cardiotomskСибирский журнал клинической и экспериментальной медициныSiberian Journal of Clinical and Experimental Medicine2713-29272713-265XTSU publishing10.29001/2073-8552-2021-36-4-144-155cardiotomsk-1299Research ArticleЭКСПЕРИМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯEXPERIMENTAL STUDIESАнализ коэкспрессии генов плацентарного транскриптома как основа для поиска ключевых сигнальных путей и биомаркеров больших акушерских синдромовCo-expression analysis of placental genes in the search for key signaling pathways and biomarkers of the great obstetrical syndromeshttps://orcid.org/0000-0003-1311-7403ТрифоноваЕ. А.TrifonovaE. A.

 канд. мед. наук, старший научный сотрудник

 634050, Российская Федерация, Томск, наб. р. Ушайки, 10 

 634050, Российская Федерация, Томск, Московский тракт, 2 

 Cand. Sci. (Med.), Senior Research Scientist

 10, Nab. Ushaiki, Tomsk, 634050, Russian Federation 

 2, Moscovsky tract, Tomsk, 634050, Russian Federation 

ekaterina-trifonova@medgenetics.ruhttps://orcid.org/0000-0002-5824-6439МарковА. В.MarkovA. V.

 канд. мед. наук, научный сотрудник

 634050, Российская Федерация, Томск, наб. р. Ушайки, 10 

 Cand. Sci. (Med.), Research Scientist

 10, Nab. Ushaiki, Tomsk, 634050, Russian Federation 

anton.markov@medgenetics.ruhttps://orcid.org/0000-0001-6568-6339ЗарубинА. А.ZarubinA. A.

 младший научный сотрудник

 634050, Российская Федерация, Томск, наб. р. Ушайки, 10 

 Junior Research Scientist

 10, Nab. Ushaiki, Tomsk, 634050, Russian Federation 

aleksei.zarubin@medgenetics.ruhttps://orcid.org/0000-0002-1193-5579БабовскаяА. А.BabovskayaA. A.

 лаборант-исследователь 

 634050, Российская Федерация, Томск, наб. р. Ушайки, 10 

 Research Assistant

 10, Nab. Ushaiki, Tomsk, 634050, Russian Federation 

anastasia.babovskaya@medgenetics.ruКуценкоИ. Г.KutsenkoI. G.

 д-р мед. наук, заведующий кафедрой акушерства и гинекологии

 634050, Российская Федерация, Томск, Московский тракт, 2 

 Dr. Sci. (Med.), Head of the Department of Obstetrics and Gynecology

 2, Moscovsky tract, Tomsk, 634050, Russian Federation 

kutsenko.ig@ssmu.ruhttps://orcid.org/0000-0003-2752-726XГабидулинаТ. В.GabidulinaT. V.

 канд. мед. наук, доцент кафедры акушерства и гинекологии  

 634050, Российская Федерация, Томск, Московский тракт, 2 

 Cand. Sci. (Med.), Associate Professor, Department of Obstetrics and Gynecolog

 2, Moscovsky tract, Tomsk, 634050, Russian Federation 

helen556@yandex.ruhttps://orcid.org/0000-0001-9857-4368ИжойкинаЕ. В.IzhoykinaE. V.

 соискатель кафедры акушерства и гинекологии

634050, Российская Федерация, Томск, Московский тракт, 2 

 Postgraduate Student, Department of Obstetrics and Gynecology 

 2, Moscovsky tract, Tomsk, 634050, Russian Federation 

katushkabig@mail.ruhttps://orcid.org/0000-0003-1024-2305СереброваВ. Н.SerebrovaV. N.

 младший научный сотрудник

 634050, Российская Федерация, Томск, наб. р. Ушайки, 10 

 Junior Research Scientist

 10, Nab. Ushaiki, Tomsk, 634050, Russian Federation 

vika.serebrova@medgenetics.ruhttps://orcid.org/0000-0002-5166-331XСтепановВ. А.StepanovV. A.

 д-р биол. наук, профессор, чл.-корр. РАН, руководитель лаборатории эволюционной генетики, директор  

 634050, Российская Федерация, Томск, наб. р. Ушайки, 10 

 Dr. Sci. (Med.), Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Laboratory of Evolutionary Genetics, Research Institute of Medical Genetics, Director 

 10, Nab. Ushaiki, Tomsk, 634050, Russian Federation 

vadim.stepanov@medgenetics.ruНаучно-исследовательский институт генетики, Томский национальный исследовательский медицинский центр Российской академии наук; Сибирский государственный медицинский университет Министерства здравоохранения Российской ФедерацииРоссияResearch Institute of Medical Genetics, Tomsk National Research Medical Center, Russian Academy of Sciences; Siberian State Medical University  Russian FederationНаучно-исследовательский институт генетики, Томский национальный исследовательский медицинский центр Российской академии наукРоссияResearch Institute of Medical Genetics, Tomsk National Research Medical Center, Russian Academy of SciencesRussian FederationСибирский государственный медицинский университет Министерства здравоохранения Российской ФедерацииРоссияSiberian State Medical University Russian FederationНаучно-исследовательский институт генетики, Томский национальный исследовательский медицинский центр Российской академии наукРоссияResearch Institute of Medical Genetics, Tomsk National Research Medical Center, Russian Academy of Sciences Russian Federation202105012022364144155Copyright © Трифонова Е.А., Марков А.В., Зарубин А.А., Бабовская А.А., Куценко И.Г., Габидулина Т.В., Ижойкина Е.В., Сереброва В.Н., Степанов В.А., 20222022Трифонова Е.А., Марков А.В., Зарубин А.А., Бабовская А.А., Куценко И.Г., Габидулина Т.В., Ижойкина Е.В., Сереброва В.Н., Степанов В.А.Trifonova E.A., Markov A.V., Zarubin A.A., Babovskaya A.A., Kutsenko I.G., Gabidulina T.V., Izhoykina E.V., Serebrova V.N., Stepanov V.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.sibjcem.ru/jour/article/view/1299

Цель: изучение молекулярных механизмов развития заболеваний группы больших акушерских синдромов (БАС) на уровне транскриптома материнской части плаценты человека.Материал и методы. С помощью базы данных Gene Expression Omnibus (GEO) был осуществлен поиск результатов полногеномного профилирования плацентарной ткани человека для следующих фенотипов: физиологическая беременность, преэклампсия (ПЭ), невынашивание беременности и задержка роста плода (ЗРП). Было отобрано 11 наборов данных, которые были дополнены результатами собственного исследования, суммарно в интегративный анализ был включен 481 образец плацентарной ткани человека. Биоинформатическая обработка и статистический анализ данных были выполнены в программной среде R 3.6.1 с использованием пакетов Bioconductor. Итоговые наборы данных, объединенные по трем патологиям беременности, были использованы для поиска общих молекулярных мишеней БАС посредством анализа взвешенных сетей коэкспрессии генов (WGCNA). Функциональную аннотацию генов и полученных кластеров осуществляли в базе данных DAVID, сеть белок-белковых взаимодействий продуктов генов была построена с использованием программного обеспечения STRING, центральные гены для сети были идентифицированы с помощью анализа MCC плагина сytoHubba программного обеспечения Cytoscape 3.7.2.Результаты. Получена таблица уровней экспрессии 15167 генов в 246 образцах. Иерархическая кластеризация этой сети позволила обнаружить 55 модулей коэкспрессирующихся генов в группе с ПЭ, 109 – в группе с преждевременными родами (ПР), 75 – для больных ЗРП и 56 – для контрольной группы. Результаты анализа общности набора модулей коэкспрессии для изучаемых фенотипов свидетельствуют о наличии общего кластера, состоящего из 8 генов, специфичного только для больных ПЭ и ЗРП, а также модуля коэкспрессии из 23 генов, характерного только для больных ПР и ЗРП. Для данных генов была построена сеть белок-белковых взаимодействий, в которой центральное место заняли гены SOD1, TXNRD1 и UBB. Оценив топологию сети в cytoHubba, были идентифицированы 6 наиболее функционально активных генов (rank ˂ 5): SOD1, TKT, TXNRD1, GCLM, GOT1, ACO1.Заключение. Полученные результаты позволили идентифицировать перспективные генетические маркеры преэклампсии, задержки роста плода и невынашивания беременности, а также обозначить наиболее важные общие молекулярные механизмы данных заболеваний, протекающие в плацентарной ткани.

Objective. To study the molecular mechanisms responsible for the development of diseases grouped within the great obstetrical syndromes (GOS) at the level of the transcriptome of human maternal placenta.Material and Methods. We gathered the results of genome-wide transcriptome studies of the human placental tissue using Gene Expression Omnibus (GEO) data repository for the following phenotypes: physiological pregnancy, preeclampsia (PE), premature birth, and intrauterine growth restriction (IUGR). Eleven data sets were selected and supplemented with our experimental data; a total of 481 samples of human placental tissue were included in the integrative analysis. Bioinformatic data processing and statistical analyses were performed in the R v3.6.1 software environment using the Bioconductor packages. The pooled dataset was used to search for common molecular targets for GOS via weighted gene co-expression network analysis (WGCNA). The functional annotation of genes and the resulting clusters was carried out with the DAVID database; protein-protein interaction network was built using the STRING software; and the hub genes for the network were identified using the MCC analysis with plugin cytoHubba in Cytoscape software 3.7.2.Results. We obtained a table of expression levels for 15,167 genes in 246 samples. Hierarchical clustering of this network allowed to find 55 modules of co-expressed genes in the group with PE, 109 modules in the group with PB, 75 modules in patients with IUGR, and 56 modules in the control group. The preservation analysis of co-expressed modules for the studied phenotypes suggested the presence of a common cluster comprising eight genes specific only for patients with PE and IUGR, as well as the module of 23 co-expressed genes typical only for patients with PB and IUGR. Protein-protein interaction network was built for these gene sets, and the SOD1, TXNRD1, and UBB genes were the central nodes in the network. Based on network topology evaluation with cytoHubba, six hub genes (rank ˂ 5) were identified as follows: SOD1, TKT, TXNRD1, GCLM, GOT1, and ACO1.Conclusion. The obtained results allowed to identify promising genetic markers for preeclampsia, intrauterine growth restriction, and miscarriage. Moreover, the study also made it possible to identify the most important overlapping molecular mechanisms of these diseases occurring in the placental tissue.

большие акушерские синдромыкоэкспрессия геновплацентаинтегративный анализgreat obstetrical syndromesgene co-expressionplacentaintegrative analysisисследование выполнено при финансовой поддержке РФФИ и Администрации Томской области в рамках научных проектов № 18-29-13045, № 18-44-700007the research was funded by RFBR and Tomsk region, projects No. 18-29-13045 and No. 18- 44-700007ReferencesRomero R. Prenatal medicine: The child is the father of the man. 1996. J. Matern. Fetal Neonatal Med. 2009;22(8):636–639. DOI: 10.1080/14767050902784171.Romero R. Prenatal medicine: The child is the father of the man. 1996. J. Matern. Fetal Neonatal Med. 2009;22(8):636–639. DOI: 10.1080/14767050902784171.Di Renzo G.C. The great obstetrical syndromes. J. Matern. Fetal Neonata. Med. 2009;22(8):633–635. DOI: 10.1080/14767050902866804.Di Renzo G.C. The great obstetrical syndromes. J. Matern. Fetal Neonata. Med. 2009;22(8):633–635. DOI: 10.1080/14767050902866804.Eidem H.R., Ackerman W.E., McGary K.L., Abbot P., Rokas A. Gestational tissue transcriptomics in term and preterm human pregnancies: A systematic review and meta-analysis. BMC Med. Genomics. 2015;8:27. DOI: 10.1186/s12920-015-0099-8.Eidem H.R., Ackerman W.E., McGary K.L., Abbot P., Rokas A. Gestational tissue transcriptomics in term and preterm human pregnancies: A systematic review and meta-analysis. BMC Med. Genomics. 2015;8:27. DOI: 10.1186/s12920-015-0099-8.Rajakumar A., Chu T., Handley D.E., Bunce K.D., Burke B., Hubel C.A. et al. Maternal gene expression profiling during pregnancy and preeclampsia in human peripheral blood mononuclear cells. Placenta. 2011;32(1):70–78. DOI: 10.1016/j.placenta.2010.10.004.Rajakumar A., Chu T., Handley D.E., Bunce K.D., Burke B., Hubel C.A. et al. Maternal gene expression profiling during pregnancy and preeclampsia in human peripheral blood mononuclear cells. Placenta. 2011;32(1):70–78. DOI: 10.1016/j.placenta.2010.10.004.Krieg S.A., Fan X., Hong Y., Sang Q.X., Giaccia A., Westphal L.M. et al. Global alteration in gene expression profiles of deciduas from women with idiopathic recurrent pregnancy loss. Mol. Hum. Reprod. 2012;18(9):442–450. DOI: 10.1093/molehr/gas017.Krieg S.A., Fan X., Hong Y., Sang Q.X., Giaccia A., Westphal L.M. et al. Global alteration in gene expression profiles of deciduas from women with idiopathic recurrent pregnancy loss. Mol. Hum. Reprod. 2012;18(9):442–450. DOI: 10.1093/molehr/gas017.Mayor-Lynn K., Toloubeydokhti T., Cruz A.C., Chegini N. Expression profile of microRNAs and mRNAs in human placentas from pregnancies complicated by preeclampsia and preterm labor. Reprod. Sci. 2011;18(1):46–56. DOI: 10.1177/1933719110374115.Mayor-Lynn K., Toloubeydokhti T., Cruz A.C., Chegini N. Expression profile of microRNAs and mRNAs in human placentas from pregnancies complicated by preeclampsia and preterm labor. Reprod. Sci. 2011;18(1):46–56. DOI: 10.1177/1933719110374115.Toft J.H., Lian I.A., Tarca A.L., Erez O., Espinoza J., Eide I.P. et al. Whole-genome microarray and targeted analysis of angiogenesis-regulating gene expression (ENG, FLT1, VEGF, PlGF) in placentas from pre-eclamptic and small-for-gestational-age pregnancies. J. Matern. Fetal Neonatal Med. 2008;21(4):267–273. DOI: 10.1080/14767050801924118.Toft J.H., Lian I.A., Tarca A.L., Erez O., Espinoza J., Eide I.P. et al. Whole-genome microarray and targeted analysis of angiogenesis-regulating gene expression (ENG, FLT1, VEGF, PlGF) in placentas from pre-eclamptic and small-for-gestational-age pregnancies. J. Matern. Fetal Neonatal Med. 2008;21(4):267–273. DOI: 10.1080/14767050801924118.Buimer M., Keijser R., Jebbink J.M., Wehkamp D., van Kampen A.H., Boer K. et al. Seven placental transcripts characterize HELLP-syndrome. Placenta. 2008;29(5):444–453. DOI: 10.1016/j.placenta.2008.02.007.Buimer M., Keijser R., Jebbink J.M., Wehkamp D., van Kampen A.H., Boer K. et al. Seven placental transcripts characterize HELLP-syndrome. Placenta. 2008;29(5):444–453. DOI: 10.1016/j.placenta.2008.02.007.Van Dijk M., Oudejans C.B.M. STOX1: Key player in trophoblast dysfunction underlying early onset preeclampsia with growth retardation. J. Pregnancy. 2010;2011:521826. DOI: 10.1155/2011/521826.Van Dijk M., Oudejans C.B.M. STOX1: Key player in trophoblast dysfunction underlying early onset preeclampsia with growth retardation. J. Pregnancy. 2010;2011:521826. DOI: 10.1155/2011/521826.Junus K., Centlow M., Wikström A.K., Larsson I., Hansson S.R., Olovsson M. Gene expression profi ling of placentae from women with earlyand late-onset pre-eclampsia: down-regulation of the angiogenesis-related genes ACVRL1 and EGFL7 in early-onset disease. Mol. Hum. Reprod. 2012;18(3):146–155. DOI: 10.1093/molehr/gar067.Junus K., Centlow M., Wikström A.K., Larsson I., Hansson S.R., Olovsson M. Gene expression profi ling of placentae from women with earlyand late-onset pre-eclampsia: down-regulation of the angiogenesis-related genes ACVRL1 and EGFL7 in early-onset disease. Mol. Hum. Reprod. 2012;18(3):146–155. DOI: 10.1093/molehr/gar067.Lyu S.W., Song H., Yoon J.A., Chin M.U., Sung S.R., Kim Y.S. et al. Transcriptional profi ling with a pathway-oriented analysis in the placental villi of unexplained miscarriage. Placenta. 2013;34(2):133–140. DOI: 10.1016/j.placenta.2012.12.003.Lyu S.W., Song H., Yoon J.A., Chin M.U., Sung S.R., Kim Y.S. et al. Transcriptional profi ling with a pathway-oriented analysis in the placental villi of unexplained miscarriage. Placenta. 2013;34(2):133–140. DOI: 10.1016/j.placenta.2012.12.003.Trifonova E.A., Gabidulina T.V., Ershov N.I., Serebrova V.N., Vorozhishcheva A.Y., Stepanov V.A. Analysis of the placental tissue transcriptome of normal and preeclampsia complicated pregnancies. Acta Naturae. 2014;6(2):71–83.Trifonova E.A., Gabidulina T.V., Ershov N.I., Serebrova V.N., Vorozhishcheva A.Y., Stepanov V.A. Analysis of the placental tissue transcriptome of normal and preeclampsia complicated pregnancies. Acta Naturae. 2014;6(2):71–83.Tsai S., Hardison N.E., James A.H., Motsinger-Reif A.A., Bischoff S.R., Thames B.H. et al. Transcriptional profi ling of human placentas from pregnancies complicated by preeclampsia reveals disregulation of sialic acid acetylesterase and immune signalling pathways. Placenta. 2011;32(2):175–182. DOI: 10.1016/j.placenta.2010.11.014.Tsai S., Hardison N.E., James A.H., Motsinger-Reif A.A., Bischoff S.R., Thames B.H. et al. Transcriptional profi ling of human placentas from pregnancies complicated by preeclampsia reveals disregulation of sialic acid acetylesterase and immune signalling pathways. Placenta. 2011;32(2):175–182. DOI: 10.1016/j.placenta.2010.11.014.Meng T., Chen H., Sun M., Wang H., Zhao G., Wang X. Identifi cation of diff erential gene expression profi les in placentas from preeclamptic pregnancies versus normal pregnancies by DNA microarrays. OMICS. 2012;16(6):301–311. DOI: 10.1089/omi.2011.0066.Meng T., Chen H., Sun M., Wang H., Zhao G., Wang X. Identifi cation of diff erential gene expression profi les in placentas from preeclamptic pregnancies versus normal pregnancies by DNA microarrays. OMICS. 2012;16(6):301–311. DOI: 10.1089/omi.2011.0066.Guo L., Tsai S.Q., Hardison N.E., James A.H., Motsinger-Reif A.A., Thames B. et al. Diff erentially expressed microRNAs and aff ected biological pathways revealed by modulated modularity clustering (MMC) analysis of human preeclamptic and IUGR placentas. Placenta. 2013;34(7):599–605. DOI: 10.1016/j.placenta.2013.04.007.Guo L., Tsai S.Q., Hardison N.E., James A.H., Motsinger-Reif A.A., Thames B. et al. Diff erentially expressed microRNAs and aff ected biological pathways revealed by modulated modularity clustering (MMC) analysis of human preeclamptic and IUGR placentas. Placenta. 2013;34(7):599–605. DOI: 10.1016/j.placenta.2013.04.007.Blair J.D., Yuen R.K., Lim B.K., McFadden D.E., von Dadelszen P., Robinson W.P. Widespread DNA hypomethylation at gene enhancer regions in placentas associated with early-onset pre-eclampsia. Mol. Hum. Reprod. 2013;19(10):697–708. DOI: 10.1093/molehr/gat044.Blair J.D., Yuen R.K., Lim B.K., McFadden D.E., von Dadelszen P., Robinson W.P. Widespread DNA hypomethylation at gene enhancer regions in placentas associated with early-onset pre-eclampsia. Mol. Hum. Reprod. 2013;19(10):697–708. DOI: 10.1093/molehr/gat044.Yong H.E., Melton P.E., Johnson M.P., Freed K.A., Kalionis B., Murthi P. et al. Genome-wide transcriptome directed pathway analysis of maternal pre-eclampsia susceptibility genes. PLoS One. 2015;10(5):e0128230. DOI: 10.1371/journal.pone.0128230.Yong H.E., Melton P.E., Johnson M.P., Freed K.A., Kalionis B., Murthi P. et al. Genome-wide transcriptome directed pathway analysis of maternal pre-eclampsia susceptibility genes. PLoS One. 2015;10(5):e0128230. DOI: 10.1371/journal.pone.0128230.Herse F., Dechend R., Harsem N.K., Wallukat G., Janke J., Qadri F. et al. Dysregulation of the circulating and tissue-based renin-angiotensin system in preeclampsia. Hypertension. 2007;49(3):604–611. DOI: 10.1161/01.HYP.0000257797.49289.71.Herse F., Dechend R., Harsem N.K., Wallukat G., Janke J., Qadri F. et al. Dysregulation of the circulating and tissue-based renin-angiotensin system in preeclampsia. Hypertension. 2007;49(3):604–611. DOI: 10.1161/01.HYP.0000257797.49289.71.Martin E., Ray P.D., Smeester L., Grace M.R., Boggess K., Fry R.C. Epigenetics and preeclampsia: Defi ning functional epimutations in the preeclamptic placenta related to the TGF-β pathway. PLoS One. 2015;10(10):e0141294. DOI: 10.1371/journal.pone.0141294.Martin E., Ray P.D., Smeester L., Grace M.R., Boggess K., Fry R.C. Epigenetics and preeclampsia: Defi ning functional epimutations in the preeclamptic placenta related to the TGF-β pathway. PLoS One. 2015;10(10):e0141294. DOI: 10.1371/journal.pone.0141294.Garrido-Gomez T., Dominguez F., Quiñonero A., Diaz-Gimeno P., Kapidzic M., Gormley M. et al. Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology. Proc. Natl. Acad. Sci. USA. 2017;114(40):E8468–E8477. DOI: 10.1073/pnas.1706546114.Garrido-Gomez T., Dominguez F., Quiñonero A., Diaz-Gimeno P., Kapidzic M., Gormley M. et al. Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology. Proc. Natl. Acad. Sci. USA. 2017;114(40):E8468–E8477. DOI: 10.1073/pnas.1706546114.Nishizawa H., Ota S., Suzuki M., Kato T., Sekiya T., Kurahashi H. et al. Comparative gene expression profi ling of placentas from patients with severe pre-eclampsia and unexplained fetal growth restriction. Reprod. Biol. Endocrinol. 2011;9:107. DOI: 10.1186/1477-7827-9-107.Nishizawa H., Ota S., Suzuki M., Kato T., Sekiya T., Kurahashi H. et al. Comparative gene expression profi ling of placentas from patients with severe pre-eclampsia and unexplained fetal growth restriction. Reprod. Biol. Endocrinol. 2011;9:107. DOI: 10.1186/1477-7827-9-107.Bukowski R., Sadovsky Y., Goodarzi H., Zhang H., Biggio J.R., Varner M. et al. Onset of human preterm and term birth is related to unique infl ammatory transcriptome profi les at the maternal fetal interface. Peer J. 2017;5:e3685. DOI: 10.7717/peerj.3685.Bukowski R., Sadovsky Y., Goodarzi H., Zhang H., Biggio J.R., Varner M. et al. Onset of human preterm and term birth is related to unique infl ammatory transcriptome profi les at the maternal fetal interface. Peer J. 2017;5:e3685. DOI: 10.7717/peerj.3685.Rull K., Tomberg K., Kõks S., Männik J., Möls M., Sirotkina M. et al. Increased placental expression and maternal serum levels of apoptosis-inducing TRAIL in recurrent miscarriage. Placenta. 2013;34(2):141–148. DOI: 10.1016/j.placenta.2012.11.032.Rull K., Tomberg K., Kõks S., Männik J., Möls M., Sirotkina M. et al. Increased placental expression and maternal serum levels of apoptosis-inducing TRAIL in recurrent miscarriage. Placenta. 2013;34(2):141–148. DOI: 10.1016/j.placenta.2012.11.032.Davis S., Meltzer P.S. GEOquery: A bridge between the Gene Expression Omnibus (GEO) and BioConductor. Bioinformatics. 2007;23(14):1846–1847. DOI: 10.1093/bioinformatics/btm254.Davis S., Meltzer P.S. GEOquery: A bridge between the Gene Expression Omnibus (GEO) and BioConductor. Bioinformatics. 2007;23(14):1846–1847. DOI: 10.1093/bioinformatics/btm254.Durinck S., Spellman P.T., Birney E., Huber W. Mapping identifi - ers for the integration of genomic datasets with the R/Bioconductor package biomaRt. Nat. Protoc. 2009;4(8):1184–1191. DOI: 10.1038/nprot.2009.97.Durinck S., Spellman P.T., Birney E., Huber W. Mapping identifi - ers for the integration of genomic datasets with the R/Bioconductor package biomaRt. Nat. Protoc. 2009;4(8):1184–1191. DOI: 10.1038/nprot.2009.97.Zhang B., Horvath S. A general framework for weighted gene co-expression network analysis. Stat. Appl. Genet. Mol. Biol. 2005;4:17. DOI: 10.2202/1544-6115.1128.Zhang B., Horvath S. A general framework for weighted gene co-expression network analysis. Stat. Appl. Genet. Mol. Biol. 2005;4:17. DOI: 10.2202/1544-6115.1128.Szklarczyk D., Gable A.L., Nastou K.C., Lyon D., Kirsch R., Pyysalo S. et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021; 49(D1):D605–D612. DOI: 10.1093/nar/gkaa1074.Szklarczyk D., Gable A.L., Nastou K.C., Lyon D., Kirsch R., Pyysalo S. et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021; 49(D1):D605–D612. DOI: 10.1093/nar/gkaa1074.Leek J.T., Johnson W.E., Parker H.S., Jaff e A.E., Storey J.D. The sva package for removing batch eff ects and other unwanted variation in high-throughput experiments. Bioinformatics. 2012;28(6):882–883. DOI: 10.1093/bioinformatics/bts034.Leek J.T., Johnson W.E., Parker H.S., Jaff e A.E., Storey J.D. The sva package for removing batch eff ects and other unwanted variation in high-throughput experiments. Bioinformatics. 2012;28(6):882–883. DOI: 10.1093/bioinformatics/bts034.Louwen F., Muschol-Steinmetz C., Reinhard J., Reitter A., Yuan J. A lesson for cancer research: Placental microarray gene analysis in preeclampsia. Oncotarget. 2012;3(8):759–773. DOI:10.18632/oncotarget.595.Louwen F., Muschol-Steinmetz C., Reinhard J., Reitter A., Yuan J. A lesson for cancer research: Placental microarray gene analysis in preeclampsia. Oncotarget. 2012;3(8):759–773. DOI:10.18632/oncotarget.595.Smith Z.D., Shi J., Gu H., Donaghey J., Clement K., Cacchiarelli D. Et al. Epigenetic restriction of extraembryonic lineages mirrors the somatic transition to cancer. Nature. 2017;549(7673):543–547. DOI: 10.1038/nature23891.Smith Z.D., Shi J., Gu H., Donaghey J., Clement K., Cacchiarelli D. Et al. Epigenetic restriction of extraembryonic lineages mirrors the somatic transition to cancer. Nature. 2017;549(7673):543–547. DOI: 10.1038/nature23891.Macaulay E.C., Chatterjee A., Cheng X., Baguley B.C., Eccles M.R., Morison I.M. The genes of life and death: A potential role for placental-specifi c genes in cancer: Active retrotransposons in the placenta encode unique functional genes that may also be used by cancer cells to promote malignancy. Bioessays. 2017;39(11). DOI: 10.1002/bies.201700091.Macaulay E.C., Chatterjee A., Cheng X., Baguley B.C., Eccles M.R., Morison I.M. The genes of life and death: A potential role for placental-specifi c genes in cancer: Active retrotransposons in the placenta encode unique functional genes that may also be used by cancer cells to promote malignancy. Bioessays. 2017;39(11). DOI: 10.1002/bies.201700091.Kshitiz, Afzal J., Maziarz J.D., Hamidzadeh A., Liang C., Erkenbrack E.M. et al. Evolution of placental invasion and cancer metastasis are causally linked. Nat. Ecol. Evol. 2019;3(12):1743–1753. DOI: 10.1038/s41559-019-1046-4.Kshitiz, Afzal J., Maziarz J.D., Hamidzadeh A., Liang C., Erkenbrack E.M. et al. Evolution of placental invasion and cancer metastasis are causally linked. Nat. Ecol. Evol. 2019;3(12):1743–1753. DOI: 10.1038/s41559-019-1046-4.Donabela F.C., Meola J., Padovan C.C., de Paz C.C., Navarro P.A. Higher SOD1 gene expression in cumulus cells from infertile women with moderate and severe endometriosis. Reprod. Sci. 2015;22(11):1452–1460. DOI: 10.1177/1933719115585146.Donabela F.C., Meola J., Padovan C.C., de Paz C.C., Navarro P.A. Higher SOD1 gene expression in cumulus cells from infertile women with moderate and severe endometriosis. Reprod. Sci. 2015;22(11):1452–1460. DOI: 10.1177/1933719115585146.Roland L., Beauchemin D., Acteau G., Fradette C., St-Pierre I., Bilodeau J.F. Eff ects of labor on placental expression of superoxide dismutases in preeclampsia. Placenta. 2010;31(5):392–400. DOI: 10.1016/j.placenta.2010.02.007.Roland L., Beauchemin D., Acteau G., Fradette C., St-Pierre I., Bilodeau J.F. Eff ects of labor on placental expression of superoxide dismutases in preeclampsia. Placenta. 2010;31(5):392–400. DOI: 10.1016/j.placenta.2010.02.007.Lin P., Lai X., Wu L., Liu W., Lin S., Ye J. Network analysis reveals important genes in human placenta. J. Obstet. Gynaecol. Res. 2021;47(8):2607–2615. DOI: 10.1111/jog.14820.Lin P., Lai X., Wu L., Liu W., Lin S., Ye J. Network analysis reveals important genes in human placenta. J. Obstet. Gynaecol. Res. 2021;47(8):2607–2615. DOI: 10.1111/jog.14820.Gomez M.L., Shah N., Kenny T.C., Jenkins E.C. Jr., Germain D. SOD1 is essential for oncogene-driven mammary tumor formation but dispensable for normal development and proliferation. Oncogene. 2019;38(29):5751–5765. DOI: 10.1038/s41388-019-0839-x.Gomez M.L., Shah N., Kenny T.C., Jenkins E.C. Jr., Germain D. SOD1 is essential for oncogene-driven mammary tumor formation but dispensable for normal development and proliferation. Oncogene. 2019;38(29):5751–5765. DOI: 10.1038/s41388-019-0839-x.Wang X., Zhang H., Sapio R., Yang J., Wong J., Zhang X. et al. SOD1 regulates ribosome biogenesis in KRAS mutant non-small cell lung cancer. Nat. Commun. 2021;12(1):2259. DOI: 10.1038/s41467-021-22480-x.Wang X., Zhang H., Sapio R., Yang J., Wong J., Zhang X. et al. SOD1 regulates ribosome biogenesis in KRAS mutant non-small cell lung cancer. Nat. Commun. 2021;12(1):2259. DOI: 10.1038/s41467-021-22480-x.Schierding W., Antony J., Karhunen V., Vääräsmäki M., Franks S., Elliott P. et al. GWAS on prolonged gestation (post-term birth): Analysis of successive Finnish birth cohorts. J. Med. Genet. 2018;55(1):55–63. DOI: 10.1136/jmedgenet-2017-104880.Schierding W., Antony J., Karhunen V., Vääräsmäki M., Franks S., Elliott P. et al. GWAS on prolonged gestation (post-term birth): Analysis of successive Finnish birth cohorts. J. Med. Genet. 2018;55(1):55–63. DOI: 10.1136/jmedgenet-2017-104880.Xu Z.P., Wawrousek E.F., Piatigorsky J. Transketolase haploinsuffi ciency reduces adipose tissue and female fertility in mice. Mol. Cell Biol. 2002;22(17):6142–6147. DOI: 10.1128/MCB.22.17.6142-6147.2002.Xu Z.P., Wawrousek E.F., Piatigorsky J. Transketolase haploinsuffi ciency reduces adipose tissue and female fertility in mice. Mol. Cell Biol. 2002;22(17):6142–6147. DOI: 10.1128/MCB.22.17.6142-6147.2002.Xu I.M., Lai R.K., Lin S.H., Tse A.P., Chiu D.K., Koh H.Y. et al. Transketolase counteracts oxidative stress to drive cancer development. Proc. Natl. Acad. Sci. USA. 2016;113(6):E725–734. DOI: 10.1073/pnas.1508779113.Xu I.M., Lai R.K., Lin S.H., Tse A.P., Chiu D.K., Koh H.Y. et al. Transketolase counteracts oxidative stress to drive cancer development. Proc. Natl. Acad. Sci. USA. 2016;113(6):E725–734. DOI: 10.1073/pnas.1508779113.Qin Z., Xiang C., Zhong F., Liu Y., Dong Q., Li K. et al. Transketolase (TKT) activity and nuclear localization promote hepatocellular carcinoma in a metabolic and a non-metabolic manner. J. Exp. Clin. Cancer Res. 2019;38(1):154. DOI: 10.1186/s13046-019-1131-1.Qin Z., Xiang C., Zhong F., Liu Y., Dong Q., Li K. et al. Transketolase (TKT) activity and nuclear localization promote hepatocellular carcinoma in a metabolic and a non-metabolic manner. J. Exp. Clin. Cancer Res. 2019;38(1):154. DOI: 10.1186/s13046-019-1131-1.

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