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01-05-2022 | Cholangiocarcinoma | Original Article

Epigenetic upregulation of TET2 is an independent poor prognostic factor for intrahepatic cholangiocarcinoma

Authors: Hironori Yamashita, Aikaterini Tourna, Masayuki Akita, Tomoo Itoh, Shilpa Chokshi, Tetsuo Ajiki, Takumi Fukumoto, Neil A. Youngson, Yoh Zen

Published in: Virchows Archiv | Issue 5/2022

Abstract

Mutations in IDH1/2 and the epigenetic silencing of TET2 occur in leukaemia or glioma in a mutually exclusive manner. Although intrahepatic cholangiocarcinoma (iCCA) may harbour IDH1/2 mutations, the contribution of TET2 to carcinogenesis remains unknown. In the present study, the expression and promoter methylation of TET2 were investigated in iCCA. The expression of TET2 was assessed in 52 cases of iCCA (small-duct type, n = 33; large-duct type, n = 19) by quantitative PCR, immunohistochemistry (IHC) and a sequencing-based methylation assay, and its relationships with clinicopathological features and alterations in cancer-related genes (e.g., KRAS and IDH1) were investigated. In contrast to non-neoplastic bile ducts, which were negative for TET2 on IHC, 42 cases (81%) of iCCA showed the nuclear overexpression of TET2. Based on IHC scores (area × intensity), these cases were classified as TET2-high (n = 25) and TET2-low (n = 27). The histological type, tumour size, lymph node metastasis and frequency of mutations in cancer-related genes did not significantly differ between the two groups. Overall and recurrence-free survival were significantly worse in patients with TET2-high iCCA than in those with TET2-low iCCA. A multivariate analysis identified the high expression of TET2 as an independent prognostic factor (HR = 2.94; p = 0.007). The degree of methylation at two promoter CpG sites was significantly less in TET2-high iCCA than in TET2-low iCCA or non-cancer tissue. In conclusion, in contrast to other IDH-related neoplasms, TET2 overexpression is common in iCCA of both subtypes, and its high expression, potentially induced by promoter hypomethylation, is an independent poor prognostic factor.

Akita M, Fujikura K, Ajiki T, Fukumoto T, Otani K, Azuma T, Itoh T, Ku Y, Zen Y (2017) Dichotomy in intrahepatic cholangiocarcinomas based on histologic similarities to hilar cholangiocarcinomas. Mod Pathol 30:986–997. https://doi.org/10.1038/modpathol.2017.22CrossRefPubMed

Akita M, Sofue K, Fujikura K, Otani K, Itoh T, Ajiki T, Fukumoto T, Zen Y (2019) Histological and molecular characterization of intrahepatic bile duct cancers suggests an expanded definition of perihilar cholangiocarcinoma. HPB (Oxford) 21:226–234. https://doi.org/10.1016/j.hpb.2018.07.021CrossRef

Andersen JB, Factor VM, Marquardt JU, Raggi C, Lee YH, Seo D, Conner EA, Thorgeirsson SS (2010) An integrated genomic and epigenomic approach predicts therapeutic response to zebularine in human liver cancer. Sci Transl Med 2:54ra77. https://doi.org/10.1126/scitranslmed.3001338CrossRefPubMedPubMedCentral

Bacher U, Haferlach C, Schnittger S, Kohlmann A, Kern W, Haferlach T (2010) Mutations of the TET2 and CBL genes: novel molecular markers in myeloid malignancies. Ann Hematol 89:643–652. https://doi.org/10.1007/s00277-010-0920-6CrossRefPubMed

Dong ZR, Zhang C, Cai JB, Zhang PF, Shi GM, Gao DM, Sun HC, Qiu SJ, Zhou J, Ke AW, Fan J (2015) Role of 5-hydroxymethylcytosine level in diagnosis and prognosis prediction of intrahepatic cholangiocarcinoma. Tumour Biol 36:2763–2771. https://doi.org/10.1007/s13277-014-2900-2CrossRefPubMed

Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, Tallman MS, Sun Z, Wolniak K, Peeters JK, Liu W, Choe SE, Fantin VR, Paietta E, Löwenberg B, Licht JD, Godley LA, Delwel R, Valk PJ, Thompson CB, Levine RL, Melnick A (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18:553–567. https://doi.org/10.1016/j.ccr.2010.11.015CrossRefPubMedPubMedCentral

Goeppert B, Toth R, Singer S, Albrecht T, Lipka DB, Lutsik P, Brocks D, Baehr M, Muecke O, Assenov Y, Gu L, Endris V, Stenzinger A, Mehrabi A, Schirmacher P, Plass C, Weichenhan D, Roessler S (2019) Integrative analysis defines distinct prognostic subgroups of intrahepatic cholangiocarcinoma. Hepatology 69:2091–2106. https://doi.org/10.1002/hep.30493CrossRefPubMed

Hayashi A, Misumi K, Shibahara J, Arita J, Sakamoto Y, Hasegawa K, Kokudo N, Fukayama M (2016) Distinct clinicopathologic and genetic features of 2 histologic subtypes of intrahepatic cholangiocarcinoma. Am J Surg Pathol 40:1021–1030. https://doi.org/10.1097/pas.0000000000000670CrossRefPubMed

Kim SJ, Akita M, Sung YN, Fujikura K, Lee JH, Hwang S, Yu E, Otani K, Hong SM, Zen Y (2018) MDM2 amplification in intrahepatic cholangiocarcinomas: its relationship with large-duct type morphology and uncommon KRAS mutations. Am J Surg Pathol 42:512–521. https://doi.org/10.1097/pas.0000000000001006CrossRefPubMed

10.

Kim YH, Pierscianek D, Mittelbronn M, Vital A, Mariani L, Hasselblatt M, Ohgaki H (2011) TET2 promoter methylation in low-grade diffuse gliomas lacking IDH1/2 mutations. J Clin Pathol 64:850–852. https://doi.org/10.1136/jclinpath-2011-200133CrossRefPubMed

11.

Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, Stevens-Linders E, van Hoogen P, van Kessel AG, Raymakers RA, Kamping EJ, Verhoef GE, Verburgh E, Hagemeijer A, Vandenberghe P, de Witte T, van der Reijden BA, Jansen JH (2009) Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet 41:838–842. https://doi.org/10.1038/ng.391CrossRefPubMed

12.

Li LC, Dahiya R (2002) MethPrimer: designing primers for methylation PCRs. Bioinformatics 18:1427–1431. https://doi.org/10.1093/bioinformatics/18.11.1427CrossRefPubMed

13.

Liau JY, Tsai JH, Yuan RH, Chang CN, Lee HJ, Jeng YM (2014) Morphological subclassification of intrahepatic cholangiocarcinoma: etiological, clinicopathological, and molecular features. Mod Pathol 27:1163–1173. https://doi.org/10.1038/modpathol.2013.241CrossRefPubMed

14.

Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR (2003) TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23). Leukemia 17:637–641. https://doi.org/10.1038/sj.leu.2402834CrossRefPubMed

15.

Lutsik P, Feuerbach L, Arand J, Lengauer T, Walter J, Bock C (2011) BiQ Analyzer HT: locus-specific analysis of DNA methylation by high-throughput bisulfite sequencing. Nucleic Acids Res 39:W551-556. https://doi.org/10.1093/nar/gkr312CrossRefPubMedPubMedCentral

16.

Ma B, Meng H, Tian Y, Wang Y, Song T, Zhang T, Wu Q, Cui Y, Li H, Zhang W, Li Q (2020) Distinct clinical and prognostic implication of IDH1/2 mutation and other most frequent mutations in large duct and small duct subtypes of intrahepatic cholangiocarcinoma. BMC Cancer 20:318. https://doi.org/10.1186/s12885-020-06804-6CrossRefPubMedPubMedCentral

17.

Moolmuang B, Singhirunnusorn P, Ruchirawat M (2016) Effects of 5-Aza-2’-deoxycytidine, bromodeoxyuridine, interferons and hydrogen peroxide on cellular senescence in cholangiocarcinoma cells. Asian Pac J Cancer Prev 17:957–963. https://doi.org/10.7314/apjcp.2016.17.3.957CrossRefPubMed

18.

Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, Hama N, Hosoda F, Urushidate T, Ohashi S, Hiraoka N, Ojima H, Shimada K, Okusaka T, Kosuge T, Miyagawa S, Shibata T (2015) Genomic spectra of biliary tract cancer. Nat Genet 47:1003–1010. https://doi.org/10.1038/ng.3375CrossRefPubMed

19.

Nakanuma Y, Klimstra D, Komuta M, Zen Y (2019) Intrahepatic cholangiocarcinomaWorld Health Organization classification of digestive system tumours. Lyon, International Agency for Research on Cancer, pp 254–259

20.

Nepal C, O’Rourke CJ, Oliveira D, Taranta A, Shema S, Gautam P, Calderaro J, Barbour A, Raggi C, Wennerberg K, Wang XW, Lautem A, Roberts LR, Andersen JB (2018) Genomic perturbations reveal distinct regulatory networks in intrahepatic cholangiocarcinoma. Hepatology 68:949–963. https://doi.org/10.1002/hep.29764CrossRefPubMed

21.

O’Rourke CJ, Lafuente-Barquero J, Andersen JB (2019) Epigenome remodeling in cholangiocarcinoma trends. Cancer 5:335–350. https://doi.org/10.1016/j.trecan.2019.05.002CrossRef

22.

O’Rourke CJ, Munoz-Garrido P, Aguayo EL, Andersen JB (2018) Epigenome dysregulation in cholangiocarcinoma. Biochim Biophys Acta Mol Basis Dis 1864:1423–1434. https://doi.org/10.1016/j.bbadis.2017.06.014CrossRefPubMed

23.

Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, Van Vlierberghe P, Dolgalev I, Thomas S, Aminova O, Huberman K, Cheng J, Viale A, Socci ND, Heguy A, Cherry A, Vance G, Higgins RR, Ketterling RP, Gallagher RE, Litzow M, van den Brink MR, Lazarus HM, Rowe JM, Luger S, Ferrando A, Paietta E, Tallman MS, Melnick A, Abdel-Wahab O, Levine RL (2012) Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 366:1079–1089. https://doi.org/10.1056/NEJMoa1112304CrossRefPubMedPubMedCentral

24.

Puig I, Tenbaum SP, Chicote I, Arqués O, Martínez-Quintanilla J, Cuesta-Borrás E, Ramírez L, Gonzalo P, Soto A, Aguilar S, Eguizabal C, Caratù G, Prat A, Argilés G, Landolfi S, Casanovas O, Serra V, Villanueva A, Arroyo AG, Terracciano L, Nuciforo P, Seoane J, Recio JA, Vivancos A, Dienstmann R, Tabernero J, Palmer HG (2018) TET2 controls chemoresistant slow-cycling cancer cell survival and tumor recurrence. J Clin Invest 128:3887–3905. https://doi.org/10.1172/jci96393CrossRefPubMedPubMedCentral

25.

Rasmussen KD, Helin K (2016) Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev 30:733–750. https://doi.org/10.1101/gad.276568.115CrossRefPubMedPubMedCentral

26.

Shu Y, Wang B, Wang J, Wang JM, Zou SQ (2011) Identification of methylation profile of HOX genes in extrahepatic cholangiocarcinoma. World J Gastroenterol 17:3407–3419. https://doi.org/10.3748/wjg.v17.i29.3407CrossRefPubMedPubMedCentral

27.

Turkalp Z, Karamchandani J, Das S (2014) IDH mutation in glioma: new insights and promises for the future. JAMA Neurol 71:1319–1325. https://doi.org/10.1001/jamaneurol.2014.1205CrossRefPubMed

28.

Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773. https://doi.org/10.1056/NEJMoa0808710CrossRefPubMedPubMedCentral

Title: Epigenetic upregulation of TET2 is an independent poor prognostic factor for intrahepatic cholangiocarcinoma
Authors: Hironori Yamashita
Aikaterini Tourna
Masayuki Akita
Tomoo Itoh
Shilpa Chokshi
Tetsuo Ajiki
Takumi Fukumoto
Neil A. Youngson
Yoh Zen
Publication date: 01-05-2022
Publisher: Springer Berlin Heidelberg
Keywords: Cholangiocarcinoma
Cholangiocarcinoma
Epigenetics
Published in: Virchows Archiv / Issue 5/2022
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-021-03251-x

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Epigenetic upregulation of TET2 is an independent poor prognostic factor for intrahepatic cholangiocarcinoma

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

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