Blood cancers may be potentially cured with hematopoietic stem cell transplantation (HCT); however, standard pre-assessments for transplant eligibility do not capture all contributing factors for transplant outcomes. Epigenetic biomarkers predict outcomes in various diseases. This pilot study aims to explore epigenetic changes (epigenetic age and differentially methylated genes) in patients before and after autologous HCT, that can serve as potential biomarkers to better predict HCT outcomes.
Methods
This study used a prospective longitudinal study design to compare genome wide DNA methylation changes in 36 autologous HCT eligible patients recruited from the Cellular Immunotherapies and Transplant clinic at a designated National Cancer Center.
Results
Genome-wide DNA methylation, measured by the Illumina Infinium Human Methylation 850K BeadChip, showed a significant difference in DNA methylation patterns post-HCT compared to pre-HCT. Compared to baseline levels of DNA methylation pre-HCT, 3358 CpG sites were hypo-methylated and 3687 were hyper-methylated. Identified differentially methylated positions overlapped with genes involved in hematopoiesis, blood cancers, inflammation and immune responses. Enrichment analyses showed significant alterations in biological processes such as immune response and cell structure organization, however no significant pathways were noted. Though participants had an advanced epigenetic age compared to chronologic age before and after HCT, both epigenetic age and accelerated age decreased post-HCT.
Conclusion
Epigenetic changes, both in epigenetic age and differentially methylated genes were observed in autologous HCT recipients, and should be explored as biomarkers to predict transplant outcomes after autologous HCT in larger, longitudinal studies.
AkiyamaM.IshidaN.OgawaT.YogoK.TakeyaT. (2005). Molecular cloning and functional analysis of a novel Cx43 partner protein CIP150. Biochemical and Biophysical Research Communications, 335(4), 1264–1271. https://doi.org/10.1016/j.bbrc.2005.08.019
2.
ArchackaK.GrabowskaI.MierzejewskiB.GraffsteinJ.GórzyńskaA.KrawczykM.RóżyckaA. M.KalaszczyńskaI.MurasG.StremińskaW.Jańczyk-IlachK.WalczakP.JanowskiM.CiemerychM. A.BrzoskaE. (2021). Hypoxia preconditioned bone marrow-derived mesenchymal stromal/stem cells enhance myoblast fusion and skeletal muscle regeneration. Stem Cell Research & Therapy Electronic Resource, 12(1), 448. https://doi.org/10.1186/s13287-021-02530-3
3.
AroraM.ChenY.WuJ.HagemanL.NessE.KungM.FranciscoL.BosworthA.WeisdorfD. J.FormanS. J.LandierW.PamukçuoğluM.ArmenianS. H.WongF. L.BhatiaS. (2021). Longitudinal trajectory of frailty in blood or marrow transplant survivors: Report from the blood or marrow transplant survivor study. Cancer, 127(5), 794–800. https://doi.org/10.1002/cncr.33313
4.
Arroyo VarelaM.Salcedo LoberaE.Larrosa JiménezR.Bautista MorenoR.De La Cruz RíosJ. L.Claros DíazM. G. (2019). Identification of genes with diagnostic and prognostic value in lung cancer. European Respiratory Journal, 54(63). https://doi.org/10.1183/13993003.congress-2019.pa3662
5.
AryeeM. J.JaffeA. E.Corrada-BravoH.Ladd-AcostaC.FeinbergA. P.HansenK. D.IrizarryR. A. (2014). Minfi: A flexible and comprehensive bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics, 30(10), 1363–1369. https://doi.org/10.1093/bioinformatics/btu049
6.
BalatoniC. E.DawsonD. W.SuhJ.ShermanM. H.SandersG.HongJ. S.FrankM. J.MaloneC. S.SaidJ. W.TeitellM. A. (2009). Epigenetic silencing of Stk39 in B-cell lymphoma inhibits apoptosis from genotoxic stress. American Journal of Pathology, 175(4), 1653–1661. https://doi.org/10.2353/ajpath.2009.090091
7.
BarthD.SingletonM.MonohanG.McCluneB.AdamsV. (2022). Age adjusted comorbidity risk index does not predict outcomes in an autologous hematopoietic stem cell transplant population. Cell Transplantation, 31. https://doi.org/10.1177/09636897221080385
8.
BerginC. J.ZouggarA.HaebeJ. R.MasibagA. N.DesrochersF. M.ReilleyS. Y.AgrawalG.BenoitY. D. (2021). G9a controls pluripotent-like identity and tumor-initiating function in human colorectal cancer. Oncogene, 40(6), 1–12. https://doi.org/10.1038/s41388-020-01591-7
9.
BjerreM. T.StrandS. H.NørgaardM.KristensenH.RasmussenA. K.MortensenM. M.FredsøeJ.MouritzenP.UlhøiB.ØrntoftT.BorreM.SørensenK. D. (2019). Aberrant DOCK2, GRASP, HIF3A and PKFP hypermethylation has potential as a prognostic biomarker for prostate cancer. International Journal of Molecular Sciences, 20(5), 1173. https://doi.org/10.3390/ijms20051173
BreitlingL. P.SaumK. U.PernaL.SchöttkerB.HolleczekB.BrennerH. (2016). Frailty is associated with the epigenetic clock but not with telomere length in a German cohort. Clinical Epigenetics, 8(1), 21. https://doi.org/10.1186/s13148-016-0186-5
12.
ChenL.LiY.LuJ. (2020). Identification of circulating miR-762 as a novel diagnostic and prognostic biomarker for non-small cell lung cancer. Technology in Cancer Research & Treatment, 19. https://doi.org/10.1177/1533033820964222
13.
ChenX.QiM.YangQ.LiJ. Y. (2019). MiR-299-3p functions as a tumor suppressor in thyroid cancer by regulating SHOC2. European Review for Medical and Pharmacological Sciences, 23(1), 232–240. https://doi.org/10.26355/eurrev_201901_16769
14.
ChenY.FengZ.KuangX.ZhaoP.ChenB.FangQ.ChengW.WangJ. (2021). Increased lactate in AML blasts upregulates TOX expression, leading to exhaustion of CD8+ cytolytic T cells. American Journal of Cancer Research, 11(11), 5726–5742. https://www.ncbi.nlm.nih.gov/pubmed/34873490
15.
ChristopherM. J.KaterndahlC. D. S.LeBlancH. R.ElmendorfT. T.BasuV.GangM.MenssenA. J.SpencerD. H.DuncavageE. J.KetkarS.WartmanL. D.RamakrishnanS. M.MillerC. A.LeyT. J. (2022). Tumor suppressor function of WT1 in acute promyelocytic leukemia. Haematologica, 107(1), 342–346. https://doi.org/10.3324/haematol.2021.279601
16.
ChungD. J.PronschinskeK. B.ShyerJ. A.SharmaS.LeungS.CurranS. A.LesokhinA. M.DevlinS. M.GiraltS. A.YoungJ. W. (2016). T-cell exhaustion in Multiple myeloma relapse after autotransplant: Optimal timing of immunotherapy. Cancer Immunology Research, 4(1), 61–71. https://doi.org/10.1158/2326-6066.CIR-15-0055
17.
DangS.ZhouJ.WangZ.WangK.DaiS.HeS. (2018). MiR-299-3p functions as a tumor suppressor via targeting Sirtuin 5 in hepatocellular carcinoma. Biomedicine and Pharmacotherapy, 106, 966–975. https://doi.org/10.1016/j.biopha.2018.06.042
18.
D’SouzaA.FrethamC.LeeS. J.AroraM.BrunnerJ.ChhabraS.DevineS.EapenM.HamadaniM.HariP.PasquiniM. C.PerezW.PhelanR. A.RichesM. L.RizzoJ. D.SaberW.ShawB. E.SpellmanS. R.SteinertP.HorowitzM. M. (2020). Current use of and trends in hematopoietic cell transplantation in the United States. Biology of Blood and Marrow Transplantation, 26(8), e177–e182. https://doi.org/10.1016/j.bbmt.2020.04.013
19.
DuguéP. A.BassettJ. K.JooJ. H. E.JungC. H.Ming WongE.Moreno-BetancurM.SchmidtD.MakalicE.LiS.SeveriG.HodgeA. M.BuchananD. D.EnglishD. R.HopperJ. L.SoutheyM. C.GilesG. G.MilneR. L. (2018). DNA methylation-based biological aging and cancer risk and survival: Pooled analysis of seven prospective studies. International Journal of Cancer, 142(8), 1611–1619. https://doi.org/10.1002/ijc.31189
20.
FanS.ChenW. X.LvX. BinTangQ. L.SunL. J.LiuB. DuZhongJ. L.LinZ. Y.WangY. Y.LiQ. X.YuX.ZhangH. Q.LiY. L.WenB.ZhangZ.ChenW. L.LiJ. S. (2015). MiR-483-5p determines mitochondrial fission and cisplatin sensitivity in tongue squamous cell carcinoma by targeting FIS1. Cancer Letters, 362(2), 183–191. https://doi.org/10.1016/j.canlet.2015.03.045
21.
FanW.YuX.LiK.ZhuM. (2021). The alerting expression of microRNA-411 predicts clinical prognosis and regulates tumor progression of glioblastoma. Bioengineered, 12(1), 8650–8657. https://doi.org/10.1080/21655979.2021.1988365
22.
FlamantL.RoegiersE.PierreM.HayezA.SterpinC.De BackerO.ArnouldT.PoumayY.MichielsC. (2012). TMEM45A is essential for hypoxia-induced chemoresistance in breast and liver cancer cells. BMC Cancer, 12(1), 391. https://doi.org/10.1186/1471-2407-12-391
23.
FranceschiniA.SzklarczykD.FrankildS.KuhnM.SimonovicM.RothA.LinJ.MinguezP.BorkP.Von MeringC.JensenL. J. (2013). String v9.1: Protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Research, 41(Database issue), D808–D8015. https://doi.org/10.1093/nar/gks1094
24.
FriedmanJ.SmithD. E.IssaM. Y.StanleyV.WangR.MendesM. I.WrightM. S.WigbyK.HildrethA.CrawfordJ. R.KoehlerA. E.ChowdhuryS.NahasS.ZhaiL.XuZ.LoW. S.JamesK. N.MusaevD.AccogliA.GleesonJ. G. (2019). Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy. Nature Communications, 10(1), 707. https://doi.org/10.1038/s41467-018-07067-3
25.
GeA.GaoS.LiuY.ZhangH.WangX.ZhangL.PangD.ZhaoY. (2020). Methylation of WT1, CA10 in peripheral blood leukocyte is associated with breast cancer risk: A case-control study. BMC Cancer, 20(1), 713. https://doi.org/10.1186/s12885-020-07183-8
26.
GerberJ. P.RussJ.ChandrasekarV.OffermannN.LeeH. M.SpearS.GuzziN.MaidaS.PattabiramanS.ZhangR.KayvanjooA. H.DattaP.KasturiarachchiJ.SpositoT.IzotovaN.HändlerK.AdamsP. D.MarafiotiT.EnverT.SalomoniP. (2021). Aberrant chromatin landscape following loss of the H3.3 chaperone Daxx in haematopoietic precursors leads to Pu.1-mediated neutrophilia and inflammation. Nature Cell Biology, 23(12), 123. https://doi.org/10.1038/s41556-021-00774-y
27.
GhanbariM.DarweeshS. K. L.De LooperH. W. J.van LuijnM. M.HofmanA.IkramM. A.FrancoO. H.ErkelandS. J.DehghanA. (2016). Genetic variants in MicroRNAs and their binding sites are associated with the risk of Parkinson disease. Human Mutation, 37(3), 292–300. https://doi.org/10.1002/humu.22943
28.
HanY.LiuD.LiL. (2020). PD-1/PD-L1 pathway: Current researches in cancer. American Journal of Cancer Research, 10(3), 727–742
29.
HennrichM. L.RomanovN.HornP.JaegerS.EcksteinV.SteeplesV.YeF.DingX.Poisa-BeiroL.LaiM. C.LangB.BoultwoodJ.LuftT.ZauggJ. B.PellagattiA.BorkP.AloyP.GavinA. C.HoA. D. (2018). Cell-specific proteome analyses of human bone marrow reveal molecular features of age-dependent functional decline. Nature Communications, 9(1), 4004. https://doi.org/10.1038/s41467-018-06353-4
HorvathS.RajK. (2018). DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nature Reviews Genetics, 19(6), 371–384. https://doi.org/10.1038/s41576-018-0004-3
32.
HouP.LiuG.ZhaoY.ShiZ.ZhengQ.BuG.XuH.ZhangY. wu. (2015). The role of copper and the copper-related protein CUTA in mediating APP processing and Aβ generation. Neurobiology of Aging, 36(3), 1310–1315. https://doi.org/10.1016/j.neurobiolaging.2014.12.005
33.
HuK.LiJ. L.YuanX. W. (2019). MicroRNA-411 plays a protective role in diabetic retinopathy through targeted regulating Robo4. European Review for Medical and Pharmacological Sciences, 23(21), 9171–9179. https://doi.org/10.26355/eurrev_201911_19407
34.
HuangC.HaoQ.ShiG.ZhouX.ZhangY. (2021a). BCL7C suppresses ovarian cancer growth by inactivating mutant p53. Journal of Molecular Cell Biology, 13(2), 141–150. https://doi.org/10.1093/jmcb/mjaa065
35.
IhenachoU. K.MeachamK. A.HarwigM. C.WidlanskyM. E.HillR. B. (2021). Mitochondrial fission protein 1: Emerging roles in organellar form and function in health and disease. Frontiers in Endocrinology, 12, 660095. https://doi.org/10.3389/fendo.2021.660095
36.
IwakawaR.TakenakaM.KohnoT.ShimadaY.TotokiY.ShibataT.TsutaK.NishikawaR.NoguchiM.Sato-OtsuboA.OgawaS.YokotaJ. (2013). Genome-wide identification of genes with amplification and/or fusion in small cell lung cancer. Genes Chromosomes and Cancer, 52(9), 802–816. https://doi.org/10.1002/gcc.22076
37.
JiX.LinL.ShenS.DongX.ChenC.LiY.ZhuY.HuangH.ChenJ.ChenX.WeiL.HeJ.DuanW.SuL.JiangY.FanJ.GuanJ.YouD.ShaferA.ChristianiD. C. (2020). Epigenetic–smoking interaction reveals histologically heterogeneous effects of TRIM27 DNA methylation on overall survival among early-stage NSCLC patients. Molecular Oncology, 14(11), 2759–2774. https://doi.org/10.1002/1878-0261.12785
38.
JosephJ.RadulovichN.WangT.RaghavanV.ZhuC. Q.TsaoM. S. (2020). Rho guanine nucleotide exchange factor ARHGEF10 is a putative tumor suppressor in pancreatic ductal adenocarcinoma. Oncogene, 39(2), 308–321. https://doi.org/10.1038/s41388-019-0985-1
39.
KangW.ZhangM.WangQ.GuD.HuangZ.WangH.XiangY.XiaQ.CuiZ.JinX. (2020). The SLC family are candidate diagnostic and prognostic biomarkers in clear cell renal cell carcinoma. Biomed Research International, 2020, 1932948. https://doi.org/10.1155/2020/1932948
40.
KarimiD.PedramN.KakaeiF.AsadiM.PoursaeiE.KermaniT. A. (2022). FIS1 overexpression is correlated with tumor metastasis in gastric adenocarcinoma. Journal of Gastrointestinal Cancer, 53(2), 466–471. https://doi.org/10.1007/s12029-021-00639-5
41.
KikuchiT.KubonishiS.ShibakuraM.NambaN.MatsuiT.FukuiY.TanimotoM.KatayamaY. (2008). Dock2 participates in bone marrow lympho-hematopoiesis. Biochemical and Biophysical Research Communications, 367(1), 90–96. https://doi.org/10.1016/j.bbrc.2007.12.093
42.
KimK.ParkS.ParkS. Y.KimG.ParkS. M.ChoJ. W.KimD. H.ParkY. M.KohY. W.KimH. R.HaS. J.LeeI. (2020). Single-cell transcriptome analysis reveals TOX as a promoting factor for T cell exhaustion and a predictor for anti-PD-1 responses in human cancer. Genome Medicine, 12(1), 22. https://doi.org/10.1186/s13073-020-00722-9
43.
KraiczyJ.NayakK. M.HowellK. J.RossA.ForbesterJ.SalvestriniC.MustataR.PerkinsS.Andersson-RolfA.LeenenE.LiebertA.VallierL.RosenstielP. C.StegleO.DouganG.HeuschkelR.KooB. K.ZilbauerM. (2019). DNA methylation defines regional identity of human intestinal epithelial organoids and undergoes dynamic changes during development. Gut, 68(1), 49–61. https://doi.org/10.1136/gutjnl-2017-314817
44.
KremerA. N.Van der MeijdenE. D.HondersM. W.PontM. J.GoemanJ. J.FalkenburgJ. H. F.GriffioenM. (2014). Human leukocyte antigen-DO regulates surface presentation of human leukocyte antigen class II-restricted antigens on B cell malignancies. Biology of Blood and Marrow Transplantation, 20(5), 742–747. https://doi.org/10.1016/j.bbmt.2014.02.005
45.
LangloisF.VuT. T. M.KergoatM. J.ChasséK.DupuisG.BhererL. (2012). The multiple dimensions of frailty: Physical capacity, cognition, and quality of life. International Psychogeriatrics, 24(9), 1429–1436. https://doi.org/10.1017/S1041610212000634
46.
Leukemia and Lymphoma Society. (n.d.) Facts and statistics overview.
47.
LiH.YuS.WangR.SunZ.ZhouX.ZhengL.YinZ.ZhangX.SunY. (2017). ARHGEF10 gene polymorphism is closely associated with the risk of ischemic stroke in Northern Han Chinese population. Neurological Research, 39(2), 158–164. https://doi.org/10.1080/01616412.2016.1263175
48.
LinQ.WeidnerC. I.CostaI. G.MarioniR. E.FerreiraM. R. P.DearyI. J.WagnerW. (2016). DNA methylation levels at individual age-associated CpG sites can be indicative for life expectancy. Aging, 8(2), 394–401. https://doi.org/10.18632/aging.100908
49.
LiuS.TianY.ZhengY.ChengY.ZhangD.JiangJ.LiS. (2020). TRIM27 acts as an oncogene and regulates cell proliferation and metastasis in non-small cell lung cancer through SIX3-β-catenin signaling. Aging, 12(24), 25564–25580. https://doi.org/10.18632/aging.104163
50.
LuH.FengY.HuY.GuoY.LiuY.MaoQ.XueW. (2020). Spondin 2 promotes the proliferation, migration and invasion of gastric cancer cells. Journal of Cellular and Molecular Medicine, 24(1), 98–113. https://doi.org/10.1111/jcmm.14618
51.
LuoZ.WuF.XueE.HuangL.YanP.PanX.ZhouY. (2019). Hypoxia preconditioning promotes bone marrow mesenchymal stem cells survival by inducing HIF-1α in injured neuronal cells derived exosomes culture system. Cell Death & Disease Electronic Resource, 10(2), 134. https://doi.org/10.1038/s41419-019-1410-y
52.
MadridA.HoganK. J.PapaleL. A.ClarkL. R.AsthanaS.JohnsonS. C.AlischR. S. (2018). DNA hypomethylation in blood links B3GALT4 and ZADH2 to alzheimer’s disease. Journal of Alzheimer’s Disease, 66(3), 927–934. https://doi.org/10.3233/JAD-180592
53.
Manawapat-KlopferA.ThomsenL. T.MartusP.MunkC.RussR.GmuenderH.FrederiksenK.Haedicke-JarbouiJ.StubenrauchF.KjaerS. K.IftnerT. (2016). TMEM45A, SERPINB5 and p16INK4A transcript levels are predictive for development of high-grade cervical lesions. American Journal of Cancer Research, 6(7), 1524–1536. https://doi.org/10.15496/PUBLIKATION-18924
54.
MarioniR. E.ShahS.McRaeA. F.ChenB. H.ColicinoE.HarrisS. E.GibsonJ.HendersA. K.RedmondP.CoxS. R.PattieA.CorleyJ.MurphyL.MartinN. G.MontgomeryG. W.FeinbergA. P.FallinM. D.MulthaupM. L.JaffeA. E.DearyI. J. (2015a). DNA methylation age of blood predicts all-cause mortality in later life. Genome Biology, 16(1), 25. https://doi.org/10.1186/s13059-015-0584-6
55.
MarioniR. E.ShahS.McRaeA. F.RitchieS. J.Muniz-TerreraG.HarrisS. E.GibsonJ.RedmondP.CoxS. R.PattieA.CorleyJ.TaylorA.MurphyL.StarrJ. M.HorvathS.VisscherP. M.WrayN. R.DearyI. J. (2015b). The epigenetic clock is correlated with physical and cognitive fitness in the Lothian Birth Cohort 1936. International Journal of Epidemiology, 44(4), 1388–1396. https://doi.org/10.1093/ije/dyu277
56.
MatsuyamaM.SøraasA.YuS.KimK.StavrouE. X.CaimiP. F.WaldD.deLimaM.DahlJ. A.HorvathS.MatsuyamaS. (2020). Analysis of epigenetic aging in vivo and in vitro: Factors controlling the speed and direction. Experimental Biology and Medicine, 245(17), 1543–1551. https://doi.org/10.1177/1535370220947015
57.
MohanrajL.SargentL.ElswickR. K.ToorA.Swift-ScanlanT. (2021). Factors affecting quality of life in patients receiving autologous hematopoietic stem cell transplantation. Cancer Nursing, 45(2), E552–E559. https://doi.org/10.1097/ncc.0000000000000990
58.
MohantyA. F.FarinF. M.BammlerT. K.MacDonaldJ. W.AfsharinejadZ.BurbacherT. M.SiscovickD. S.WilliamsM. A.EnquobahrieD. A. (2015). Infant sex-specific placental cadmium and DNA methylation associations. Environmental Research, 138, 74–81. https://doi.org/10.1016/j.envres.2015.02.004
59.
MohtyM.HarousseauJ. L. (2014). Treatment of autologous stem cell transplant-eligible multiple myeloma patients: Ten questions and answers. Haematologica, 99(3), 408–416. https://doi.org/10.3324/haematol.2013.096149
60.
NausC. C.LairdD. W. (2010). Implications and challenges of connexin connections to cancer. Nature Reviews Cancer, 10(6), 435–441. https://doi.org/10.1038/nrc2841
61.
NgoD.BensonM. D.LongJ. Z.ChenZ. Z.WangR.NathA. K.KeyesM. J.ShenD.SinhaS.KuhnE.MorningstarJ. E.ShiX.PetersonB. D.ChanC.KatzD. H.TahirU. A.FarrellL. A.MelanderO.MosleyJ. D.GersztenR. E. (2021). Proteomic profiling reveals biomarkers and pathways in type 2 diabetes risk. JCI Insight, 6(5), e144392. https://doi.org/10.1172/jci.insight.144392
62.
PantaleoE.MonacoA.AmorosoN.LombardiA.BellantuonoL.UrsoD.Lo GiudiceC.PicardiE.TafuriB.NigroS.PesoleG.TangaroS.LogroscinoG.BellottiR. (2022). A machine learning approach to Parkinson’s disease blood transcriptomics. Genes, 13(5), 727. https://doi.org/10.3390/genes13050727
63.
PasajeC. F. A.BaeJ. S.ParkB. L.CheongH. S.KimJ. H.UhS. T.ParkC. S.ShinH. D. (2012). WDR46 is a genetic risk factor for aspirin-exacerbated respiratory disease in a Korean population. Allergy, Asthma and Immunology Research, 4(4), 199–205. https://doi.org/10.4168/aair.2012.4.4.199
64.
PernaL.ZhangY.MonsU.HolleczekB.SaumK. U.BrennerH. (2016). Epigenetic age acceleration predicts cancer, cardiovascular, and all-cause mortality in a German case cohort. Clinical Epigenetics, 8(1), 64. https://doi.org/10.1186/s13148-016-0228-z
65.
PetersT. J.BuckleyM. J.ChenY.SmythG. K.GoodnowC. C.ClarkS. J. (2021). Calling differentially methylated regions from whole genome bisulphite sequencing with DMRcate. Nucleic Acids Research, 49(19), e109. https://doi.org/10.1093/nar/gkab637
66.
PhipsonB.MaksimovicJ.OshlackA. (2016). MissMethyl: An R package for analyzing data from Illumina’s HumanMethylation450 platform. Bioinformatics, 32(2), 286–288. https://doi.org/10.1093/bioinformatics/btv560
67.
PlanteI.StewartM. K. G.BarrK.AllanA. L.LairdD. W. (2011). Cx43 suppresses mammary tumor metastasis to the lung in a Cx43 mutant mouse model of human disease. Oncogene, 30(14), 1681–1692. https://doi.org/10.1038/onc.2010.551
68.
Pruszkowska-PrzybylskaP.BrenneckeS.MosesE. K.MeltonP. E. (2022). Evaluation of epigenetic age calculators between preeclampsia and normotensive pregnancies in an Australian cohort. Scientific Reports, 12(1), 1664. https://doi.org/10.1038/s41598-022-05744-4
69.
RitchieM. E.PhipsonB.WuD.HuY.LawC. W.ShiW.SmythG. K. (2015). Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic acids research, 43(7), e47. https://doi.org/10.1093/nar/gkv007
70.
RoetkerN. S.PankowJ. S.BresslerJ.MorrisonA. C.BoerwinkleE. (2018). Prospective study of epigenetic age acceleration and incidence of cardiovascular disease outcomes in the ARIC study (atherosclerosis risk in communities). Circulation. Genomic and Precision Medicine, 11(3), e001937. https://doi.org/10.1161/CIRCGEN.117.001937
71.
ShaoL.Elujoba-BridenstineA.ZinkK. E.SanchezL. M.CoxB. J.PollokK. E.SinnA. L.BaileyB. J.SimsE. C.CooperS. H.BroxmeyerH. E.PajciniK. V.TamplinO. J. (2021). The neurotransmitter receptor Gabbr1 regulates proliferation and function of hematopoietic stem and progenitor cells. Blood, 137(6), 775–787. https://doi.org/10.1182/blood.2019004415
72.
SøraasA.MatsuyamaM.De LimaM.WaldD.BuechnerJ.Gedde-DahlT.SøraasC. L.ChenB.FerrucciL.DahlJ. A.HorvathS.MatsuyamaS. (2019). Epigenetic age is a cell-intrinsic property in transplanted human hematopoietic cells. Aging Cell, 18(2), e12897. https://doi.org/10.1111/acel.12897
73.
SouzaB. K.FreireN. H.JaegerM.de FariasC. B.BrunettoA. L.BrunettoA. T.RoeslerR. (2021). EHMT2/G9a as an epigenetic target in pediatric and adult brain tumors. International Journal of Molecular Sciences, 22(20), 11292. https://doi.org/10.3390/ijms222011292
74.
StephenJ.NampoothiriS.BanerjeeA.TolmanN. J.PenningerJ. M.EllingU.AguC. A.BurkeJ. D.DevadathanK.KannanR.HuangY.SteinbachP. J.MartinisS. A.GahlW. A.MalicdanM. C. V. (2018). Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy. Human Genetics, 137(4), 293–303. https://doi.org/10.1007/s00439-018-1882-3
75.
StölzelF.BroschM.HorvathS.KramerM.ThiedeC.Von BoninM.AmmerpohlO.MiddekeM.ScheteligJ.EhningerG.HampeJ.BornhäuserM. (2017). Dynamics of epigenetic age following hematopoietic stem cell transplantation. Haematologica, 102(8), e321–e323. https://doi.org/10.3324/haematol.2016.160481
76.
StumpfM.YueX.SchmitzS.LucheH.ReddyJ. K.BorggrefeT. (2010). Specific erythroid-lineage defect in mice conditionally deficient for Mediator subunit Med1. Proceedings of the National Academy of Sciences of the United States of America, 107(50), 21541–21546. https://doi.org/10.1073/pnas.1005794107
77.
SumitomoA.IshinoR.UrahamaN.InoueK.YonezawaK.HasegawaN.HorieO.MatsuokaH.KondoT.RoederR. G.ItoM. (2010). The transcriptional mediator subunit MED1/trap220 in stromal cells is involved in hematopoietic stem/progenitor cell support through osteopontin expression. Molecular and Cellular Biology, 30(20), 250. https://doi.org/10.1128/mcb.01348-09
78.
SungH. Y.YangS. D.ParkA. K.JuW.AhnJ. H. (2017). Aberrant hypomethylation of solute carrier family 6 member 12 promoter induces metastasis of Ovarian cancer. Yonsei Medical Journal, 58(1), 27–34. https://doi.org/10.3349/ymj.2017.58.1.27
79.
SwarbrickA.WoodsS. L.ShawA.BalakrishnanA.PhuaY.NguyenA.ChantheryY.LimL.AshtonL. J.JudsonR. L.HuskeyN.BlellochR.HaberM.NorrisM. D.LengyelP.HackettC. S.PreissT.ChetcutiA.SullivanC. S.GogaA. (2010). MiR-380-5p represses p53 to control cellular survival and is associated with poor outcome in MYCN-amplified neuroblastoma. Nature Medicine, 16(10), 1134–1140. https://doi.org/10.1038/nm.2227
80.
TerstappenF.CalisJ. J. A.PaauwN. D.JolesJ. A.van RijnB. B.MokryM.PlöschT.LelyA. T. (2020). Developmental programming in human umbilical cord vein endothelial cells following fetal growth restriction. Clinical Epigenetics, 12(1), 185. https://doi.org/10.1186/s13148-020-00980-9
81.
TrinoS.ZoppoliP.CarellaA. M.LaurenzanaI.WeiszA.MemoliD.CaliceG.RoccaF. LaSimeonV.SavinoL.VecchioL. P.CaivanoA.De LucaL. (2019). DNA methylation dynamic of bone marrow hematopoietic stem cells after allogeneic transplantation. Stem Cell Research & Therapy Electronic Resource, 10(1), 38. https://doi.org/10.1186/s13287-019-1245-6
82.
TwaD. D. W.ChanF. C.Ben-NeriahS.WoolcockB. W.MottokA.TanK. L.SlackG. W.GunawardanaJ.LimR. S.McPhersonA. W.KridelR.TeleniusA.ScottD. W.SavageK. J.ShahS. P.GascoyneR. D.SteidlC. (2014). Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood, 123(13), 2062–2065. https://doi.org/10.1182/blood-2013-10-535443
83.
UsluA.CanbolatO. (2021). Relationship between frailty and fatigue in older cancer patients. Seminars in Oncology Nursing, 37(4), 151179. https://doi.org/10.1016/j.soncn.2021.151179
84.
VangeelE. B.PishvaE.HompesT.van den HoveD.LambrechtsD.AllegaertK.FresonK.IzziB.ClaesS. (2017). Newborn genome-wide DNA methylation in association with pregnancy anxiety reveals a potential role for GABBR1. Clinical Epigenetics, 9(1), 107. https://doi.org/10.1186/s13148-017-0408-5
85.
WangW.AuerP.ZhangT.SpellmanS.CarlsonK. S.NazhaA.BolonY. T.SaberW. (2021b). Impact of epigenomic hypermethylation at TP53 on allogeneic hematopoietic cell transplantation outcomes for myelodysplastic syndromes. Transplantation and Cellular Therapy, 27(8), 659.e1–659.e6. https://doi.org/10.1016/j.jtct.2021.04.027
86.
WangZ.WangP.LiY.PengH.ZhuY.MohandasN.LiuJ. (2021c). Interplay between cofactors and transcription factors in hematopoiesis and hematological malignancies. Signal Transduction and Targeted Therapy, 6(1), 24. https://doi.org/10.1038/s41392-020-00422-1
87.
WangT.XiaC.DongY.ChenX.WangJ.DuJ. (2018). Trim27 confers myeloid hematopoiesis competitiveness by up-regulating myeloid master genes. Journal of Leukocyte Biology, 104(4), 799–809. https://doi.org/10.1002/JLB.1A1217-480R
88.
WangR.LiS.WenW.ZhangJ. (2021a). Multi-omics analysis of the effects of smoking on human tumors. Frontiers in Molecular Biosciences, 8, 704910. https://doi.org/10.3389/fmolb.2021.704910
89.
WangY.LiuS.ChenY.ZhuB.XingQ. (2022). Survival prognosis, tumor immune landscape, and immune responses of PPP1R18 in kidney renal clear cell carcinoma and its potentially double mechanisms. World Journal of Oncology, 13(1), 27–37. https://doi.org/10.14740/wjon1446
90.
WethkampN.KlempnauerK. H. (2009). Daxx is a transcriptional repressor of CCAAT/enhancer-binding Protein β. Journal of Biological Chemistry, 284(42), 28783–28794. https://doi.org/10.1074/jbc.M109.041186
91.
WilliamsA. M.ZentC. S.JanelsinsM. C. (2016). What is known and unknown about chemotherapy-related cognitive impairment in patients with haematological malignancies and areas of needed researchBritish Journal of Haematology, 174(6), 835–846. https://doi.org/10.1111/bjh.14211
92.
WuX. (2020). Depletion of miR-380 mitigates human bronchial epithelial cells injury to improve chronic obstructive pulmonary disease through targeting CHRNA4. Molecular and Cellular Probes, 49, 101492. https://doi.org/10.1016/j.mcp.2019.101492
93.
XuP.SunX.SongX.PengY.HeB.WuZ.ZhuJ. (2021). Prognostic value of lymphocyte-to-monocyte ratio and histone methyltransferase G9a histone methyltransferase in patients with double expression lymphoma A retrospective observational study. Medicine (United States), 100(4), e24449. https://doi.org/10.1097/MD.0000000000024449
94.
XueW.WuX.WangF.HanP.CuiB. (2018). Genome-wide methylation analysis identifies novel prognostic methylation markers in colon adenocarcinoma. Biomedicine and Pharmacotherapy, 108, 288–296. https://doi.org/10.1016/j.biopha.2018.09.043
95.
YokotaC.KagawaN.TakanoK.ChibaY.KinoshitaM.KijimaN.OjiY.OkaY.SugiyamaH.TsuboiA.IzumotoS.KishimaH.HashimotoN. (2022). Maintenance of WT1 expression in tumor cells is associated with a good prognosis in malignant glioma patients treated with WT1 peptide vaccine immunotherapy. Cancer ImmunologyImmunotherapy, 71(1), 189–201. https://doi.org/10.1007/s00262-021-02954-z
96.
ZhangT.WangF.WuJ. Y.QiuZ. C.WangY.LiuF.GeX. S.QiX. W.MaoY.HuaD. (2018a). Clinical correlation of B7-H3 and B3GALT4 with the prognosis of colorectal cancer. World Journal of Gastroenterology, 24(31), 3538–3546. https://doi.org/10.3748/wjg.v24.i31.3538
97.
ZhangY.ZhangY.SunK.MengZ.ChenL. (2018b). The SLC transporter in nutrient and metabolic sensing, regulation, and drug development. Journal of Molecular Cell Biology, 11(1), 1–43. https://doi.org/10.1093/jmcb/mjy052
98.
ZhouH.SunH.LiuX.ChenJ.ZhangL.LinS.HanX.NieC.LiuY.TianW.ZhaoY. (2019). Combined effect between WT1 methylation and Helicobacter pylori infection, smoking, and alcohol consumption on the risk of gastric cancer. Helicobacter, 24(5), e12650. https://doi.org/10.1111/hel.12650
99.
ZhuL.HanJ.LiL.WangY.LiY.ZhangS. (2019). Claudin family participates in the pathogenesis of inflammatory bowel diseases and colitis-associated colorectal cancer. Frontiers in Immunology, 10, 1441. https://doi.org/10.3389/fimmu.2019.01441
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