyńska M., Głogowski M., Barinow-Wojewódzki A., Milanowski J., Krzakowski M. Comparison of the effectiveness of erlotinib, gefitinib, and afatinib for treatment of non-small cell lung cancer in patients with common and rare <i>EGFR</i> gene mutations. Oncol. Lett. 2017;(6):4433-4444. Epub 2017; Apr 3. DOI 10.3892/ol.2017.5980.Krawczyk P., Kowalski D.M., Ramlau R., Kalinka-Warzocha E., Winiarczyk K., Stencel K., Powrózek T., Reszka K., Wojas-Krawczyk K., Bryl M., Wójcik-Superczyńska M., Głogowski M., Barinow-Wojewódzki A., Milanowski J., Krzakowski M. Comparison of the effectiveness of erlotinib, gefitinib, and afatinib for treatment of non-small cell lung cancer in patients with common and rare <i>EGFR</i> gene mutations. Oncol. Lett. 2017;(6):4433-4444. Epub 2017; Apr 3. DOI 10.3892/ol.2017.5980.Leong S.P., Mihm M.C. Jr., Murphy G.F., Hoon D.S., Kashani-Sabet M., Agarwala S.S., Zager J.S., Hauschild A., Sondak V.K., Guild V., Kirkwood J.M. Progression of cutaneous melanoma: implications for treatment. Clin. Exp. Metastasis. 2012;29(7):775-796. DOI 10.1007/s10585-012-9521-1.Leong S.P., Mihm M.C. Jr., Murphy G.F., Hoon D.S., Kashani-Sabet M., Agarwala S.S., Zager J.S., Hauschild A., Sondak V.K., Guild V., Kirkwood J.M. Progression of cutaneous melanoma: implications for treatment. Clin. Exp. Metastasis. 2012;29(7):775-796. DOI 10.1007/s10585-012-9521-1.Martin-Liberal J., Larkin J. Vemurafenib for the treatment of BRAF mutant metastatic melanoma. Future Oncol. 2015;11(4):579-589. DOI 10.2217/fon.14.252.Martin-Liberal J., Larkin J. Vemurafenib for the treatment of BRAF mutant metastatic melanoma. Future Oncol. 2015;11(4):579-589. DOI 10.2217/fon.14.252.Milik S.N., Lasheen D.S., Serya R.A.T., Abouzid K.A.M. How to train your inhibitor: Design strategies to overcome resistance to Epidermal Growth Factor Receptor inhibitors. Eur. J. Med. Chem. 2017;142:131-151. DOI 10.1016/j.ejmech.2017.07.023.Milik S.N., Lasheen D.S., Serya R.A.T., Abouzid K.A.M. How to train your inhibitor: Design strategies to overcome resistance to Epidermal Growth Factor Receptor inhibitors. Eur. J. Med. Chem. 2017;142:131-151. DOI 10.1016/j.ejmech.2017.07.023.Monteith G.R., Davis F.M., Roberts-Thomson S.J. Calcium channels and pumps in cancer: changes and consequences. J. Biol. Chem. 2012;287(38):31666-31673. Epub 2012; Jul 20. DOI 10.1074/jbc. R112.343061.Monteith G.R., Davis F.M., Roberts-Thomson S.J. Calcium channels and pumps in cancer: changes and consequences. J. Biol. Chem. 2012;287(38):31666-31673. Epub 2012; Jul 20. DOI 10.1074/jbc. R112.343061.Muhali F.S., Song R.H., Wang X., Shi X.H., Jiang W.J., Xiao L., Li D.F., He S.T., Xu J., Zhang J.A. Genetic variants of BANK1 gene in autoimmune thyroid diseases: a case-control association study. Exp. Clin. Endocrinol. Diabetes. 2013;121(9):556-560. Epub 2013; Oct 14. DOI 10.1055/s-0033-1348220.Muhali F.S., Song R.H., Wang X., Shi X.H., Jiang W.J., Xiao L., Li D.F., He S.T., Xu J., Zhang J.A. Genetic variants of BANK1 gene in autoimmune thyroid diseases: a case-control association study. Exp. Clin. Endocrinol. Diabetes. 2013;121(9):556-560. Epub 2013; Oct 14. DOI 10.1055/s-0033-1348220.Müller S., van den Boom D., Zirkel D., Köster H., Berthold F., Schwab M., Westphal M., Zumkeller W. Retention of imprinting of the human apoptosis-related gene TSSC3 in human brain tumors. Hum. Mol. Genet. 2000;22;9(5):757-763. PMID: 10749982.Müller S., van den Boom D., Zirkel D., Köster H., Berthold F., Schwab M., Westphal M., Zumkeller W. Retention of imprinting of the human apoptosis-related gene TSSC3 in human brain tumors. Hum. Mol. Genet. 2000;22;9(5):757-763. PMID: 10749982.O’Dowd B.F., Nguyen T., Jung B.P., Marchese A., Cheng R., Heng H.H., Kolakowski L.F. Jr., Lynch K.R., George S.R. Cloning and chromosomal mapping of four putative novel human G-proteincoupled receptor genes. Gene. 1997;187(1):75-81.O’Dowd B.F., Nguyen T., Jung B.P., Marchese A., Cheng R., Heng H.H., Kolakowski L.F. Jr., Lynch K.R., George S.R. Cloning and chromosomal mapping of four putative novel human G-proteincoupled receptor genes. Gene. 1997;187(1):75-81.Pang Z.P., Yang N., Vierbuchen T., Ostermeier A., Fuentes D.R., Yang T.Q., Citri A., Sebastiano V., Marro S., Südhof T.C., Wernig M. Induction of human neuronal cells by defined transcription factors. Nature. 2011;26;476(7359):220-223. DOI 10.1038/nature10202.Pang Z.P., Yang N., Vierbuchen T., Ostermeier A., Fuentes D.R., Yang T.Q., Citri A., Sebastiano V., Marro S., Südhof T.C., Wernig M. Induction of human neuronal cells by defined transcription factors. Nature. 2011;26;476(7359):220-223. DOI 10.1038/nature10202.Petrova G.V., Kaprin A.D., Starinskij V.V., Gretsova O.P. The incidence of malignant neoplasms in the Russian population. Onkologiya. Zhurnal imeni P.A. Gertsena = P.A. Herzen Journal of Oncology. 2014;2(5):5-10. (in Russian)Petrova G.V., Kaprin A.D., Starinskij V.V., Gretsova O.P. The incidence of malignant neoplasms in the Russian population. Onkologiya. Zhurnal imeni P.A. Gertsena = P.A. Herzen Journal of Oncology. 2014;2(5):5-10. (in Russian)Rix U., Colinge J., Blatt K., Gridling M., Remsing Rix L.L., Parapatics K., Cerny-Reiterer S., Burkard T.R., Jäger U., Melo J.V., Bennett K.L., Valent P., Superti-Furga G. A target-disease network model of second-generation BCR-ABL inhibitor action in Ph+ ALL. PLoS One. 2013;8(10):e77155. DOI 10.1371/journal.pone.0077155.Rix U., Colinge J., Blatt K., Gridling M., Remsing Rix L.L., Parapatics K., Cerny-Reiterer S., Burkard T.R., Jäger U., Melo J.V., Bennett K.L., Valent P., Superti-Furga G. A target-disease network model of second-generation BCR-ABL inhibitor action in Ph+ ALL. PLoS One. 2013;8(10):e77155. DOI 10.1371/journal.pone.0077155.Roh W., Chen P.L., Reuben A., Spencer C.N., Prieto P.A., Miller J.P., Gopalakrishnan V., Wang F., Cooper Z.A., Reddy S.M., Gumbs C., Little L., Chang Q., Chen W.S., Wani K., De Mace do M.P., Chen E., Austin-Breneman J.L., Jiang H., Roszik J., Tetzlaff M.T., Davies M.A., Gershenwald J.E., Tawbi H., Lazar A.J., Hwu P., Hwu W.J., Diab A., Glitza I.C., Patel S.P., Woodman S.E., Amaria R.N., Prieto V.G., Hu J., Sharma P., Allison J.P., Chin L., Zhang J., Wargo J.A., Futreal P.A. Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance. Sci. Transl. Med. 2017;9(379). DOI 10.1126/scitranslmed.aah3560. Erratum: Sci. Transl. Med. 2017. Apr 12;9(385).Roh W., Chen P.L., Reuben A., Spencer C.N., Prieto P.A., Miller J.P., Gopalakrishnan V., Wang F., Cooper Z.A., Reddy S.M., Gumbs C., Little L., Chang Q., Chen W.S., Wani K., De Mace do M.P., Chen E., Austin-Breneman J.L., Jiang H., Roszik J., Tetzlaff M.T., Davies M.A., Gershenwald J.E., Tawbi H., Lazar A.J., Hwu P., Hwu W.J., Diab A., Glitza I.C., Patel S.P., Woodman S.E., Amaria R.N., Prieto V.G., Hu J., Sharma P., Allison J.P., Chin L., Zhang J., Wargo J.A., Futreal P.A. Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance. Sci. Transl. Med. 2017;9(379). DOI 10.1126/scitranslmed.aah3560. Erratum: Sci. Transl. Med. 2017. Apr 12;9(385).Ryu B., Kim D.S., Deluca A.M., Alani R.M. Comprehensive expression profiling of tumor cell lines identifies molecular signatures of melanoma progression. PLoS One. 2007;2(7):e594. DOI 10.1371/journal.pone.0000594.Ryu B., Kim D.S., Deluca A.M., Alani R.M. Comprehensive expression profiling of tumor cell lines identifies molecular signatures of melanoma progression. PLoS One. 2007;2(7):e594. DOI 10.1371/journal.pone.0000594.Schwienbacher C., Sabbioni S., Campi M., Veronese A., Bernardi G., Menegatti A., Hatada I., Mukai T., Ohashi H., Barbanti-Brodano G., Croce C.M., Negrini M. Transcriptional map of 170-kb region at chromosome 11p15.5: identification and mutational analysis of the BWR1A gene reveals the presence of mutations in tumor samples. Proc. Natl. Acad. Sci USA. 1998;95(7):3873-3878.Schwienbacher C., Sabbioni S., Campi M., Veronese A., Bernardi G., Menegatti A., Hatada I., Mukai T., Ohashi H., Barbanti-Brodano G., Croce C.M., Negrini M. Transcriptional map of 170-kb region at chromosome 11p15.5: identification and mutational analysis of the BWR1A gene reveals the presence of mutations in tumor samples. Proc. Natl. Acad. Sci USA. 1998;95(7):3873-3878.Shindo Y., Hazama S., Nakamura Y., Inoue Y., Kanekiyo S., Suzuki N., Takenouchi H., Tsunedomi R., Nakajima M., Ueno T., Takeda S., Yoshino S., Okuno K., Fujita Y., Hamamoto Y., Kawakami Y., Oka M., Nagano H. miR-196b, miR-378a and miR-486 are predictive biomarkers for the efficacy of vaccine treatment in colorectal cancer. Oncol. Lett. 2017;14(2):1355-1362. Epub 2017; Jun 2. DOI 10.3892/ol.2017.6303.Shindo Y., Hazama S., Nakamura Y., Inoue Y., Kanekiyo S., Suzuki N., Takenouchi H., Tsunedomi R., Nakajima M., Ueno T., Takeda S., Yoshino S., Okuno K., Fujita Y., Hamamoto Y., Kawakami Y., Oka M., Nagano H. miR-196b, miR-378a and miR-486 are predictive biomarkers for the efficacy of vaccine treatment in colorectal cancer. Oncol. Lett. 2017;14(2):1355-1362. Epub 2017; Jun 2. DOI 10.3892/ol.2017.6303.Sokolenko A.P., Imyanitov E.N. Molecular tests for the choice of cancer therapy. Curr. Pharm. Des. 2017; DOI 10.2174/1381612823666170719110125.Sokolenko A.P., Imyanitov E.N. Molecular tests for the choice of cancer therapy. Curr. Pharm. Des. 2017; DOI 10.2174/1381612823666170719110125.Szczepaniak Sloane R.A., Gopalakrishnan V., Reddy S.M., Zhang X., Reuben A., Wargo J.A. Interaction of molecular alterations with immune response in melanoma. Cancer. 2017;123(S11):2130-2142. DOI 10.1002/cncr.30681.28543700.Szczepaniak Sloane R.A., Gopalakrishnan V., Reddy S.M., Zhang X., Reuben A., Wargo J.A. Interaction of molecular alterations with immune response in melanoma. Cancer. 2017;123(S11):2130-2142. DOI 10.1002/cncr.30681.28543700.Tiffen J., Wilson S., Gallagher S.J., Hersey P., Filipp F.V. Somatic copy number amplification and hyperactivating somatic mutations of EZH2 correlate with DNA methylation and drive epigenetic silencing of genes involved in tumor suppression and immune responses in melanoma. Neoplasia. 2016;18(2):121-132. DOI 10.1016/j.neo.2016.01.003.Tiffen J., Wilson S., Gallagher S.J., Hersey P., Filipp F.V. Somatic copy number amplification and hyperactivating somatic mutations of EZH2 correlate with DNA methylation and drive epigenetic silencing of genes involved in tumor suppression and immune responses in melanoma. Neoplasia. 2016;18(2):121-132. DOI 10.1016/j.neo.2016.01.003.Wang T., Wang G., Hao D., Liu X., Wang D., Ning N., Li X. Aberrant regulation of the LIN28A/LIN28B and let-7 loop in human malignant tumors and its effects on the hallmarks of cancer. Mol. Cancer. 2015;14:125. DOI 10.1186/s12943-015-0402-5.Wang T., Wang G., Hao D., Liu X., Wang D., Ning N., Li X. Aberrant regulation of the LIN28A/LIN28B and let-7 loop in human malignant tumors and its effects on the hallmarks of cancer. Mol. Cancer. 2015;14:125. DOI 10.1186/s12943-015-0402-5.Yang S., Ji Y., Gattinoni L., Zhang L., Yu Z., Restifo N.P., Rosenberg S.A., Morgan R.A. Modulating the differentiation status of ex vivo-cultured anti-tumor T cells using cytokine cocktails. Cancer Immunol. Immunother. 2013;62(4):727-736. Epub 2012; Dec 4. DOI 10.1007/s00262-012-1378-2.Yang S., Ji Y., Gattinoni L., Zhang L., Yu Z., Restifo N.P., Rosenberg S.A., Morgan R.A. Modulating the differentiation status of ex vivo-cultured anti-tumor T cells using cytokine cocktails. Cancer Immunol. Immunother. 2013;62(4):727-736. Epub 2012; Dec 4. DOI 10.1007/s00262-012-1378-2.Yoo A.S., Sun A.X., Li L., Shcheglovitov A., Portmann T., Li Y., LeeMesser C., Dolmetsch R.E., Tsien R.W., Crabtree G.R. MicroRNAmediated conversion of human fibroblasts to neurons. Nature. 2011; 476(7359):228-231. DOI 10.1038/nature10323.Yoo A.S., Sun A.X., Li L., Shcheglovitov A., Portmann T., Li Y., LeeMesser C., Dolmetsch R.E., Tsien R.W., Crabtree G.R. MicroRNAmediated conversion of human fibroblasts to neurons. Nature. 2011; 476(7359):228-231. DOI 10.1038/nature10323.

The authors declare that there are no conflicts of interest present.