Cancer epigenetics in clinical practice

Veronica Davalos, Manel Esteller, Veronica Davalos, Manel Esteller

Abstract

Cancer development is driven by the accumulation of alterations affecting the structure and function of the genome. Whereas genetic changes disrupt the DNA sequence, epigenetic alterations contribute to the acquisition of hallmark tumor capabilities by regulating gene expression programs that promote tumorigenesis. Shifts in DNA methylation and histone mark patterns, the two main epigenetic modifications, orchestrate tumor progression and metastasis. These cancer-specific events have been exploited as useful tools for diagnosis, monitoring, and treatment choice to aid clinical decision making. Moreover, the reversibility of epigenetic modifications, in contrast to the irreversibility of genetic changes, has made the epigenetic machinery an attractive target for drug development. This review summarizes the most advanced applications of epigenetic biomarkers and epigenetic drugs in the clinical setting, highlighting commercially available DNA methylation-based assays and epigenetic drugs already approved by the US Food and Drug Administration.

Keywords: DNA methylation; cancer; epigenetic biomarkers; epigenetic drugs; epigenetics.

© 2022 The Authors. CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer Society.

References

REFERENCES

    1. Holliday R. The inheritance of epigenetic defects. Science. 1987;238(4824):163-170. doi:10.1126/science.3310230
    1. Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12(1):31-46. doi:10.1158/-21-1059
    1. Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983;301(5895):89-92. doi:10.1038/301089a0
    1. Berdasco M, Esteller M. Clinical epigenetics: seizing opportunities for translation. Nat Rev Genet. 2019;20(2):109-127. doi:10.1038/s41576-018-0074-2
    1. Mattei AL, Bailly N, Meissner A. DNA methylation: a historical perspective. Trends Genet. 2022;38(7):676-707. doi:10.1016/j.tig.2022.03.010
    1. Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet. 2012;13(7):484-492. doi:10.1038/nrg3230
    1. Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet. 2007;8(4):286-298. doi:10.1038/nrg2005
    1. Baylin SB. DNA methylation and gene silencing in cancer. Nat Clin Pract Oncol. 2005;2(suppl 1):S4-S11. doi:10.1038/ncponc0354
    1. Aran D, Toperoff G, Rosenberg M, Hellman A. Replication timing-related and gene body-specific methylation of active human genes. Hum Mol Genet. 2011;20(4):670-680. doi:10.1093/hmg/ddq513
    1. Goelz SE, Vogelstein B, Hamilton SR, Feinberg AP. Hypomethylation of DNA from benign and malignant human colon neoplasms. Science. 1985;228(4696):187-190. doi:10.1126/science.2579435
    1. Gaudet F, Hodgson JG, Eden A, et al. Induction of tumors in mice by genomic hypomethylation. Science. 2003;300(5618):489-492. doi:10.1126/science.1083558
    1. Zhao S, Allis CD, Wang GG. The language of chromatin modification in human cancers. Nat Rev Cancer. 2021;21(7):413-430. doi:10.1038/s41568-021-00357-x
    1. Kouzarides T. Chromatin modifications and their function. Cell. 2007;128(4):693-705. doi:10.1016/j.cell.2007.02.005
    1. Chi P, Allis CD, Wang GG. Covalent histone modifications-miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer. 2010;10(7):457-469. doi:10.1038/nrc2876
    1. Howlader N, Forjaz G, Mooradian MJ, et al. The effect of advances in lung-cancer treatment on population mortality. N Engl J Med. 2020;383(7):640-649. doi:10.1056/NEJMoa1916623
    1. Greger V, Passarge E, Hopping W, Messmer E, Horsthemke B. Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum Genet. 1989;83(2):155-158. doi:10.1007/BF00286709
    1. Herman JG, Latif F, Weng Y, et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A. 1994;91(21):9700-9704. doi:10.1073/pnas.91.21.9700
    1. Clark SJ, Harrison J, Paul CL, Frommer M. High sensitivity mapping of methylated cytosines. Nucleic Acids Res. 1994;22(15):2990-2997. doi:10.1093/nar/22.15.2990
    1. Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A. 1996;93(18):9821-9826. doi:10.1073/pnas.93.18.9821
    1. Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349(21):2042-2054. doi:10.1056/NEJMra023075
    1. Lister R, Pelizzola M, Dowen RH, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009;462(7271):315-322. doi:10.1038/nature08514
    1. Meissner A, Gnirke A, Bell GW, Ramsahoye B, Lander ES, Jaenisch R. Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis. Nucleic Acids Res. 2005;33(18):5868-5877. doi:10.1093/nar/gki901
    1. Gu H, Smith ZD, Bock C, Boyle P, Gnirke A, Meissner A. Preparation of reduced representation bisulfite sequencing libraries for genome-scale DNA methylation profiling. Nat Protoc. 2011;6(4):468-481. doi:10.1038/nprot.2010.190
    1. Weber M, Davies JJ, Wittig D, et al. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet. 2005;37(8):853-862. doi:10.1038/ng1598
    1. Lopez-Serra L, Ballestar E, Fraga MF, Alaminos M, Setien F, Esteller M. A profile of methyl-CpG binding domain protein occupancy of hypermethylated promoter CpG islands of tumor suppressor genes in human cancer. Cancer Res. 2006;66(17):8342-8346. doi:10.1158/0008-5472.CAN-06-1932
    1. Li N, Ye M, Li Y, et al. Whole genome DNA methylation analysis based on high throughput sequencing technology. Methods. 2010;52(3):203-212. doi:10.1016/j.ymeth.2010.04.009
    1. Grossman RL, Heath AP, Ferretti V, et al. Toward a shared vision for cancer genomic data. N Engl J Med. 2016;375(12):1109-1112. doi:10.1056/NEJMp1607591
    1. Moran S, Vizoso M, Martinez-Cardus A, et al. Validation of DNA methylation profiling in formalin-fixed paraffin-embedded samples using the Infinium HumanMethylation450 Microarray. Epigenetics. 2014;9(6):829-833. doi:10.4161/epi.28790
    1. Sandoval J, Heyn H, Moran S, et al. Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics. 2011;6(6):692-702. doi:10.4161/epi.6.6.16196
    1. Moran S, Arribas C, Esteller M. Validation of a DNA methylation microarray for 850, 000 CpG sites of the human genome enriched in enhancer sequences. Epigenomics. 2016;8(3):389-399. doi:10.2217/epi.15.114
    1. Capper D, Jones DTW, Sill M, et al. DNA methylation-based classification of central nervous system tumours. Nature. 2018;555(7697):469-474. doi:10.1038/nature26000
    1. Koelsche C, Schrimpf D, Stichel D, et al. Sarcoma classification by DNA methylation profiling. Nat Commun. 2021;12(1):498. doi:10.1038/s41467-020-20603-4
    1. Koelsche C, Hartmann W, Schrimpf D, et al. Array-based DNA-methylation profiling in sarcomas with small blue round cell histology provides valuable diagnostic information. Mod Pathol. 2018;31(8):1246-1256. doi:10.1038/s41379-018-0045-3
    1. Wu SP, Cooper BT, Bu F, et al. DNA methylation-based classifier for accurate molecular diagnosis of bone sarcomas. JCO Precis Oncol. 2017;2017(1):1-11. doi:10.1200/PO.17.00031
    1. Conway K, Edmiston SN, Parker JS, et al. Identification of a robust methylation classifier for cutaneous melanoma diagnosis. J Invest Dermatol. 2019;139(6):1349-1361. doi:10.1016/j.jid.2018.11.024
    1. Moran S, Martinez-Cardus A, Sayols S, et al. Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol. 2016;17(10):1386-1395. doi:10.1016/S1470-2045(16)30297-2
    1. Duruisseaux M, Martinez-Cardus A, Calleja-Cervantes ME, et al. Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis. Lancet Respir Med. 2018;6(10):771-781. doi:10.1016/S2213-2600(18)30284-4
    1. Rand AC, Jain M, Eizenga JM, et al. Mapping DNA methylation with high-throughput nanopore sequencing. Nat Methods. 2017;14(4):411-413. doi:10.1038/nmeth.4189
    1. Liu Y, Rosikiewicz W, Pan Z, et al. DNA methylation-calling tools for Oxford Nanopore sequencing: a survey and human epigenome-wide evaluation. Genome Biol. 2021;22(1):295. doi:10.1186/s13059-021-02510-z
    1. Eads CA, Danenberg KD, Kawakami K, et al. MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res. 2000;28(8):E32. doi:10.1093/nar/28.8.e32
    1. Yu M, Carter KT, Makar KW, et al. MethyLight droplet digital PCR for detection and absolute quantification of infrequently methylated alleles. Epigenetics. 2015;10(9):803-809. doi:10.1080/15592294.2015.1068490
    1. Ronaghi M, Uhlen M, Nyren P. A sequencing method based on real-time pyrophosphate. Science. 1998;281(5375):363-365. doi:10.1126/science.281.5375.363
    1. Luo H, Wei W, Ye Z, Zheng J, Xu RH. Liquid biopsy of methylation biomarkers in cell-free DNA. Trends Mol Med. 2021;27(5):482-500. doi:10.1016/j.molmed.2020.12.011
    1. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra24. doi:10.1126/scitranslmed.3007094
    1. Locke WJ, Guanzon D, Ma C, et al. DNA methylation cancer biomarkers: translation to the clinic. Front Genet. 2019;10:1150. doi:10.3389/fgene.2019.01150
    1. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-1297. doi:10.1056/NEJMoa1311194
    1. Church TR, Wandell M, Lofton-Day C, et al. Prospective evaluation of methylated SEPT9 in plasma for detection of asymptomatic colorectal cancer. Gut. 2014;63(2):317-325. doi:10.1136/gutjnl-2012-304149
    1. Potter NT, Hurban P, White MN, et al. Validation of a real-time PCR-based qualitative assay for the detection of methylated SEPT9 DNA in human plasma. Clin Chem. 2014;60(9):1183-1191. doi:10.1373/clinchem.2013.221044
    1. Lin N, Lin Y, Xu J, et al. A multi-analyte cell-free DNA-based blood test for early detection of hepatocellular carcinoma. Hepatol Commun. 2022;6(7):1753-1763. doi:10.1002/hep4.1918
    1. Cheishvili D, Wong C, Karim MM, et al. epiLiver a novel tumor specific, high throughput and cost-effective blood test for specific detection of liver cancer (HCC). medRxiv. Printed online February 9, 2021.doi:10.1101/2021.02.07.21251315
    1. Witjes JA, Morote J, Cornel EB, et al. Performance of the Bladder EpiCheckTM methylation test for patients under surveillance for non-muscle-invasive bladder cancer: results of a multicenter, prospective, blinded clinical trial. Eur Urol Oncol. 2018;1(4):307-313. doi:10.1016/j.euo.2018.06.011
    1. D’Andrea D, Soria F, Zehetmayer S, et al. Diagnostic accuracy, clinical utility and influence on decision-making of a methylation urine biomarker test in the surveillance of non-muscle-invasive bladder cancer. BJU Int. 2019;123(6):959-967. doi:10.1111/bju.14673
    1. Laukhtina E, Shim SR, Mori K, et al. Diagnostic accuracy of novel urinary biomarker tests in non-muscle-invasive bladder cancer: a systematic review and network meta-analysis. Eur Urol Oncol. 2021;4(6):927-942. doi:10.1016/j.euo.2021.10.003
    1. Ruan W, Chen X, Huang M, et al. A urine-based DNA methylation assay to facilitate early detection and risk stratification of bladder cancer. Clin Epigenetics. 2021;13(1):91. doi:10.1186/s13148-021-01073-x
    1. van Kessel KEM, Van Neste L, Lurkin I, Zwarthoff EC, Van Criekinge W. Evaluation of an epigenetic profile for the detection of bladder cancer in patients with hematuria. J Urol. 2016;195(3):601-607. doi:10.1016/j.juro.2015.08.085
    1. Piatti P, Chew YC, Suwoto M, et al. Clinical evaluation of Bladder CARE, a new epigenetic test for bladder cancer detection in urine samples. Clin Epigenetics. 2021;13(1):84. doi:10.1186/s13148-021-01029-1
    1. Moinova HR, LaFramboise T, Lutterbaugh JD, et al. Identifying DNA methylation biomarkers for non-endoscopic detection of Barrett’s esophagus. Sci Transl Med. 2018;10(424):aao5848. doi:10.1126/scitranslmed.aao5848
    1. Huang J, Wang G, Tang J, et al. DNA methylation status of PAX1 and ZNF582 in esophageal squamous cell carcinoma. Int J Environ Res Public Health. 2017;14(2):216. doi:10.3390/ijerph14020216
    1. Darwiche K, Zarogoulidis P, Baehner K, et al. Assessment of SHOX2 methylation in EBUS-TBNA specimen improves accuracy in lung cancer staging. Ann Oncol. 2013;24(11):2866-2870. doi:10.1093/annonc/mdt365
    1. Ilse P, Biesterfeld S, Pomjanski N, Wrobel C, Schramm M. Analysis of SHOX2 methylation as an aid to cytology in lung cancer diagnosis. Cancer Genomics Proteomics. 2014;11(5):251-258.
    1. Weiss G, Schlegel A, Kottwitz D, Konig T, Tetzner R. Validation of the SHOX2/PTGER4 DNA methylation marker panel for plasma-based discrimination between patients with malignant and nonmalignant lung disease. J Thorac Oncol. 2017;12(1):77-84. doi:10.1016/j.jtho.2016.08.123
    1. Liang W, Chen Z, Li C, et al. Accurate diagnosis of pulmonary nodules using a noninvasive DNA methylation test. J Clin Invest. 2021;131(10):e145973. doi:10.1172/JCI145973
    1. Bonde J, Floore A, Ejegod D, et al. Methylation markers FAM19A4 and miR124-2 as triage strategy for primary human papillomavirus screen positive women: a large European multicenter study. Int J Cancer. 2021;148(2):396-405. doi:10.1002/ijc.33320
    1. Schmitz M, Eichelkraut K, Schmidt D, et al. Performance of a DNA methylation marker panel using liquid-based cervical scrapes to detect cervical cancer and its precancerous stages. BMC Cancer. 2018;18(1):1197. doi:10.1186/s12885-018-5125-8
    1. Hansel A, Steinbach D, Greinke C, et al. A promising DNA methylation signature for the triage of high-risk human papillomavirus DNA-positive women. PLoS One. 2014;9(3):e91905. doi:10.1371/journal.pone.0091905
    1. Schricker G, Napieralski R, Noske A, et al. Clinical performance of an analytically validated assay in comparison to microarray technology to assess PITX2 DNA-methylation in breast cancer. Sci Rep. 2018;8(1):16861. doi:10.1038/s41598-018-34919-1
    1. Stewart GD, Van Neste L, Delvenne P, et al. Clinical utility of an epigenetic assay to detect occult prostate cancer in histopathologically negative biopsies: results of the MATLOC study. J Urol. 2013;189(3):1110-1116. doi:10.1016/j.juro.2012.08.219
    1. Waterhouse RL, Van Neste L, Moses KA, et al. Evaluation of an epigenetic assay for predicting repeat prostate biopsy outcome in African American men. Urology. 2019;128:62-65. doi:10.1016/j.urology.2018.04.001
    1. Johnson DA, Barclay RL, Mergener K, et al. Plasma Septin9 versus fecal immunochemical testing for colorectal cancer screening: a prospective multicenter study. PLoS One. 2014;9(6):e98238. doi:10.1371/journal.pone.0098238
    1. Partin AW, Van Neste L, Klein EA, et al. Clinical validation of an epigenetic assay to predict negative histopathological results in repeat prostate biopsies. J Urol. 2014;192(4):1081-1087. doi:10.1016/j.juro.2014.04.013
    1. Wojno KJ, Costa FJ, Cornell RJ, et al. Reduced rate of repeated prostate biopsies observed in ConfirmMDx clinical utility field study. Am Health Drug Benefits. 2014;7(3):129-134.
    1. Aubry W, Lieberthal R, Willis A, Bagley G, Willis SM, Layton A. Budget impact model: epigenetic assay can help avoid unnecessary repeated prostate biopsies and reduce healthcare spending. Am Health Drug Benefits. 2013;6(1):15-24.
    1. Quillien V, Lavenu A, Ducray F, et al. Clinical validation of the CE-IVD marked Therascreen MGMT kit in a cohort of glioblastoma patients. Cancer Biomark. 2017;20(4):435-441. doi:10.3233/CBM-170191
    1. Vlassenbroeck I, Califice S, Diserens AC, et al. Validation of real-time methylation-specific PCR to determine O6-methylguanine-DNA methyltransferase gene promoter methylation in glioma. J Mol Diagn. 2008;10(4):332-337. doi:10.2353/jmoldx.2008.070169
    1. Liang N, Li B, Jia Z, et al. Ultrasensitive detection of circulating tumour DNA via deep methylation sequencing aided by machine learning. Nat Biomed Eng. 2021;5(6):586-599. doi:10.1038/s41551-021-00746-5
    1. Liu MC, Oxnard GR, Klein EA, Swanton C, Seiden MF, CCGA Consortium. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol. 2020;31(6):745-759. doi:10.1016/j.annonc.2020.02.011
    1. Klein EA, Richards D, Cohn A, et al. Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set. Ann Oncol. 2021;32(9):1167-1177. doi:10.1016/j.annonc.2021.05.806
    1. Nadauld LD, McDonnell CH, Beer TM, et al. The PATHFINDER study: assessment of the implementation of an investigational multi-cancer early detection test into clinical Practice. Cancers (Basel). 2021;13(14):3501. doi:10.3390/cancers13143501
    1. Wang X, Lu M, Qian J, et al. Rationales, design and recruitment of the Taizhou longitudinal study. BMC Public Health. 2009;9(1):223. doi:10.1186/1471-2458-9-223
    1. Kim CW, Kim H, Kim HR, et al. Colorectal cancer screening using a stool DNA-based SDC2 methylation test: a multicenter, prospective trial. BMC Gastroenterol. 2021;21(1):173. doi:10.1186/s12876-021-01759-9
    1. Chen X, Gole J, Gore A, et al. Non-invasive early detection of cancer four years before conventional diagnosis using a blood test. Nat Commun. 2020;11(1):3475. doi:10.1038/s41467-020-17316-z
    1. Oh TJ, Oh H, Seo YY, et al. Feasibility of quantifying SDC2 methylation in stool DNA for early detection of colorectal cancer. Clin Epigenetics. 2017;9(1):126. doi:10.1186/s13148-017-0426-3
    1. Han YD, Oh TJ, Chung TH, et al. Early detection of colorectal cancer based on presence of methylated syndecan-2 (SDC2) in stool DNA. Clin Epigenetics. 2019;11(1):51. doi:10.1186/s13148-019-0642-0
    1. Young GP, Pedersen SK, Mansfield S, et al. A cross-sectional study comparing a blood test for methylated BCAT1 and IKZF1 tumor-derived DNA with CEA for detection of recurrent colorectal cancer. Cancer Med. 2016;5(10):2763-2772. doi:10.1002/cam4.868
    1. Symonds EL, Pedersen SK, Yeo B, et al. Assessment of tumor burden and response to therapy in patients with colorectal cancer using a quantitative ctDNA test for methylated BCAT1/IKZF1. Mol Oncol. 2022;16(10):2031-2041. doi:10.1002/1878-0261.13178
    1. Lewin J, Kottwitz D, Aoyama J, et al. Plasma cell free DNA methylation markers for hepatocellular carcinoma surveillance in patients with cirrhosis: a case control study. BMC Gastroenterol. 2021;21(1):136. doi:10.1186/s12876-021-01714-8
    1. Cao J, Zhou J, Gao Y, et al. Methylation of p16 CpG island associated with malignant progression of oral epithelial dysplasia: a prospective cohort study. Clin Cancer Res. 2009;15(16):5178-5183. doi:10.1158/1078-0432.CCR-09-0580
    1. van der Stok EP, Spaander MCW, Grunhagen DJ, Verhoef C, Kuipers EJ. Surveillance after curative treatment for colorectal cancer. Nat Rev Clin Oncol. 2017;14(5):297-315. doi:10.1038/nrclinonc.2016.199
    1. Kelly H, Benavente Y, Pavon MA, De Sanjose S, Mayaud P, Lorincz AT. Performance of DNA methylation assays for detection of high-grade cervical intraepithelial neoplasia (CIN2+): a systematic review and meta-analysis. Br J Cancer. 2019;121(11):954-965. doi:10.1038/s41416-019-0593-4
    1. Vink FJ, Meijer CJLM, Clifford GM, et al. FAM19A4/miR124-2 methylation in invasive cervical cancer: a retrospective cross-sectional worldwide study. Int J Cancer. 2020;147(4):1215-1221. doi:10.1002/ijc.32614
    1. Luan T, Hua Q, Liu X, et al. PAX1 methylation as a potential biomarker to predict the progression of cervical intraepithelial neoplasia: a meta-analysis of related studies. Int J Gynecol Cancer. 2017;27(7):1480-1488. doi:10.1097/IGC.0000000000001011
    1. Kong L, Wang L, Wang Z, et al. DNA methylation for cervical cancer screening: a training set in China. Clin Epigenetics. 2020;12(1):91. doi:10.1186/s13148-020-00885-7
    1. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68(2):723-750. doi:10.1002/hep.29913
    1. Flores A, Marrero JA. Emerging trends in hepatocellular carcinoma: focus on diagnosis and therapeutics. Clin Med Insights Oncol. 2014;8:71-76. doi:10.4137/CMO.S9926
    1. Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6. doi:10.1038/s41572-020-00240-3
    1. Fiano V, Zugna D, Grasso C, et al. DNA methylation in repeat negative prostate biopsies as a marker of missed prostate cancer. Clin Epigenetics. 2019;11(1):152. doi:10.1186/s13148-019-0746-6
    1. Esteller M, Garcia-Foncillas J, Andion E, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med. 2000;343(19):1350-1354. doi:10.1056/NEJM200011093431901
    1. Jacinto FV, Esteller M. MGMT hypermethylation: a prognostic foe, a predictive friend. DNA Repair (Amst). 2007;6(8):1155-1160. doi:10.1016/j.dnarep.2007.03.013
    1. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003. doi:10.1056/NEJMoa043331
    1. Absmaier M, Napieralski R, Schuster T, et al. PITX2 DNA-methylation predicts response to anthracycline-based adjuvant chemotherapy in triple-negative breast cancer patients. Int J Oncol. 2018;52(3):755-767. doi:10.3892/ijo.2018.4241
    1. Hartmann O, Spyratos F, Harbeck N, et al. DNA methylation markers predict outcome in node-positive, estrogen receptor-positive breast cancer with adjuvant anthracycline-based chemotherapy. Clin Cancer Res. 2009;15(1):315-323. doi:10.1158/1078-0432.CCR-08-0166
    1. Pavlidis N, Pentheroudakis G. Cancer of unknown primary site. Lancet. 2012;379(9824):1428-1435. doi:10.1016/S0140-6736(11)61178-1
    1. Rassy E, Pavlidis N. Progress in refining the clinical management of cancer of unknown primary in the molecular era. Nat Rev Clin Oncol. 2020;17(9):541-554. doi:10.1038/s41571-020-0359-1
    1. Moran S, Martinez-Cardus A, Boussios S, Esteller M. Precision medicine based on epigenomics: the paradigm of carcinoma of unknown primary. Nat Rev Clin Oncol. 2017;14(11):682-694. doi:10.1038/nrclinonc.2017.97
    1. Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neurooncol. 2021;23(8):1231-1251. doi:10.1093/neuonc/noab106
    1. Pfister SM, Reyes-Mugica M, Chan JKC, et al. A summary of the inaugural WHO Classification of Pediatric Tumors: transitioning from the optical into the molecular era. Cancer Discov. 2022;12(2):331-355. doi:10.1158/-21-1094
    1. Capper D, Stichel D, Sahm F, et al. Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience. Acta Neuropathol. 2018;136(2):181-210. doi:10.1007/s00401-018-1879-y
    1. Wu Z, Abdullaev Z, Pratt D, et al. Impact of the methylation classifier and ancillary methods on CNS tumor diagnostics. Neuro Oncol. 2022;24(4):571-581. doi:10.1093/neuonc/noab227
    1. Pages M, Uro-Coste E, Colin C, et al. The implementation of DNA methylation profiling into a multistep diagnostic process in pediatric neuropathology: a 2-year real-world experience by the French Neuropathology Network. Cancers (Basel). 2021;13(6):1377. doi:10.3390/cancers13061377
    1. Rincon-Torroella J, Khela H, Bettegowda A, Bettegowda C. Biomarkers and focused ultrasound: the future of liquid biopsy for brain tumor patients. J Neurooncol. 2022;156(1):33-48. doi:10.1007/s11060-021-03837-0
    1. Li J, Zhao S, Lee M, et al. Reliable tumor detection by whole-genome methylation sequencing of cell-free DNA in cerebrospinal fluid of pediatric medulloblastoma. Sci Adv. 2020;6(42). doi:10.1126/sciadv.abb5427
    1. Wen H, Feng Z, Ge H, et al. 603P Multi-cancer early detection in gynaecological malignancies based on integrating multi-omics assays by liquid biopsy: a prospective study [abstract]. Ann Oncol. 2022;33(S7):S821-S822. doi:10.1016/j.annonc.2022.07.731
    1. Ravera F, Cirmena G, Dameri M, et al. Development of a hoRizontal data intEgration classifier for NOn-invasive early diAgnosis of breasT cancEr: the RENOVATE study protocol. BMJ Open. 2021;11(12):e054256. doi:10.1136/bmjopen-2021-054256
    1. Fraga MF, Ballestar E, Villar-Garea A, et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet. 2005;37(4):391-400. doi:10.1038/ng1531
    1. Nguyen CT, Weisenberger DJ, Velicescu M, et al. Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2′-deoxycytidine. Cancer Res. 2002;62(22):6456-6461.
    1. Seligson DB, Horvath S, McBrian MA, et al. Global levels of histone modifications predict prognosis in different cancers. Am J Pathol. 2009;174(5):1619-1628. doi:10.2353/ajpath.2009.080874
    1. Barlesi F, Giaccone G, Gallegos-Ruiz MI, et al. Global histone modifications predict prognosis of resected non small-cell lung cancer. J Clin Oncol. 2007;25(28):4358-4364. doi:10.1200/JCO.2007.11.2599
    1. Elsheikh SE, Green AR, Rakha EA, et al. Global histone modifications in breast cancer correlate with tumor phenotypes, prognostic factors, and patient outcome. Cancer Res. 2009;69(9):3802-3809. doi:10.1158/0008-5472.CAN-08-3907
    1. Ellinger J, Kahl P, Mertens C, et al. Prognostic relevance of global histone H3 lysine 4 (H3K4) methylation in renal cell carcinoma. Int J Cancer. 2010;127(10):2360-2366. doi:10.1002/ijc.25250
    1. Seligson DB, Horvath S, Shi T, et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature. 2005;435(7046):1262-1266. doi:10.1038/nature03672
    1. Komar D, Juszczynski P. Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy. Clin Epigenetics. 2020;12(1):147. doi:10.1186/s13148-020-00941-2
    1. Busam KJ, Shah KN, Gerami P, Sitzman T, Jungbluth AA, Kinsler V. Reduced H3K27me3 expression is common in nodular melanomas of childhood associated with congenital melanocytic nevi but not in proliferative nodules. Am J Surg Pathol. 2017;41(3):396-404. doi:10.1097/PAS.0000000000000769
    1. Van den Ackerveken P, Lobbens A, Turatsinze JV, et al. A novel proteomics approach to epigenetic profiling of circulating nucleosomes. Sci Rep. 2021;11(1):7256. doi:10.1038/s41598-021-86630-3
    1. Nacev BA, Feng L, Bagert JD, et al. The expanding landscape of ‘oncohistone’ mutations in human cancers. Nature. 2019;567(7749):473-478. doi:10.1038/s41586-019-1038-1
    1. Schwartzentruber J, Korshunov A, Liu XY, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012;482(7384):226-231. doi:10.1038/nature10833
    1. Sturm D, Witt H, Hovestadt V, et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell. 2012;22(4):425-437. doi:10.1016/j.ccr.2012.08.024
    1. Khuong-Quang DA, Buczkowicz P, Rakopoulos P, et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. 2012;124(3):439-447. doi:10.1007/s00401-012-0998-0
    1. Karremann M, Gielen GH, Hoffmann M, et al. Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location. Neuro Oncol. 2018;20(1):123-131. doi:10.1093/neuonc/nox149
    1. Chase A, Cross NCP. Aberrations of EZH2 in cancer. Clin Cancer Res. 2011;17(9):2613-2618. doi:10.1158/1078-0432.CCR-10-2156
    1. Kim KH, Roberts CWM. Targeting EZH2 in cancer. Nat Med. 2016;22(2):128-134. doi:10.1038/nm.4036
    1. Kaminskas E, Farrell A, Abraham S, et al. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res. 2005;11(10):3604-3608. doi:10.1158/1078-0432.CCR-04-2135
    1. DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19(2):216-228. doi:10.1016/S1470-2045(18)30010-X
    1. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17. doi:10.1182/blood-2018-08-868752
    1. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971
    1. Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med. 2022;386(16):1519-1531. doi:10.1056/NEJMoa2117344
    1. Niemeyer CM, Flotho C, Lipka DB, et al. Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial. Blood Adv. 2021;5(14):2901-2908. doi:10.1182/bloodadvances.2020004144
    1. Wei AH, Dohner H, Pocock C, et al. Oral azacitidine maintenance therapy for acute myeloid leukemia in first remission. N Engl J Med. 2020;383(26):2526-2537. doi:10.1056/NEJMoa2004444
    1. Kantarjian H, Issa JPJ, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106(8):1794-1803. doi:10.1002/cncr.21792
    1. Garcia-Manero G, Griffiths EA, Steensma DP, et al. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood. 2020;136(6):674-683. doi:10.1182/blood.2019004143
    1. Kim N, Norsworthy KJ, Subramaniam S, et al. FDA approval summary: decitabine and cedazuridine tablets for myelodysplastic syndromes. Clin Cancer Res. 2022;28(16):3411-3416. doi:10.1158/1078-0432.CCR-21-4498
    1. Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist. 2007;12(10):1247-1252. doi:10.1634/theoncologist.12-10-1247
    1. Piekarz RL, Frye R, Turner M, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2009;27(32):5410-5417. doi:10.1200/JCO.2008.21.6150
    1. Whittaker SJ, Demierre MF, Kim EJ, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol. 2010;28(29):4485-4491. doi:10.1200/JCO.2010.28.9066
    1. Coiffier B, Pro B, Prince HM, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol. 2012;30(6):631-636. doi:10.1200/JCO.2011.37.4223
    1. Bachy E, Camus V, Thieblemont C, et al. Romidepsin plus CHOP versus CHOP in patients with previously untreated peripheral T-cell lymphoma: results of the Ro-CHOP phase III study (conducted by LYSA). J Clin Oncol. 2022;40(3):242-251. doi:10.1200/JCO.21.01815
    1. Lee HZ, Kwitkowski VE, Del Valle PL, et al. FDA approval: belinostat for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Clin Cancer Res. 2015;21(12):2666-2670. doi:10.1158/1078-0432.CCR-14-3119
    1. San-Miguel JF, Hungria VTM, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15(11):1195-1206. doi:10.1016/S1470-2045(14)70440-1
    1. Shi Y, Dong M, Hong X, et al. Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma. Ann Oncol. 2015;26(8):1766-1771. doi:10.1093/annonc/mdv237
    1. Jiang Z, Li W, Hu X, et al. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(6):806-815. doi:10.1016/S1470-2045(19)30164-0
    1. Yardley DA, Ismail-Khan RR, Melichar B, et al. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromata. J Clin Oncol. 2013;31(17):2128-2135. doi:10.1200/JCO.2012.43.7251
    1. Connolly RM, Zhao F, Miller KD, et al. E2112: randomized phase III trial of endocrine therapy plus entinostat or placebo in hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN Cancer Research Group. J Clin Oncol. 2021;39(28):3171-3181. doi:10.1200/JCO.21.00944
    1. Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 2020;21(11):1433-1442. doi:10.1016/S1470-2045(20)30441-1
    1. Gounder M, Schoffski P, Jones RL, et al. Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study. Lancet Oncol. 2020;21(11):1423-1432. doi:10.1016/S1470-2045(20)30451-4
    1. Izutsu K, Makita S, Nosaka K, et al. An open-label, single-arm, phase 2 trial of valemetostat in relapsed or refractory adult T-cell leukemia/lymphoma [abstract]. Blood. Published online September 23, 2022. doi:10.1182/blood.2022016862
    1. Salamero O, Montesinos P, Willekens C, et al. First-in-human phase I study of iadademstat (ORY-1001): a first-in-class lysine-specific histone demethylase 1A inhibitor, in relapsed or refractory acute myeloid leukemia. J Clin Oncol. 2020;38(36):4260-4273. doi:10.1200/JCO.19.03250
    1. Salamero O, Somervaille TC, Molero A, et al. Iadademstat in combination with azacitidine generates robust and long lasting responses in AML patients (ALICE trial) [abstract]. Blood. 2021;138(suppl 1):3376. doi:10.1182/blood-2021-152183
    1. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731. doi:10.1182/blood-2017-04-779405
    1. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398. doi:10.1056/NEJMoa1716984
    1. Roboz GJ, DiNardo CD, Stein EM, et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood. 2020;135(7):463-471. doi:10.1182/blood.2019002140
    1. Zhu AX, Macarulla T, Javle MM, et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation. JAMA Oncol. 2021;7(11):1669-1677. doi:10.1001/jamaoncol.2021.3836
    1. Tap WD, Villalobos VM, Cote GM, et al. Phase I study of the mutant IDH1 inhibitor ivosidenib: safety and clinical activity in patients with advanced chondrosarcoma. J Clin Oncol. 2020;38(15):1693-1701. doi:10.1200/JCO.19.02492
    1. Yang X, Lay F, Han H, Jones PA. Targeting DNA methylation for epigenetic therapy. Trends Pharmacol Sci. 2010;31(11):536-546. doi:10.1016/j.tips.2010.08.001
    1. Roboz GJ, Sanz G, Griffiths EA, et al. Results from a global randomized phase 3 study of guadecitabine (G) vs treatment choice (TC) in 302 patients with relapsed or refractory (r/r) acute myeloid leukemia after intensive chemotherapy (ASTRAL-2 study) [abstract]. Blood. 2021;138(suppl 1):2344. doi:10.1182/blood-2021-147769
    1. Topper MJ, Vaz M, Marrone KA, Brahmer JR, Baylin SB. The emerging role of epigenetic therapeutics in immuno-oncology. Nat Rev Clin Oncol. 2020;17(2):75-90. doi:10.1038/s41571-019-0266-5
    1. Mazzone R, Zwergel C, Mai A, Valente S. Epi-drugs in combination with immunotherapy: a new avenue to improve anticancer efficacy. Clin Epigenetics. 2017;9(1):59. doi:10.1186/s13148-017-0358-y
    1. Morel D, Jeffery D, Aspeslagh S, Almouzni G, Postel-Vinay S. Combining epigenetic drugs with other therapies for solid tumours-past lessons and future promise. Nat Rev Clin Oncol. 2020;17(2):91-107. doi:10.1038/s41571-019-0267-4
    1. Villanueva L, Alvarez-Errico D, Esteller M. The contribution of epigenetics to cancer immunotherapy. Trends Immunol. 2020;41(8):676-691. doi:10.1016/j.it.2020.06.002
    1. Pappalardi MB, Keenan K, Cockerill M, et al. Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia. Nat Cancer. 2021;2(10):1002-1017. doi:10.1038/s43018-021-00249-x.
    1. Terranova-Barberio M, Thomas S, Ali N, et al. HDAC inhibition potentiates immunotherapy in triple negative breast cancer. Oncotarget. 2017;8(69):114156-114172. doi:10.18632/oncotarget.23169
    1. Shen L, Ciesielski M, Ramakrishnan S, et al. Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models. PLoS One. 2012;7(1):e30815. doi:10.1371/journal.pone.0030815
    1. Thomas S, Thurn KT, Bicaku E, Marchion DC, Munster PN. Addition of a histone deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction of autophagy. Breast Cancer Res Treat. 2011;130(2):437-447. doi:10.1007/s10549-011-1364-y
    1. Munster PN, Thurn KT, Thomas S, et al. A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer. Br J Cancer. 2011;104(12):1828-1835. doi:10.1038/bjc.2011.156
    1. Terranova-Barberio M, Pawlowska N, Dhawan M, et al. Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer. Nat Commun. 2020;11(1):3584. doi:10.1038/s41467-020-17414-y
    1. Groselj B, Sharma NL, Hamdy FC, Kerr M, Kiltie AE. Histone deacetylase inhibitors as radiosensitisers: effects on DNA damage signalling and repair. Br J Cancer. 2013;108(4):748-754. doi:10.1038/bjc.2013.21
    1. Xu WS, Parmigiani RB, Marks PA. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007;26(37):5541-5552. doi:10.1038/sj.onc.1210620
    1. DuBois SG, Granger MM, Groshen S, et al. Randomized phase II trial of MIBG versus MIBG, vincristine, and irinotecan versus MIBG and vorinostat for patients with relapsed or refractory neuroblastoma: a report from NANT Consortium. J Clin Oncol. 2021;39(31):3506-3514. doi:10.1200/JCO.21.00703
    1. Poklepovic AS, Fields EC, Bandyopadhyay D, et al. A phase 1 study of neoadjuvant chemotherapy followed by concurrent chemoradiation with gemcitabine, sorafenib, and vorinostat in pancreatic cancer [abstract]. J Clin Oncol. 2021;39(15 suppl):e16268. doi:10.1200/JCO.2021.39.15_suppl.e16268
    1. Juergens RA, Wrangle J, Vendetti FP, et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 2011;1(7):598-607. doi:10.1158/-11-0214
    1. Connolly RM, Li H, Jankowitz RC, et al. Combination epigenetic therapy in advanced breast cancer with 5-azacitidine and entinostat: a phase II National Cancer Institute/Stand Up to Cancer study. Clin Cancer Res. 2017;23(11):2691-2701. doi:10.1158/1078-0432.CCR-16-1729
    1. Sun X, Gao H, Yang Y, et al. PROTACs: great opportunities for academia and industry. Signal Transduct Target Ther. 2019;4(1):64. doi:10.1038/s41392-019-0101-6
    1. Yang K, Song Y, Xie H, et al. Development of the first small molecule histone deacetylase 6 (HDAC6) degraders. Bioorg Med Chem Lett. 2018;28(14):2493-2497. doi:10.1016/j.bmcl.2018.05.057
    1. An Z, Lv W, Su S, Wu W, Rao Y. Developing potent PROTACs tools for selective degradation of HDAC6 protein. Protein Cell. 2019;10(8):606-609. doi:10.1007/s13238-018-0602-z
    1. Wu H, Yang K, Zhang Z, et al. Development of multifunctional histone deacetylase 6 degraders with potent antimyeloma activity. J Med Chem. 2019;62(15):7042-7057. doi:10.1021/acs.jmedchem.9b00516
    1. Pulya S, Amin SA, Adhikari N, Biswas S, Jha T, Ghosh B. HDAC6 as privileged target in drug discovery: a perspective. Pharmacol Res. 2021;163:105274. doi:10.1016/j.phrs.2020.105274
    1. Simo-Riudalbas L, Esteller M. Targeting the histone orthography of cancer: drugs for writers, erasers and readers. Br J Pharmacol. 2015;172(11):2716-2732. doi:10.1111/bph.12844
    1. Morin RD, Johnson NA, Severson TM, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42(2):181-185. doi:10.1038/ng.518
    1. Modena P, Lualdi E, Facchinetti F, et al. SMARCB1/INI1 tumor suppressor gene is frequently inactivated in epithelioid sarcomas. Cancer Res. 2005;65(10):4012-4019. doi:10.1158/0008-5472.CAN-04-3050
    1. Honma D, Kanno O, Watanabe J, et al. Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor. Cancer Sci. 2017;108(10):2069-2078. doi:10.1111/cas.13326
    1. LaFave LM, Beguelin W, Koche R, et al. Loss of BAP1 function leads to EZH2-dependent transformation. Nat Med. 2015;21(11):1344-1349. doi:10.1038/nm.3947
    1. Zauderer MG, Szlosarek PW, Le Moulec S, et al. Safety and efficacy of tazemetostat, an enhancer of zeste-homolog 2 inhibitor, in patients with relapsed or refractory malignant mesothelioma. J Clin Oncol. 2020;38(15 suppl):9058. doi:10.1200/JCO.2020.38.15_suppl.9058
    1. Okada Y, Feng Q, Lin Y, et al. hDOT1L links histone methylation to leukemogenesis. Cell. 2005;121(2):167-178. doi:10.1016/j.cell.2005.02.020
    1. Lonetti A, Indio V, Laginestra MA, et al. Inhibition of methyltransferase DOT1L sensitizes to sorafenib treatment AML cells irrespective of MLL-rearrangements: a novel therapeutic strategy for pediatric AML. Cancers (Basel). 2020;12(7):1972. doi:10.3390/cancers12071972
    1. Lim S, Janzer A, Becker A, et al. Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology. Carcinogenesis. 2010;31(3):512-520. doi:10.1093/carcin/bgp324
    1. Lv T, Yuan D, Miao X, et al. Over-expression of LSD1 promotes proliferation, migration and invasion in non-small cell lung cancer. PLoS One. 2012;7(4):e35065. doi:10.1371/journal.pone.0035065
    1. Ding J, Zhang ZM, Xia Y, et al. LSD1-mediated epigenetic modification contributes to proliferation and metastasis of colon cancer. Br J Cancer. 2013;109(4):994-1003. doi:10.1038/bjc.2013.364
    1. Kahl P, Gullotti L, Heukamp LC, et al. Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence. Cancer Res. 2006;66(23):11341-11347. doi:10.1158/0008-5472.CAN-06-1570
    1. Shi Y, Lan F, Matson C, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004;119(7):941-953. doi:10.1016/j.cell.2004.12.012
    1. Metzger E, Wissmann M, Yin N, et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature. 2005;437(7057):436-439. doi:10.1038/nature04020
    1. Zhou M, Venkata PP, Viswanadhapalli S, et al. KDM1A inhibition is effective in reducing stemness and treating triple negative breast cancer. Breast Cancer Res Treat. 2021;185(2):343-357. doi:10.1007/s10549-020-05963-1
    1. Cuyas E, Gumuzio J, Verdura S, et al. The LSD1 inhibitor iadademstat (ORY-1001) targets SOX2-driven breast cancer stem cells: a potential epigenetic therapy in luminal-B and HER2-positive breast cancer subtypes. Aging (Albany NY). 2020;12(6):4794-4814. doi:10.18632/aging.102887
    1. Verigos J, Karakaidos P, Kordias D, et al. The histone demethylase LSD1/ΚDM1A mediates chemoresistance in breast cancer via regulation of a stem cell program. Cancers (Basel). 2019;11(10):1585. doi:10.3390/cancers11101585
    1. Hollebecque A, Salvagni S, Plummer R, et al. Phase I study of lysine-specific demethylase 1 inhibitor, CC-90011, in patients with advanced solid tumors and relapsed/refractory non-Hodgkin lymphoma. Clin Cancer Res. 2021;27(2):438-446. doi:10.1158/1078-0432.CCR-20-2380
    1. Kanouni T, Severin C, Cho RW, et al. Discovery of CC-90011: a potent and selective reversible inhibitor of lysine specific demethylase 1 (LSD1). J Med Chem. 2020;63(23):14522-14529. doi:10.1021/acs.jmedchem.0c00978
    1. Chawla SP, Chua-Alcala VS, Sachdev JC, et al. Preliminary efficacy from an ongoing phase 1 dose escalation study of seclidemstat (SP-2577) in patients (pts) with advanced solid tumors (AST) [abstract]. J Clin Oncol. 2021;39(15 suppll):3073. doi:10.1200/JCO.2021.39.15_suppl.3073
    1. Sankar S, Bell R, Stephens B, et al. Mechanism and relevance of EWS/FLI-mediated transcriptional repression in Ewing sarcoma. Oncogene. 2016;35(47):6155-6156. doi:10.1038/onc.2016.142
    1. Theisen ER, Selich-Anderson J, Miller KR, et al. Chromatin profiling reveals relocalization of lysine-specific demethylase 1 by an oncogenic fusion protein. Epigenetics. 2021;16(4):405-424. doi:10.1080/15592294.2020.1805678
    1. Perillo B, Tramontano A, Pezone A, Migliaccio A. LSD1: more than demethylation of histone lysine residues. Exp Mol Med. 2020;52(12):1936-1947. doi:10.1038/s12276-020-00542-2
    1. Wang J, Hevi S, Kurash JK, et al. The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat Genet. 2009;41(1):125-129. doi:10.1038/ng.268
    1. Sheng W, LaFleur MW, Nguyen TH, et al. LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell. 2018;174(3):549-563.e19. doi:10.1016/j.cell.2018.05.052
    1. Xu S, Wang X, Yang Y, Li Y, Wu S. LSD1 silencing contributes to enhanced efficacy of anti-CD47/PD-L1 immunotherapy in cervical cancer. Cell Death Dis. 2021;12(4):282. doi:10.1038/s41419-021-03556-4
    1. Qin Y, Vasilatos SN, Chen L, et al. Inhibition of histone lysine-specific demethylase 1 elicits breast tumor immunity and enhances antitumor efficacy of immune checkpoint blockade. Oncogene. 2019;38(3):390-405. doi:10.1038/s41388-018-0451-5
    1. Sivanandhan D, Rajagopal S, Nair S, et al. Abstract 1756: JBI-802, novel dual inhibitor of LSD1-HDAC6 for treatment of cancer. Cancer Res. 2020;80(16 suppl):1756. doi:10.1158/1538-7445.AM2020-1756
    1. Loven J, Hoke HA, Lin CY, et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 2013;153(2):320-334. doi:10.1016/j.cell.2013.03.036
    1. Winter GE, Mayer A, Buckley DL, et al. BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment. Mol Cell. 2017;67(1):5-18.e19. doi:10.1016/j.molcel.2017.06.004
    1. French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 2003;63(2):304-307.
    1. French CA, Ramirez CL, Kolmakova J, et al. BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene. 2008;27(15):2237-2242. doi:10.1038/sj.onc.1210852
    1. Piha-Paul SA, Hann CL, French CA, et al. Phase 1 study of molibresib (GSK525762), a bromodomain and extra-terminal domain protein inhibitor, in NUT carcinoma and other solid tumors. JNCI Cancer Spectr. 2020;4(2):pkz093. doi:10.1093/jncics/pkz093
    1. Roboz GJ, Desai P, Lee S, et al. A dose escalation study of RO6870810/TEN-10 in patients with acute myeloid leukemia and myelodysplastic syndrome. Leuk Lymphoma. 2021;62(7):1740-1748. doi:10.1080/10428194.2021.1881509
    1. Shapiro GI, LoRusso P, Dowlati A, et al. A phase 1 study of RO6870810, a novel bromodomain and extra-terminal protein inhibitor, in patients with NUT carcinoma, other solid tumours, or diffuse large B-cell lymphoma. Br J Cancer. 2021;124(4):744-753. doi:10.1038/s41416-020-01180-1
    1. Dickinson M, Briones J, Herrera AF, et al. Phase 1b study of the BET protein inhibitor RO6870810 with venetoclax and rituximab in patients with diffuse large B-cell lymphoma. Blood Adv. 2021;5(22):4762-4770. doi:10.1182/bloodadvances.2021004619
    1. Stuhlmiller TJ, Miller SM, Zawistowski JS, et al. Inhibition of lapatinib-induced kinome reprogramming in ERBB2-positive breast cancer by targeting BET family bromodomains. Cell Rep. 2015;11(3):390-404. doi:10.1016/j.celrep.2015.03.037
    1. Leonard B, Brand TM, O’Keefe RA, et al. BET inhibition overcomes receptor tyrosine kinase-mediated cetuximab resistance in HNSCC. Cancer Res. 2018;78(15):4331-4343. doi:10.1158/0008-5472.CAN-18-0459
    1. Tiago M, Capparelli C, Erkes DA, et al. Targeting BRD/BET proteins inhibits adaptive kinome upregulation and enhances the effects of BRAF/MEK inhibitors in melanoma. Br J Cancer. 2020;122(6):789-800. doi:10.1038/s41416-019-0724-y
    1. Yang L, Zhang Y, Shan W, et al. Repression of BET activity sensitizes homologous recombination-proficient cancers to PARP inhibition. Sci Transl Med. 2017;9(400):eaal1645. doi:10.1126/scitranslmed.aal1645
    1. Sun C, Yin J, Fang Y, et al. BRD4 inhibition is synthetic lethal with PARP inhibitors through the induction of homologous recombination deficiency. Cancer Cell. 2018;33(3):401-416.e8. doi:10.1016/j.ccell.2018.01.019
    1. Fiorentino FP, Marchesi I, Schroder C, Schmidt R, Yokota J, Bagella L. BET-inhibitor I-BET762 and PARP-inhibitor talazoparib synergy in small cell lung cancer cells. Int J Mol Sci. 2020;21(24):9595. doi:10.3390/ijms21249595
    1. Karakashev S, Zhu H, Yokoyama Y, et al. BET bromodomain inhibition synergizes with PARP inhibitor in epithelial ovarian cancer. Cell Rep. 2017;21(12):3398-3405. doi:10.1016/j.celrep.2017.11.095
    1. Raina K, Lu J, Qian Y, et al. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc Natl Acad Sci U S A. 2016;113(26):7124-7129. doi:10.1073/pnas.1521738113
    1. Qin C, Hu Y, Zhou B, et al. Discovery of QCA570 as an exceptionally potent and efficacious proteolysis targeting chimera (PROTAC) degrader of the bromodomain and extra-terminal (BET) proteins capable of inducing complete and durable tumor regression. J Med Chem. 2018;61(15):6685-6704. doi:10.1021/acs.jmedchem.8b00506
    1. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765-773. doi:10.1056/NEJMoa0808710
    1. Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361(11):1058-1066. doi:10.1056/NEJMoa0903840
    1. Amary MF, Bacsi K, Maggiani F, et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol. 2011;224(3):334-343. doi:10.1002/path.2913
    1. Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739-744. doi:10.1038/nature08617
    1. Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17-30. doi:10.1016/j.ccr.2010.12.014
    1. Turcan S, Rohle D, Goenka A, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012;483(7390):479-483. doi:10.1038/nature10866
    1. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553-567. doi:10.1016/j.ccr.2010.11.015
    1. Mellinghoff IK, Penas-Prado M, Peters KB, et al. Vorasidenib, a dual inhibitor of mutant IDH1/2, in recurrent or progressive glioma; results of a first-in-human phase I trial. Clin Cancer Res. 2021;27(16):4491-4499. doi:10.1158/1078-0432.CCR-21-0611
    1. Schumacher T, Bunse L, Pusch S, et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature. 2014;512(7514):324-327. doi:10.1038/nature13387
    1. Platten M, Bunse L, Wick A, et al. A vaccine targeting mutant IDH1 in newly diagnosed glioma. Nature. 2021;592(7854):463-468. doi:10.1038/s41586-021-03363-z
    1. Casado-Pelaez M, Bueno-Costa A, Esteller M. Single cell cancer epigenetics. Trends Cancer. 2022;8(10):820-838. doi:10.1016/j.trecan.2022.06.005
    1. Gaiti F, Chaligne R, Gu H, et al. Epigenetic evolution and lineage histories of chronic lymphocytic leukaemia. Nature. 2019;569(7757):576-580. doi:10.1038/s41586-019-1198-z
    1. Nam AS, Chaligne R, Landau DA. Integrating genetic and non-genetic determinants of cancer evolution by single-cell multi-omics. Nat Rev Genet. 2021;22(1):3-18. doi:10.1038/s41576-020-0265-5
    1. Litzenburger UM, Buenrostro JD, Wu B, et al. Single-cell epigenomic variability reveals functional cancer heterogeneity. Genome Biol. 2017;18(1):15. doi:10.1186/s13059-016-1133-7
    1. Satpathy AT, Granja JM, Yost KE, et al. Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion. Nat Biotechnol. 2019;37(8):925-936. doi:10.1038/s41587-019-0206-z
    1. Guo F, Li L, Li J, et al. Single-cell multi-omics sequencing of mouse early embryos and embryonic stem cells. Cell Res. 2017;27(8):967-988. doi:10.1038/cr.2017.82
    1. Fan X, Lu P, Wang H, et al. Integrated single-cell multiomics analysis reveals novel candidate markers for prognosis in human pancreatic ductal adenocarcinoma. Cell Discov. 2022;8(1):13. doi:10.1038/s41421-021-00366-y

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