vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ18.416vavilov-1659Research ArticleГЕНЕТИКА ЧЕЛОВЕКАHUMAN GENETICSАнализ мутаций в генах CDC27, CTBP2, HYDIN и KMT5A при каротидных параганглиомахAnalysis of mutations in CDC27, CTBP2, HYDIN and KMT5A genes in carotid paragangliomashttps://orcid.org/0000-0003-3566-5873ЛукьяноваЕ. Н.LukyanovaE. N.

Москва.

Moscow.

https://orcid.org/0000-0002-4421-4364СнежкинаА. В.SnezhkinaA. V.

Москва.

Moscow.

https://orcid.org/0000-0001-6247-9481КалининД. В.KalininD. V.

Москва.

Moscow.

https://orcid.org/0000-0003-0366-3750ПокровскийА. В.PokrovskyA. V.

Москва.

Moscow.

https://orcid.org/0000-0001-6830-7832ГоловюкА. Л.GolovyukA. L.

Москва.

Moscow.

https://orcid.org/0000-0001-6129-6499СтепановО. А.StepanovO. A.

Москва.

Moscow.

https://orcid.org/0000-0002-5492-1361ПудоваЕ. А.PudovaE. A.

Москва.

Moscow.

https://orcid.org/0000-0002-3979-8940РазмахаевГ. С.RazmakhaevG. S.

Москва.

Moscow.

https://orcid.org/0000-0002-8213-4461ОрловаМ. В.OrlovaM. V.

Москва.

Moscow.

https://orcid.org/0000-0003-2095-5931ПоляковА. П.PolyakovA. P.

Москва.

Moscow.

https://orcid.org/0000-0001-8464-1726КиселеваМ. В.KiselevaM. V.

Москва.

Moscow.

https://orcid.org/0000-0001-8784-8415КапринА. Д.KaprinA. D.

Москва.

Moscow.

https://orcid.org/0000-0002-3722-8207КудрявцеваА. 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 хирургии им. А.В. Вишневского Министерства здравоохранения Российской Федерации.РоссияVishnevsky Institute of Surgery, Ministry of Health of the Russian Federation.Russian FederationИнститут молекулярной биологии им. В.А. Энгельгардта Российской академии наукРоссияEngelhardt Institute of Molecular Biology, RAS.Russian FederationИнститут молекулярной биологии им. В.А. Энгельгардта Российской академии наук.РоссияVishnevsky Institute of Surgery, Ministry of Health of the Russian Federation.Russian FederationНациональный медицинский исследовательский радиологический центр Министерства здравоохранения Российской Федерации.РоссияNational Medical Research Radiological Center, Ministry of Health of the Russian Federation.Russian FederationРоссийский университет дружбы народов.РоссияPeoples’ Friendship University of Russia (RUDN University).Russian FederationИнститут молекулярной биологии им. В.А. Энгельгардта Российской академии наук; Национальный медицинский исследовательский радиологический центр Министерства здравоохранения Российской Федерации.РоссияEngelhardt Institute of Molecular Biology, RAS; National Medical Research Radiological Center, Ministry of Health of the Russian Federation.Russian Federation201826092018226726733Copyright © Лукьянова Е.Н., Снежкина А.В., Калинин Д.В., Покровский А.В., Головюк А.Л., Степанов О.А., Пудова Е.А., Размахаев Г.С., Орлова М.В., Поляков А.П., Киселева М.В., Каприн А.Д., Кудрявцева А.В., 20182018Лукьянова Е.Н., Снежкина А.В., Калинин Д.В., Покровский А.В., Головюк А.Л., Степанов О.А., Пудова Е.А., Размахаев Г.С., Орлова М.В., Поляков А.П., Киселева М.В., Каприн А.Д., Кудрявцева А.В.Lukyanova E.N., Snezhkina A.V., Kalinin D.V., Pokrovsky A.V., Golovyuk A.L., Stepanov O.A., Pudova E.A., Razmakhaev G.S., Orlova M.V., Polyakov A.P., Kiseleva M.V., Kaprin A.D., Kudryavtseva A.V.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/1659

Каротидные параганглиомы (КПГ) – редкие нейроэндокринные опухоли, которые развиваются из параганглионарной ткани каротидного тельца и располагаются в области бифуркации сонной артерии. Эти опухоли характеризуются медленным  ростом, однако в ряде случаев наблюдается агрессивное течение заболевания и метастазирование. Операции по удалению каротидных параганглиом сопряжены с высоким риском осложнений, в то время как лучевая и химиотерапия малоэффективны. Изучение молекулярного патогенеза КПГ может способствовать разработке новых подходов к терапии и открытию биомаркеров. Ранее нами выполнено высокопроизводительное секвенирование экзома 52 архивных образцов КПГ, одной из задач которого была оценка мутационной нагрузки. Из-за отсутствия парных образцов гистологически нормальных тка ней или крови потенциально герминальные мутации были исключены из выборки с использованием баз данных 1000 Genomes Project и ExAC при строгих параметрах фильтрации. В настоящем исследовании проанализированы десять генов (ZNF717, CDC27, FRG2C, FAM104B, CTBP2, HLA-DRB1, HYDIN, KMT5A, MUC3A и PRSS3), характеризующихся наиболее высокой мутационной нагрузкой. В четырех генах (CDC27, CTBP2, HYDIN и KMT5A) идентифицированы потенциально патогенные мутации, согласно нескольким предсказательным алгоритмам (SIFT, PolyPhen-2, MutationTaster и LRT). Многие выявленные мутации оказались представленными в большом количестве образцов выборки, что заставило проверить их соматический статус с использованием дополнительных данных секвенирования экзома крови, выполненного с таким же набором для экзомного обогащения, как и при анализе опухолей КПГ. Обнаружено, что значительное число выявленных потенциально патогенных мутаций являются герминальными, что, по-видимому, связано с наличием ошибок аннотации в базах данных 1000 Genomes Project и ExAC. Однако часть идентифицированных мутаций в генах CDC27, CTBP2, HYDIN и KMT5A остаются предположительно патогенными, кроме того, имеются многочисленные данные о вовлеченности этих генов в формирование и прогрессию других видов опухолей. Это позволяет считать гены CDC27, CTBP2, HYDIN и KMT5A потенциально связанными с патогенезом КПГ и требует обратить на них особое внимание в дальнейших исследованиях. Таким образом, необходимо совершенствовать методики для выявления онко-ассоциированных генов и патогенных мутаций.

Carotid paragangliomas (CPGLs) are rare neuroendocrine tumors that arise from paraganglionic tissue of the carotid body localizing at the bifurcation of carotid artery. These tumors are slowly growing, but occasionally they become aggressive and metastatic. Surgical treatment remains high-risk and extremely challenging; radiation and chemotherapy are poorly effective. The study of molecular pathogenesis of CPGLs will allow developing novel therapeutic approaches and revealing biomarkers. Previously, we performed the exome sequencing of 52 CPGLs and estimated mutational load (ML). Paired histologically normal tissues or blood were unavailable, so potentially germline mutations were excluded from the analysis with strong filtering conditions using 1000 Genomes Project and ExAC databases. In this work, ten genes (ZNF717, CDC27, FRG2C, FAM104B, CTBP2, HLA-DRB1, HYDIN, KMT5A, MUC3A, and PRSS3) characterized by the highest level of mutational load were analyzed. Using several prediction algorithms (SIFT, PolyPhen-2, MutationTaster, and LRT), potentially pathogenic mutations were identified in four genes (CDC27, CTBP2, HYDIN, and KMT5A). Many of these mutations occurred in the majority of cases, and their mutation type was checked using exome sequencing data of blood prepared with the same exome enrichment kit that was used for preparation of exome libraries from CPGLs. The majority of the mutations were germline that can apparently be associated with annotation errors in 1000 Genomes Pro ject and ExAC. However, part of the mutations identified in CDC27, CTBP2, HYDIN, and KMT5A remain potentially pathogenic, and there is a large body of data on the involvement of these genes in the formation and progression of other tumors. This allows considering CDC27, CTBP2, HYDIN, and KMT5A genes as potentially associated with CPGL pathogenesis and requires taking them into account in further investigations. Thus, there is a necessity to improve the methods for identification of cancer-asso ciated genes as well as pathogenic mutations. 

каротидные параганглиомыэкзоммутационная нагрузкамутациивысокопроизводительное секвенированиеcarotid paragangliomasexomemutation loadmutationshigh-throughput sequencingReferencesAlao J.P. The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention. Mol. Cancer. 2007;6:24. DOI 10.1186/1476­4598­6­24.Alao J.P. The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention. Mol. Cancer. 2007;6:24. DOI 10.1186/1476­4598­6­24.Alexandrov L.B., Nik­Zainal S., Wedge D.C., Aparicio S.A., Behjati S., Biankin A.V., Bignell G.R., Bolli N., Borg A., Børresen­Dale 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., López­Otín 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., Valdés­Mas R., van Buuren M.M., van ‘t Veer L., Vincent­Salomon A., Waddell N., Yates L.R., Australian Pancreatic Cancer Genome Initiative, ICGC Breast Cancer Consortium, ICGC MMML­Seq Consortium, ICGC PedBrain, Zucman­Rossi 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;500(7463):415­421. DOI 10.1038/nature12477.Alexandrov L.B., Nik­Zainal S., Wedge D.C., Aparicio S.A., Behjati S., Biankin A.V., Bignell G.R., Bolli N., Borg A., Børresen­Dale 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., López­Otín 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., Valdés­Mas R., van Buuren M.M., van ‘t Veer L., Vincent­Salomon A., Waddell N., Yates L.R., Australian Pancreatic Cancer Genome Initiative, ICGC Breast Cancer Consortium, ICGC MMML­Seq Consortium, ICGC PedBrain, Zucman­Rossi 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;500(7463):415­421. DOI 10.1038/nature12477.Barroilhet L., Yang J., Hasselblatt K., Paranal R.M., Ng S.K., RauhHain J.A., Welch W.R., Bradner J.E., Berkowitz R.S., Ng S.W. C­ terminal binding protein­2 regulates response of epithelial ovarian cancer cells to histone deacetylase inhibitors. Oncogene. 2013; 32(33):3896­3903. DOI 10.1038/onc.2012.380.Barroilhet L., Yang J., Hasselblatt K., Paranal R.M., Ng S.K., RauhHain J.A., Welch W.R., Bradner J.E., Berkowitz R.S., Ng S.W. C­ terminal binding protein­2 regulates response of epithelial ovarian cancer cells to histone deacetylase inhibitors. Oncogene. 2013; 32(33):3896­3903. DOI 10.1038/onc.2012.380.Beck D.B., Oda H., Shen S.S., Reinberg D. PR­Set7 and H4K20me1: at the crossroads of genome integrity, cell cycle, chromosome condensation, and transcription. Genes Dev. 2012;26(4):325­337. DOI 10.1101/gad.177444.111.Beck D.B., Oda H., Shen S.S., Reinberg D. PR­Set7 and H4K20me1: at the crossroads of genome integrity, cell cycle, chromosome condensation, and transcription. Genes Dev. 2012;26(4):325­337. DOI 10.1101/gad.177444.111.Bracarda S., Altavilla A., Hamzaj A., Sisani M., Marrocolo F., Del Buono S., Danielli R. Immunologic checkpoints blockade in renal cell, prostate, and urothelial malignancies. Semin. Oncol. 2015;42(3): 495­505. DOI 10.1053/j.seminoncol.2015.02.004.Bracarda S., Altavilla A., Hamzaj A., Sisani M., Marrocolo F., Del Buono S., Danielli R. Immunologic checkpoints blockade in renal cell, prostate, and urothelial malignancies. Semin. Oncol. 2015;42(3): 495­505. DOI 10.1053/j.seminoncol.2015.02.004.Chabanon R.M., Pedrero M., Lefebvre C., Marabelle A., Soria J.C., Postel­Vinay S. Mutational landscape and sensitivity to immune checkpoint blockers. Clin. Cancer Res. 2016;22(17):4309­4321. DOI 10.1158/1078­0432.CCR­16­0903.Chabanon R.M., Pedrero M., Lefebvre C., Marabelle A., Soria J.C., Postel­Vinay S. Mutational landscape and sensitivity to immune checkpoint blockers. Clin. Cancer Res. 2016;22(17):4309­4321. DOI 10.1158/1078­0432.CCR­16­0903.Dai F., Xuan Y., Jin J.J., Yu S., Long Z.W., Cai H., Liu X.W., Zhou Y., Wang Y.N., Chen Z., Huang H. CtBP2 overexpression promotes tumor cell proliferation and invasion in gastric cancer and is associated with poor prognosis. Oncotarget. 2017;8(17):28736­28749. DOI 10.18632/oncotarget.15661.Dai F., Xuan Y., Jin J.J., Yu S., Long Z.W., Cai H., Liu X.W., Zhou Y., Wang Y.N., Chen Z., Huang H. CtBP2 overexpression promotes tumor cell proliferation and invasion in gastric cancer and is associated with poor prognosis. Oncotarget. 2017;8(17):28736­28749. DOI 10.18632/oncotarget.15661.Davy B.E., Robinson M.L. Congenital hydrocephalus in hy3 mice is caused by a frameshift mutation in Hydin, a large novel gene. Hum. Mol. Genet. 2003;12(10):1163­1170. DOI 10.1093/hmg/ddg122.Davy B.E., Robinson M.L. Congenital hydrocephalus in hy3 mice is caused by a frameshift mutation in Hydin, a large novel gene. Hum. Mol. Genet. 2003;12(10):1163­1170. DOI 10.1093/hmg/ddg122.Di L.J., Byun J.S., Wong M.M., Wakano C., Taylor T., Bilke S., Baek S., Hunter K., Yang H., Lee M., Zvosec C., Khramtsova G., Cheng F., Perou C.M., Miller C.R., Raab R., Olopade O.I., Gardner K. Genome­wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer. Nat. Commun. 2013;4:1449. DOI 10.1038/ncomms2438.Di L.J., Byun J.S., Wong M.M., Wakano C., Taylor T., Bilke S., Baek S., Hunter K., Yang H., Lee M., Zvosec C., Khramtsova G., Cheng F., Perou C.M., Miller C.R., Raab R., Olopade O.I., Gardner K. Genome­wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer. Nat. Commun. 2013;4:1449. DOI 10.1038/ncomms2438.Di L.J., Fernandez A.G., De Siervi A., Longo D.L., Gardner K. Transcriptional regulation of BRCA1 expression by a metabolic switch. Nat. Struct. Mol. Biol. 2010;17(12):1406­1413. DOI 10.1038/nsmb. 1941.Di L.J., Fernandez A.G., De Siervi A., Longo D.L., Gardner K. Transcriptional regulation of BRCA1 expression by a metabolic switch. Nat. Struct. Mol. Biol. 2010;17(12):1406­1413. DOI 10.1038/nsmb. 1941.Ding C., Li R., Peng J., Li S., Guo Z. A polymorphism at the miR­502 binding site in the 3′ untranslated region of the SET8 gene is associated with the outcome of small­cell lung cancer. Exp. Ther. Med. 2012;3(4):689­692. DOI 10.3892/etm.2012.469.Ding C., Li R., Peng J., Li S., Guo Z. A polymorphism at the miR­502 binding site in the 3′ untranslated region of the SET8 gene is associated with the outcome of small­cell lung cancer. Exp. Ther. Med. 2012;3(4):689­692. DOI 10.3892/etm.2012.469.Doggett N.A., Xie G., Meincke L.J., Sutherland R.D., Mundt M.O., Berbari N.S., Davy B.E., Robinson M.L., Rudd M.K., Weber J.L., Stallings R.L., Han C. A 360­kb interchromosomal duplication of the human HYDIN locus. Genomics. 2006;88(6):762­771. DOI 10.1016/j.ygeno.2006.07.012.Doggett N.A., Xie G., Meincke L.J., Sutherland R.D., Mundt M.O., Berbari N.S., Davy B.E., Robinson M.L., Rudd M.K., Weber J.L., Stallings R.L., Han C. A 360­kb interchromosomal duplication of the human HYDIN locus. Genomics. 2006;88(6):762­771. DOI 10.1016/j.ygeno.2006.07.012.Favier J., Amar L., Gimenez­Roqueplo A.P. Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. Nat. Rev. Endocrinol. 2015;11(2):101­111. DOI 10.1038/nrendo.2014.188.Favier J., Amar L., Gimenez­Roqueplo A.P. Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. Nat. Rev. Endocrinol. 2015;11(2):101­111. DOI 10.1038/nrendo.2014.188.Favier J., Gimenez­Roqueplo A.P. Genetics of paragangliomas and pheochromocytomas. Med. Sci. (Paris). 2012;28(6­7):625­632. DOI 10.1051/medsci/2012286016.Favier J., Gimenez­Roqueplo A.P. Genetics of paragangliomas and pheochromocytomas. Med. Sci. (Paris). 2012;28(6­7):625­632. DOI 10.1051/medsci/2012286016.Guo Z., Wu C., Wang X., Wang C., Zhang R., Shan B. A polymorphism at the miR­502 binding site in the 3′­untranslated region of the histone methyltransferase SET8 is associated with hepatocellular carcinoma outcome. Int. J. Cancer. 2012;131(6):1318­1322. DOI 10.1002/ijc.27352.Guo Z., Wu C., Wang X., Wang C., Zhang R., Shan B. A polymorphism at the miR­502 binding site in the 3′­untranslated region of the histone methyltransferase SET8 is associated with hepatocellular carcinoma outcome. Int. J. Cancer. 2012;131(6):1318­1322. DOI 10.1002/ijc.27352.Juhlin C.C., Goh G., Healy J.M., Fonseca A.L., Scholl U.I., Stenman A., Kunstman J.W., Brown T.C., Overton J.D., Mane S.M., Nelson­Williams C., Bäckdahl M., Suttorp A.C., Haase M., Choi M., Schlessinger J., Rimm D.L., Höög A., Prasad M.L., Korah R., Kim J.K., Diehl J.A. Nuclear cyclin D1: an oncogenic driver in human cancer. J. Cell Physiol. 2009;220(2):292­296. DOI 10.1002/jcp.21791.Juhlin C.C., Goh G., Healy J.M., Fonseca A.L., Scholl U.I., Stenman A., Kunstman J.W., Brown T.C., Overton J.D., Mane S.M., Nelson­Williams C., Bäckdahl M., Suttorp A.C., Haase M., Choi M., Schlessinger J., Rimm D.L., Höög A., Prasad M.L., Korah R., Kim J.K., Diehl J.A. Nuclear cyclin D1: an oncogenic driver in human cancer. J. Cell Physiol. 2009;220(2):292­296. DOI 10.1002/jcp.21791.Liao T., Wang Y.J., Hu J.Q., Wang Y., Han L.T., Ma B., Shi R.L., Qu N., Wei W.J., Guan Q., Xiang J., Chen J.Y., Sun G.H., Li D.S., Mu X.M., Ji Q.H. Histone methyltransferase KMT5A gene modulates oncogenesis and lipid metabolism of papillary thyroid cancer in vitro. Oncol. Rep. 2018;39(5):2185­2192. DOI 10.3892/or.2018.6295.Liao T., Wang Y.J., Hu J.Q., Wang Y., Han L.T., Ma B., Shi R.L., Qu N., Wei W.J., Guan Q., Xiang J., Chen J.Y., Sun G.H., Li D.S., Mu X.M., Ji Q.H. Histone methyltransferase KMT5A gene modulates oncogenesis and lipid metabolism of papillary thyroid cancer in vitro. Oncol. Rep. 2018;39(5):2185­2192. DOI 10.3892/or.2018.6295.Lindberg J., Mills I.G., Klevebring D., Liu W., Neiman M., Xu J., Wikström P., Wiklund P., Wiklund F., Egevad L., Grönberg H. The mitochondrial and autosomal mutation landscapes of prostate cancer. Eur. Urol. 2013;63(4):702­708. DOI 10.1016/j.eururo.2012.11.053.Lindberg J., Mills I.G., Klevebring D., Liu W., Neiman M., Xu J., Wikström P., Wiklund P., Wiklund F., Egevad L., Grönberg H. The mitochondrial and autosomal mutation landscapes of prostate cancer. Eur. Urol. 2013;63(4):702­708. DOI 10.1016/j.eururo.2012.11.053.Litchfield K., Summersgill B., Yost S., Sultana R., Labreche K., Dudakia D., Renwick A., Seal S., Al­Saadi R., Broderick P., Turner N.C., Houlston R.S., Huddart R., Shipley J., Turnbull C. Whole­exome sequencing reveals the mutational spectrum of testicular germ cell tumours. Nat. Commun. 2015;6:5973. DOI 10.1038/ncomms6973.Litchfield K., Summersgill B., Yost S., Sultana R., Labreche K., Dudakia D., Renwick A., Seal S., Al­Saadi R., Broderick P., Turner N.C., Houlston R.S., Huddart R., Shipley J., Turnbull C. Whole­exome sequencing reveals the mutational spectrum of testicular germ cell tumours. Nat. Commun. 2015;6:5973. DOI 10.1038/ncomms6973.Ma Z. Downregulation of SETD8 by miR­382 is involved in glioma progression. Pathol. Res. Pract. 2018;214(3):356­360. DOI 10.1016/ j.prp.2018.01.004.Ma Z. Downregulation of SETD8 by miR­382 is involved in glioma progression. Pathol. Res. Pract. 2018;214(3):356­360. DOI 10.1016/ j.prp.2018.01.004.Milite C., Feoli A., Viviano M., Rescigno D., Cianciulli A., Balzano A.L., Mai A., Castellano S., Sbardella G. The emerging role of lysine methyltransferase SETD8 in human diseases. Clin. Epigenetics. 2016;8:102. DOI 10.1186/s13148­016­0268­4.Milite C., Feoli A., Viviano M., Rescigno D., Cianciulli A., Balzano A.L., Mai A., Castellano S., Sbardella G. The emerging role of lysine methyltransferase SETD8 in human diseases. Clin. Epigenetics. 2016;8:102. DOI 10.1186/s13148­016­0268­4.Nishioka K., Rice J.C., Sarma K., Erdjument­Bromage H., Werner J., Wang Y., Chuikov S., Valenzuela P., Tempst P., Steward R., Lis J.T., Allis C.D., Reinberg D. PR­Set7 is a nucleosome­specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. Mol. Cell. 2002;9(6):1201­1213. DOI 10.1016/S1097­2765(02)00548­8.Nishioka K., Rice J.C., Sarma K., Erdjument­Bromage H., Werner J., Wang Y., Chuikov S., Valenzuela P., Tempst P., Steward R., Lis J.T., Allis C.D., Reinberg D. PR­Set7 is a nucleosome­specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. Mol. Cell. 2002;9(6):1201­1213. DOI 10.1016/S1097­2765(02)00548­8.Nölting S., Grossman A.B. Signaling pathways in pheochromocytomas and paragangliomas: prospects for future therapies. Endocr. Pathol. 2012;23(1):21­33. DOI 10.1007/s12022­012­9199­6.Nölting S., Grossman A.B. Signaling pathways in pheochromocytomas and paragangliomas: prospects for future therapies. Endocr. Pathol. 2012;23(1):21­33. DOI 10.1007/s12022­012­9199­6.Page A.M., Hieter P. The anaphase­promoting complex: new subunits and regulators. Annu. Rev. Biochem. 1999;68:583­609. DOI 10.1146/annurev.biochem.68.1.583.Page A.M., Hieter P. The anaphase­promoting complex: new subunits and regulators. Annu. Rev. Biochem. 1999;68:583­609. DOI 10.1146/annurev.biochem.68.1.583.Pawar S.A., Sarkar T.R., Balamurugan K., Sharan S., Wang J., Zhang Y., Dowdy S.F., Huang A.M., Sterneck E. C/EBPδ targets cyclin D1 for proteasome­mediated degradation via induction of CDC27/APC3 expression. Proc. Natl. Acad. Sci. USA. 2010;107(20):9210­9215. DOI 10.1073/pnas.0913813107.Pawar S.A., Sarkar T.R., Balamurugan K., Sharan S., Wang J., Zhang Y., Dowdy S.F., Huang A.M., Sterneck E. C/EBPδ targets cyclin D1 for proteasome­mediated degradation via induction of CDC27/APC3 expression. Proc. Natl. Acad. Sci. USA. 2010;107(20):9210­9215. DOI 10.1073/pnas.0913813107.Peters J.M. The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat. Rev. Mol. Cell Biol. 2006;7(9):644­656. DOI 10.1038/nrm1988.Peters J.M. The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat. Rev. Mol. Cell Biol. 2006;7(9):644­656. DOI 10.1038/nrm1988.Plouin P.F., Amar L., Dekkers O.M., Fassnacht M., Gimenez­Roqueplo A.P., Lenders J.W., Lussey­Lepoutre C., Steichen O. European Society of Endocrinology Clinical Practice Guideline for longterm follow­up of patients operated on for a phaeochromocytoma or a paraganglioma. Eur. J. Endocrinol. 2016;174(5):G1­G10. DOI 10.1530/EJE­16­0033.Plouin P.F., Amar L., Dekkers O.M., Fassnacht M., Gimenez­Roqueplo A.P., Lenders J.W., Lussey­Lepoutre C., Steichen O. European Society of Endocrinology Clinical Practice Guideline for longterm follow­up of patients operated on for a phaeochromocytoma or a paraganglioma. Eur. J. Endocrinol. 2016;174(5):G1­G10. DOI 10.1530/EJE­16­0033.Qiu L., Wu J., Pan C., Tan X., Lin J., Liu R., Chen S., Geng R., Huang W. Downregulation of CDC27 inhibits the proliferation of colorectal cancer cells via the accumulation of p21Cip1/Waf1. Cell Death Dis. 2016;7:e2074. DOI 10.1038/cddis.2015.402.Qiu L., Wu J., Pan C., Tan X., Lin J., Liu R., Chen S., Geng R., Huang W. Downregulation of CDC27 inhibits the proliferation of colorectal cancer cells via the accumulation of p21Cip1/Waf1. Cell Death Dis. 2016;7:e2074. DOI 10.1038/cddis.2015.402.Reimann E., Kõks S., Ho X.D., Maasalu K., Märtson A. Whole exome sequencing of a single osteosarcoma case–integrative analysis with whole transcriptome RNA­seq data. Hum. Genomics. 2014;8:20. DOI 10.1186/s40246­014­0020­0.Reimann E., Kõks S., Ho X.D., Maasalu K., Märtson A. Whole exome sequencing of a single osteosarcoma case–integrative analysis with whole transcriptome RNA­seq data. Hum. Genomics. 2014;8:20. DOI 10.1186/s40246­014­0020­0.Shi X., Kachirskaia I., Yamaguchi H., West L.E., Wen H., Wang E.W., Dutta S., Appella E., Gozani O. Modulation of p53 function by SET8mediated methylation at lysine 382. Mol. Cell. 2007;27(4):636­646. DOI 10.1016/j.molcel.2007.07.012.Shi X., Kachirskaia I., Yamaguchi H., West L.E., Wen H., Wang E.W., Dutta S., Appella E., Gozani O. Modulation of p53 function by SET8mediated methylation at lysine 382. Mol. Cell. 2007;27(4):636­646. DOI 10.1016/j.molcel.2007.07.012.Snezhkina A.V., Lukyanova E.N., Kalinin D.V., Pokrovsky A.V., Dmitriev A.A., Koroban N.V., Pudova E.A., Fedorova M.S., Volchenko N.N., Stepanov O.A., Zhevelyuk E.A., Kharitonov S.L., Lipatova A.V., Abramov I.S., Golovyuk A.V., Yegorov Y.E., Vishnyakova K.S., Moskalev A.A., Krasnov G.S., Melnikova N.V., Shcherbo D.S., Kiseleva M.V., Kaprin A.D., Alekseev B.Y., Zaretsky A.R., Kudryavtseva A.V. Exome analysis of carotid body tumor. BMC Med. Genomics. 2018;11(Suppl.1):17. DOI 10.1186/s12920­018­0327­0.Snezhkina A.V., Lukyanova E.N., Kalinin D.V., Pokrovsky A.V., Dmitriev A.A., Koroban N.V., Pudova E.A., Fedorova M.S., Volchenko N.N., Stepanov O.A., Zhevelyuk E.A., Kharitonov S.L., Lipatova A.V., Abramov I.S., Golovyuk A.V., Yegorov Y.E., Vishnyakova K.S., Moskalev A.A., Krasnov G.S., Melnikova N.V., Shcherbo D.S., Kiseleva M.V., Kaprin A.D., Alekseev B.Y., Zaretsky A.R., Kudryavtseva A.V. Exome analysis of carotid body tumor. BMC Med. Genomics. 2018;11(Suppl.1):17. DOI 10.1186/s12920­018­0327­0.Song F., Zheng H., Liu B., Wei S., Dai H., Zhang L., Calin G.A., Hao X., Wei Q., Zhang W., Chen K. An miR­502­binding site single­nucleotide polymorphism in the 3′­untranslated region of the SET8 gene is associated with early age of breast cancer onset. Clin. Cancer Res. 2009;15(19):6292­6300. DOI 10.1158/1078­0432.CCR­09­0826.Song F., Zheng H., Liu B., Wei S., Dai H., Zhang L., Calin G.A., Hao X., Wei Q., Zhang W., Chen K. An miR­502­binding site single­nucleotide polymorphism in the 3′­untranslated region of the SET8 gene is associated with early age of breast cancer onset. Clin. Cancer Res. 2009;15(19):6292­6300. DOI 10.1158/1078­0432.CCR­09­0826.Stevens K.N., Wang X., Fredericksen Z., Pankratz V.S., Cerhan J., Vachon C.M., Olson J.E., Couch F.J. Evaluation of associations between common variation in mitotic regulatory pathways and risk of overall and high grade breast cancer. Breast Cancer Res. Treat. 2011; 129(2):617­622. DOI 10.1007/s10549­011­1587­y.Stevens K.N., Wang X., Fredericksen Z., Pankratz V.S., Cerhan J., Vachon C.M., Olson J.E., Couch F.J. Evaluation of associations between common variation in mitotic regulatory pathways and risk of overall and high grade breast cancer. Breast Cancer Res. Treat. 2011; 129(2):617­622. DOI 10.1007/s10549­011­1587­y.Takawa M., Cho H.S., Hayami S., Toyokawa G., Kogure M., Yamane Y., Iwai Y., Maejima K., Ueda K., Masuda A., Dohmae N., Field H.I., Tsunoda T., Kobayashi T., Akasu T., Sugiyama M., Ohnuma S., Atomi Y., Ponder B.A., Nakamura Y., Hamamoto R. Histone lysine methyltransferase SETD8 promotes carcinogenesis by deregulating PCNA expression. Cancer Res. 2012;72(13):3217­3227. DOI 10.1158/0008­5472.CAN­11­3701.Takawa M., Cho H.S., Hayami S., Toyokawa G., Kogure M., Yamane Y., Iwai Y., Maejima K., Ueda K., Masuda A., Dohmae N., Field H.I., Tsunoda T., Kobayashi T., Akasu T., Sugiyama M., Ohnuma S., Atomi Y., Ponder B.A., Nakamura Y., Hamamoto R. Histone lysine methyltransferase SETD8 promotes carcinogenesis by deregulating PCNA expression. Cancer Res. 2012;72(13):3217­3227. DOI 10.1158/0008­5472.CAN­11­3701.Talvinen K., Karra H., Pitkänen R., Ahonen I., Nykänen M., Lintunen M., Söderström M., Kuopio T., Kronqvist P. Low cdc27 and high securin expression predict short survival for breast cancer patients. APMIS. 2013;121(10):945­953. DOI 10.1111/apm.12110.Talvinen K., Karra H., Pitkänen R., Ahonen I., Nykänen M., Lintunen M., Söderström M., Kuopio T., Kronqvist P. Low cdc27 and high securin expression predict short survival for breast cancer patients. APMIS. 2013;121(10):945­953. DOI 10.1111/apm.12110.Tan H., Bao J., Zhou X. Genome­wide mutational spectra analysis reveals significant cancer­specific heterogeneity. Sci. Rep. 2015;5: 12566. DOI 10.1038/srep12566.Tan H., Bao J., Zhou X. Genome­wide mutational spectra analysis reveals significant cancer­specific heterogeneity. Sci. Rep. 2015;5: 12566. DOI 10.1038/srep12566.Topalian S.L., Taube J.M., Anders R.A., Pardoll D.M. Mechanismdriven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer. 2016;16(5):275­287. DOI 10.1038/nrc.2016.36.Topalian S.L., Taube J.M., Anders R.A., Pardoll D.M. Mechanismdriven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer. 2016;16(5):275­287. DOI 10.1038/nrc.2016.36.Turner J., Crossley M. The CtBP family: enigmatic and enzymatic transcriptional co­repressors. Bioessays. 2001;23(8):683­690. DOI 10.1002/bies.1097.Turner J., Crossley M. The CtBP family: enigmatic and enzymatic transcriptional co­repressors. Bioessays. 2001;23(8):683­690. DOI 10.1002/bies.1097.Unlü Y., Becit N., Ceviz M., Koçak H. Management of carotid body tu mors and familial paragangliomas: review of 30 years’ experience. Ann. Vasc. Surg. 2009;23(5):616­620. DOI 10.1016/j.avsg.2009.06.014.Unlü Y., Becit N., Ceviz M., Koçak H. Management of carotid body tu mors and familial paragangliomas: review of 30 years’ experience. Ann. Vasc. Surg. 2009;23(5):616­620. DOI 10.1016/j.avsg.2009.06.014.Van Allen E.M., Miao D., Schilling B., Shukla S.A., Blank C., Zimmer L., Sucker A., Hillen U., Foppen M.H.G., Goldinger S.M., Utikal J., Hassel J.C., Weide B., Kaehler K.C., Loquai C., Mohr P., Gutzmer R., Dummer R., Gabriel S., Wu C.J., Schadendorf D., Garraway L.A. Genomic correlates of response to CTLA­4 blockade in metastatic melanoma. Science. 2015;350(6257):207­211. DOI 10.1126/science.aad0095.Van Allen E.M., Miao D., Schilling B., Shukla S.A., Blank C., Zimmer L., Sucker A., Hillen U., Foppen M.H.G., Goldinger S.M., Utikal J., Hassel J.C., Weide B., Kaehler K.C., Loquai C., Mohr P., Gutzmer R., Dummer R., Gabriel S., Wu C.J., Schadendorf D., Garraway L.A. Genomic correlates of response to CTLA­4 blockade in metastatic melanoma. Science. 2015;350(6257):207­211. DOI 10.1126/science.aad0095.Wang C., Guo Z., Wu C., Li Y., Kang S. A polymorphism at the miR502 binding site in the 3′ untranslated region of the SET8 gene is associated with the risk of epithelial ovarian cancer. Cancer Genet. 2012;205(7­8):373­376. DOI 10.1016/j.cancergen.2012.04.010.Wang C., Guo Z., Wu C., Li Y., Kang S. A polymorphism at the miR502 binding site in the 3′ untranslated region of the SET8 gene is associated with the risk of epithelial ovarian cancer. Cancer Genet. 2012;205(7­8):373­376. DOI 10.1016/j.cancergen.2012.04.010.Wang Y., Che S., Cai G., He Y., Chen J., Xu W. Expression and prognostic significance of CTBP2 in human gliomas. Oncol. Lett. 2016; 12(4):2429­2434. DOI 10.3892/ol.2016.4998.Wang Y., Che S., Cai G., He Y., Chen J., Xu W. Expression and prognostic significance of CTBP2 in human gliomas. Oncol. Lett. 2016; 12(4):2429­2434. DOI 10.3892/ol.2016.4998.Wu S., Rice J.C. A new regulator of the cell cycle: the PR­Set7 histone methyltransferase. Cell Cycle. 2011;10(1):68­72. DOI 10.4161/ cc.10.1.14363.Wu S., Rice J.C. A new regulator of the cell cycle: the PR­Set7 histone methyltransferase. Cell Cycle. 2011;10(1):68­72. DOI 10.4161/ cc.10.1.14363.Xu J., Yin Z., Gao W., Liu L., Yin Y., Liu P., Shu Y. Genetic variation in a microRNA­502 minding site in SET8 gene confers clinical outcome of non­small cell lung cancer in a Chinese population. PLoS One. 2013;8(10):e77024. DOI 10.1371/journal.pone.0077024.Xu J., Yin Z., Gao W., Liu L., Yin Y., Liu P., Shu Y. Genetic variation in a microRNA­502 minding site in SET8 gene confers clinical outcome of non­small cell lung cancer in a Chinese population. PLoS One. 2013;8(10):e77024. DOI 10.1371/journal.pone.0077024.Yang F., Sun L., Li Q., Han X., Lei L., Zhang H., Shang Y. SET8 promotes epithelial­mesenchymal transition and confers TWIST dual transcriptional activities. EMBO J. 2012;31(1):110­123. DOI 10.1038/emboj.2011.364.Yang F., Sun L., Li Q., Han X., Lei L., Zhang H., Shang Y. SET8 promotes epithelial­mesenchymal transition and confers TWIST dual transcriptional activities. EMBO J. 2012;31(1):110­123. DOI 10.1038/emboj.2011.364.Yu C., Yu J., Yao X., Wu W.K., Lu Y., Tang S., Li X., Bao L., Li X., Hou Y., Wu R., Jian M., Chen R., Zhang F., Xu L., Fan F., He J., Liang Q., Wang H., Hu X., He M., Zhang X., Zheng H., Li Q., Wu H., Chen Y., Yang X., Zhu S., Xu X., Yang H., Wang J., Zhang X., Sung J.J., Li Y., Wang J. Discovery of biclonal origin and a novel oncogene SLC12A5 in colon cancer by single­cell sequencing. Cell Res. 2014;24(6):701­712. DOI 10.1038/cr.2014.43.Yu C., Yu J., Yao X., Wu W.K., Lu Y., Tang S., Li X., Bao L., Li X., Hou Y., Wu R., Jian M., Chen R., Zhang F., Xu L., Fan F., He J., Liang Q., Wang H., Hu X., He M., Zhang X., Zheng H., Li Q., Wu H., Chen Y., Yang X., Zhu S., Xu X., Yang H., Wang J., Zhang X., Sung J.J., Li Y., Wang J. Discovery of biclonal origin and a novel oncogene SLC12A5 in colon cancer by single­cell sequencing. Cell Res. 2014;24(6):701­712. DOI 10.1038/cr.2014.43.Yu N., Huangyang P., Yang X., Han X., Yan R., Jia H., Shang Y., Sun L. microRNA­7 suppresses the invasive potential of breast cancer cells and sensitizes cells to DNA damages by targeting histone methyltransferase SET8. J. Biol. Chem. 2013;288(27):19633­19642. DOI 10.1074/jbc.M113.475657.Yu N., Huangyang P., Yang X., Han X., Yan R., Jia H., Shang Y., Sun L. microRNA­7 suppresses the invasive potential of breast cancer cells and sensitizes cells to DNA damages by targeting histone methyltransferase SET8. J. Biol. Chem. 2013;288(27):19633­19642. DOI 10.1074/jbc.M113.475657.Yu Z., Li Z., Jolicoeur N., Zhang L., Fortin Y., Wang E., Wu M., Shen S.H. Aberrant allele frequencies of the SNPs located in microRNA target sites are potentially associated with human cancers. Nucleic Acids Res. 2007;35(13):4535­4541. DOI 10.1093/nar/gkm480.Yu Z., Li Z., Jolicoeur N., Zhang L., Fortin Y., Wang E., Wu M., Shen S.H. Aberrant allele frequencies of the SNPs located in microRNA target sites are potentially associated with human cancers. Nucleic Acids Res. 2007;35(13):4535­4541. DOI 10.1093/nar/gkm480.Zhang C., Gao C., Xu Y., Zhang Z. CtBP2 could promote prostate cancer cell proliferation through c­Myc signaling. Gene. 2014;546(1):7379. DOI 10.1016/j.gene.2014.05.032.Zhang C., Gao C., Xu Y., Zhang Z. CtBP2 could promote prostate cancer cell proliferation through c­Myc signaling. Gene. 2014;546(1):7379. DOI 10.1016/j.gene.2014.05.032.Zhang J., Zhu J., Yang L., Guan C., Ni R., Wang Y., Ji L., Tian Y. Interaction with CCNH/CDK7 facilitates CtBP2 promoting esophageal squamous cell carcinoma (ESCC) metastasis via upregulating epithelial­mesenchymal transition (EMT) progression. Tumour Biol. 2015;36(9):6701­6714. DOI 10.1007/s13277­015­3354­x.Zhang J., Zhu J., Yang L., Guan C., Ni R., Wang Y., Ji L., Tian Y. Interaction with CCNH/CDK7 facilitates CtBP2 promoting esophageal squamous cell carcinoma (ESCC) metastasis via upregulating epithelial­mesenchymal transition (EMT) progression. Tumour Biol. 2015;36(9):6701­6714. DOI 10.1007/s13277­015­3354­x.Zhang Y., Cai Q., Shu X.O., Gao Y.T., Li C., Zheng W., Long J. Wholeexome sequencing identifies novel somatic mutations in Chinese breast cancer patients. J. Mol. Genet. Med. 2015;9(4):183. DOI 10.4172/1747­0862.1000183.Zhang Y., Cai Q., Shu X.O., Gao Y.T., Li C., Zheng W., Long J. Wholeexome sequencing identifies novel somatic mutations in Chinese breast cancer patients. J. Mol. Genet. Med. 2015;9(4):183. DOI 10.4172/1747­0862.1000183.Zhikrivetskaya S.O., Snezhkina A.V., Zaretsky A.R., Alekseev B.Y., Pokrovsky A.V., Golovyuk A.L., Melnikova N.V., Stepanov O.A., Kalinin D.V., Moskalev A.A., Krasnov G.S., Dmitriev A.A., Kudryavtseva A.V. Molecular markers of paragangliomas/pheochromocytomas. Oncotarget. 2017;8(15):25756­25782. DOI 10.18632/ oncotarget.15201.Zhikrivetskaya S.O., Snezhkina A.V., Zaretsky A.R., Alekseev B.Y., Pokrovsky A.V., Golovyuk A.L., Melnikova N.V., Stepanov O.A., Kalinin D.V., Moskalev A.A., Krasnov G.S., Dmitriev A.A., Kudryavtseva A.V. Molecular markers of paragangliomas/pheochromocytomas. Oncotarget. 2017;8(15):25756­25782. DOI 10.18632/ oncotarget.15201.

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