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Acta Neuropathologica
Published in: Acta Neuropathologica 3/2017

01-03-2017 | Original Paper

Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas

Authors: Shintaro Fukushima, Satoshi Yamashita, Hisato Kobayashi, Hirokazu Takami, Kohei Fukuoka, Taishi Nakamura, Kai Yamasaki, Yuko Matsushita, Hiromi Nakamura, Yasushi Totoki, Mamoru Kato, Tomonari Suzuki, Kazuhiko Mishima, Takaaki Yanagisawa, Akitake Mukasa, Nobuhito Saito, Masayuki Kanamori, Toshihiro Kumabe, Teiji Tominaga, Motoo Nagane, Toshihiko Iuchi, Koji Yoshimoto, Masahiro Mizoguchi, Kaoru Tamura, Keiichi Sakai, Kazuhiko Sugiyama, Mitsutoshi Nakada, Kiyotaka Yokogami, Hideo Takeshima, Yonehiro Kanemura, Masahide Matsuda, Akira Matsumura, Kazuhiko Kurozumi, Keisuke Ueki, Masahiro Nonaka, Akio Asai, Nobutaka Kawahara, Yuichi Hirose, Tatusya Takayama, Yoichi Nakazato, Yoshitaka Narita, Tatsuhiro Shibata, Masao Matsutani, Toshikazu Ushijima, Ryo Nishikawa, Koichi Ichimura, On behalf of The Intracranial Germ Cell Tumor Genome Analysis Consortium (The iGCTConsortium)

Published in: Acta Neuropathologica | Issue 3/2017

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Abstract

Intracranial germ cell tumors (iGCTs) are the second most common brain tumors among children under 14 in Japan. The World Health Organization classification recognizes several subtypes of iGCTs, which are conventionally subclassified into pure germinoma or non-germinomatous GCTs. Recent exhaustive genomic studies showed that mutations of the genes involved in the MAPK and/or PI3K pathways are common in iGCTs; however, the mechanisms of how different subtypes develop, often as a mixed-GCT, are unknown. To elucidate the pathogenesis of iGCTs, we investigated 61 GCTs of various subtypes by genome-wide DNA methylation profiling. We showed that pure germinomas are characterized by global low DNA methylation, a unique epigenetic feature making them distinct from all other iGCTs subtypes. The patterns of methylation strongly resemble that of primordial germ cells (PGC) at the migration phase, possibly indicating the cell of origin for these tumors. Unlike PGC, however, hypomethylation extends to long interspersed nuclear element retrotransposons. Histologically and epigenetically distinct microdissected components of mixed-GCTs shared identical somatic mutations in the MAPK or PI3K pathways, indicating that they developed from a common ancestral cell.
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Literature
1.
Amatruda JF, Ross JA, Christensen B, Fustino NJ, Chen KS, Hooten AJ, Nelson H, Kuriger JK, Rakheja D, Frazier AL, Poynter JN (2013) DNA methylation analysis reveals distinct methylation signatures in pediatric germ cell tumors. BMC Cancer 13:313CrossRefPubMedPubMedCentral
2.
Brait M, Maldonado L, Begum S, Loyo M, Wehle D, Tavora FF, Looijenga LH, Kowalski J, Zhang Z, Rosenbaum E, Halachmi S, Netto GJ, Hoque MO (2012) DNA methylation profiles delineate epigenetic heterogeneity in seminoma and non-seminoma. Br J Cancer 106:414–423CrossRefPubMed
3.
Dolecek TA, Propp JM, Stroup NE, Kruchko C (2012) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol 14(Suppl 5):v1–v49CrossRefPubMedPubMedCentral
4.
Fukushima S, Otsuka A, Suzuki T, Yanagisawa T, Mishima K, Mukasa A, Saito N, Kumabe T, Kanamori M, Tominaga T, Narita Y, Shibui S, Kato M, Shibata T, Matsutani M, Nishikawa R, Ichimura K (2014) Mutually exclusive mutations of KIT and RAS are associated with KIT mRNA expression and chromosomal instability in primary intracranial pure germinomas. Acta Neuropathol 127:911–925CrossRefPubMed
5.
Gobel U, Schneider DT, Calaminus G, Haas RJ, Schmidt P, Harms D (2000) Germ-cell tumors in childhood and adolescence. GPOH MAKEI and the MAHO study groups. Ann Oncol 11:263–271CrossRefPubMed
6.
Guo H, Zhu P, Yan L, Li R, Hu B, Lian Y, Yan J, Ren X, Lin S, Li J, Jin X, Shi X, Liu P, Wang X, Wang W, Wei Y, Li X, Guo F, Wu X, Fan X, Yong J, Wen L, Xie SX, Tang F, Qiao J (2014) The DNA methylation landscape of human early embryos. Nature 511:606–610CrossRefPubMed
7.
Hovestadt V, Remke M, Kool M, Pietsch T, Northcott PA, Fischer R, Cavalli FM, Ramaswamy V, Zapatka M, Reifenberger G, Rutkowski S, Schick M, Bewerunge-Hudler M, Korshunov A, Lichter P, Taylor MD, Pfister SM, Jones DT (2013) Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathol 125:913–916CrossRefPubMedPubMedCentral
8.
Ichimura K, Fukushima S, Totoki Y, Matsushita Y, Otsuka A, Tomiyama A, Niwa T, Takami H, Nakamura T, Suzuki T, Fukuoka K, Yanagisawa T, Mishima K, Nakazato Y, Hosoda F, Narita Y, Shibui S, Yoshida A, Mukasa A, Saito N, Kumabe T, Kanamori M, Tominaga T, Kobayashi K, Shimizu S, Nagane M, Iuchi T, Mizoguchi M, Yoshimoto K, Tamura K, Maehara T, Sugiyama K, Nakada M, Sakai K, Kanemura Y, Nonaka M, Asai A, Yokogami K, Takeshima H, Kawahara N, Takayama T, Yao M, Kato M, Nakamura H, Hama N, Sakai R, Ushijima T, Matsutani M, Shibata T, Nishikawa R, Intracranial Germ Cell Tumor Genome Analysis C (2016) Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy. Acta Neuropathol 131:889–901CrossRefPubMed
9.
Igarashi S, Suzuki H, Niinuma T, Shimizu H, Nojima M, Iwaki H, Nobuoka T, Nishida T, Miyazaki Y, Takamaru H, Yamamoto E, Yamamoto H, Tokino T, Hasegawa T, Hirata K, Imai K, Toyota M, Shinomura Y (2010) A novel correlation between LINE-1 hypomethylation and the malignancy of gastrointestinal stromal tumors. Clin Cancer Res 16:5114–5123CrossRefPubMed
10.
Jennings MT, Gelman R, Hochberg F (1985) Intracranial germ-cell tumors: natural history and pathogenesis. J Neurosurg 63:155–167CrossRefPubMed
11.
Jeyapalan JN, Noor DA, Lee SH, Tan CL, Appleby VA, Kilday JP, Palmer RD, Schwalbe EC, Clifford SC, Walker DA, Murray MJ, Coleman N, Nicholson JC, Scotting PJ (2011) Methylator phenotype of malignant germ cell tumours in children identifies strong candidates for chemotherapy resistance. Br J Cancer 105:575–585CrossRefPubMedPubMedCentral
12.
Kim JG, Takeshima H, Niwa T, Rehnberg E, Shigematsu Y, Yoda Y, Yamashita S, Kushima R, Maekita T, Ichinose M, Katai H, Park WS, Hong YS, Park CH, Ushijima T (2013) Comprehensive DNA methylation and extensive mutation analyses reveal an association between the CpG island methylator phenotype and oncogenic mutations in gastric cancers. Cancer Lett 330:33–40CrossRefPubMed
13.
Kobayashi H, Sakurai T, Miura F, Imai M, Mochiduki K, Yanagisawa E, Sakashita A, Wakai T, Suzuki Y, Ito T, Matsui Y, Kono T (2013) High-resolution DNA methylome analysis of primordial germ cells identifies gender-specific reprogramming in mice. Genome Res 23:616–627CrossRefPubMedPubMedCentral
14.
Korshunov A, Ryzhova M, Hovestadt V, Bender S, Sturm D, Capper D, Meyer J, Schrimpf D, Kool M, Northcott PA, Zheludkova O, Milde T, Witt O, Kulozik AE, Reifenberger G, Jabado N, Perry A, Lichter P, von Deimling A, Pfister SM, Jones DT (2015) Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol 129:669–678CrossRefPubMed
15.
Lambert SR, Witt H, Hovestadt V, Zucknick M, Kool M, Pearson DM, Korshunov A, Ryzhova M, Ichimura K, Jabado N, Fontebasso AM, Lichter P, Pfister SM, Collins VP, Jones DT (2013) Differential expression and methylation of brain developmental genes define location-specific subsets of pilocytic astrocytoma. Acta Neuropathol 126:291–301CrossRefPubMed
16.
Lee SH, Appleby V, Jeyapalan JN, Palmer RD, Nicholson JC, Sottile V, Gao E, Coleman N, Scotting PJ (2011) Variable methylation of the imprinted gene, SNRPN, supports a relationship between intracranial germ cell tumours and neural stem cells. J Neurooncol 101:419–428CrossRefPubMed
17.
Looijenga LH, Van Agthoven T, Biermann K (2013) Development of malignant germ cells—the genvironmental hypothesis. Int J Dev Biol 57:241–253CrossRefPubMed
18.
Mack SC, Witt H, Piro RM, Gu L, Zuyderduyn S, Stutz AM, Wang X, Gallo M, Garzia L, Zayne K, Zhang X, Ramaswamy V, Jager N, Jones DT, Sill M, Pugh TJ, Ryzhova M, Wani KM, Shih DJ, Head R, Remke M, Bailey SD, Zichner T, Faria CC, Barszczyk M, Stark S, Seker-Cin H, Hutter S, Johann P, Bender S, Hovestadt V, Tzaridis T, Dubuc AM, Northcott PA, Peacock J, Bertrand KC, Agnihotri S, Cavalli FM, Clarke I, Nethery-Brokx K, Creasy CL, Verma SK, Koster J, Wu X, Yao Y, Milde T, Sin-Chan P, Zuccaro J, Lau L, Pereira S, Castelo-Branco P, Hirst M, Marra MA, Roberts SS, Fults D, Massimi L, Cho YJ, Van Meter T, Grajkowska W, Lach B, Kulozik AE, von Deimling A, Witt O, Scherer SW, Fan X, Muraszko KM, Kool M, Pomeroy SL, Gupta N, Phillips J, Huang A, Tabori U, Hawkins C, Malkin D, Kongkham PN, Weiss WA, Jabado N, Rutka JT, Bouffet E, Korbel JO, Lupien M, Aldape KD, Bader GD, Eils R, Lichter P, Dirks PB, Pfister SM, Korshunov A, Taylor MD (2014) Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506:445–450CrossRefPubMedPubMedCentral
19.
Matsutani M, Sano K, Takakura K, Fujimaki T, Nakamura O, Funata N, Seto T (1997) Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases. J Neurosurg 86:446–455CrossRefPubMed
20.
Naumov VA, Generozov EV, Zaharjevskaya NB, Matushkina DS, Larin AK, Chernyshov SV, Alekseev MV, Shelygin YA, Govorun VM (2013) Genome-scale analysis of DNA methylation in colorectal cancer using Infinium HumanMethylation450 BeadChips. Epigenetics 8:921–934CrossRefPubMedPubMedCentral
21.
Netto GJ, Nakai Y, Nakayama M, Jadallah S, Toubaji A, Nonomura N, Albadine R, Hicks JL, Epstein JI, Yegnasubramanian S, Nelson WG, De Marzo AM (2008) Global DNA hypomethylation in intratubular germ cell neoplasia and seminoma, but not in nonseminomatous male germ cell tumors. Mod Pathol 21:1337–1344CrossRefPubMedPubMedCentral
22.
Ohka F, Natsume A, Motomura K, Kishida Y, Kondo Y, Abe T, Nakasu Y, Namba H, Wakai K, Fukui T, Momota H, Iwami K, Kinjo S, Ito M, Fujii M, Wakabayashi T (2011) The global DNA methylation surrogate LINE-1 methylation is correlated with MGMT promoter methylation and is a better prognostic factor for glioma. PLoS One 6:e23332CrossRefPubMedPubMedCentral
23.
Oosterhuis JW, Stoop H, Honecker F, Looijenga LH (2007) Why human extragonadal germ cell tumours occur in the midline of the body: old concepts, new perspectives. Int J Androl 30:256–263 (discussion 263–254) CrossRefPubMed
24.
Pietsch T, Schmidt R, Remke M, Korshunov A, Hovestadt V, Jones DT, Felsberg J, Kaulich K, Goschzik T, Kool M, Northcott PA, von Hoff K, von Bueren AO, Friedrich C, Mynarek M, Skladny H, Fleischhack G, Taylor MD, Cremer F, Lichter P, Faldum A, Reifenberger G, Rutkowski S, Pfister SM (2014) Prognostic significance of clinical, histopathological, and molecular characteristics of medulloblastomas in the prospective HIT2000 multicenter clinical trial cohort. Acta Neuropathol 128:137–149CrossRefPubMedPubMedCentral
25.
Rajpert-De Meyts E (2006) Developmental model for the pathogenesis of testicular carcinoma in situ: genetic and environmental aspects. Hum Reprod Update 12:303–323CrossRefPubMed
26.
Rijlaarsdam MA, Tax DM, Gillis AJ, Dorssers LC, Koestler DC, de Ridder J, Looijenga LH (2015) Genome wide DNA methylation profiles provide clues to the origin and pathogenesis of germ cell tumors. PLoS One 10:e0122146CrossRefPubMedPubMedCentral
27.
Rodriguez J, Frigola J, Vendrell E, Risques RA, Fraga MF, Morales C, Moreno V, Esteller M, Capella G, Ribas M, Peinado MA (2006) Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers. Cancer Res 66:8462–9468CrossRefPubMed
28.
Rosenblum MK, Nakazato Y, Matsutani M (2007) CNS germ cell tumours. In: Louis DN (ed) WHO Classification of Tumours of the Central Nervous System, 4th edn. International Agency for Research on Cancer, Lyon, pp 197–204
29.
Saito T, Tanaka R, Kouno M, Washiyama K, Abe S, Kumanishi T (1989) Tumor-infiltrating lymphocytes and histocompatibility antigens in primary intracranial germinomas. J Neurosurg 70:81–85CrossRefPubMed
30.
31.
Sano K, Matsutani M, Seto T (1989) So-called intracranial germ cell tumours: personal experiences and a theory of their pathogenesis. Neurol Res 11:118–126CrossRefPubMed
32.
Smiraglia DJ, Szymanska J, Kraggerud SM, Lothe RA, Peltomaki P, Plass C (2002) Distinct epigenetic phenotypes in seminomatous and nonseminomatous testicular germ cell tumors. Oncogene 21:3909–3916CrossRefPubMed
33.
Smith ZD, Chan MM, Humm KC, Karnik R, Mekhoubad S, Regev A, Eggan K, Meissner A (2014) DNA methylation dynamics of the human preimplantation embryo. Nature 511:611–615CrossRefPubMedPubMedCentral
34.
Takeshima H, Niwa T, Takahashi T, Wakabayashi M, Yamashita S, Ando T, Inagawa Y, Taniguchi H, Katai H, Sugiyama T, Kiyono T, Ushijima T (2015) Frequent involvement of chromatin remodeler alterations in gastric field cancerization. Cancer Lett 357:328–338CrossRefPubMed
35.
Tan C, Scotting PJ (2012) Stem cell research points the way to the cell of origin for intracranial germ cell tumours. An alternative cell of origin for intracranial germ cell tumours. J Pathol 229:4–11CrossRefPubMed
36.
Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A, Ellison DW, Lichter P, Gilbertson RJ, Pomeroy SL, Kool M, Pfister SM (2012) Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123:465–472CrossRefPubMed
37.
Teilum G (1965) Classification of endodermal sinus tumour (mesoblatoma vitellinum) and so-called “embryonal carcinoma” of the ovary. Acta Pathol Microbiol Scand 64:407–429PubMed
38.
The committee of brain tumor registry of Japan (2009) Report of Brain Tumor Registry of Japan (1984–2000), 12th edn. Neurol Med Chir (Tokyo) 49(Suppl):1–101
39.
Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, Campos C, Fabius AW, Lu C, Ward PS, Thompson CB, Kaufman A, Guryanova O, Levine R, Heguy A, Viale A, Morris LG, Huse JT, Mellinghoff IK, Chan TA (2012) IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483:479–483CrossRefPubMedPubMedCentral
40.
van Meir EG, Oosterhuis JW, Looijenga LHJ (1998) Genesis and genetics of intracranial germ cell tumors. In: Sawamura Y (ed) Intracranial germ cell tumors, 1st edn. Springer, New York, pp 45–76CrossRef
41.
Wang L, Yamaguchi S, Burstein MD, Terashima K, Chang K, Ng HK, Nakamura H, He Z, Doddapaneni H, Lewis L, Wang M, Suzuki T, Nishikawa R, Natsume A, Terasaka S, Dauser R, Whitehead W, Adekunle A, Sun J, Qiao Y, Marth G, Muzny DM, Gibbs RA, Leal SM, Wheeler DA, Lau CC (2014) Novel somatic and germline mutations in intracranial germ cell tumours. Nature 511:241–245CrossRefPubMedPubMedCentral
42.
Wermann H, Stoop H, Gillis AJ, Honecker F, van Gurp RJ, Ammerpohl O, Richter J, Oosterhuis JW, Bokemeyer C, Looijenga LH (2010) Global DNA methylation in fetal human germ cells and germ cell tumours: association with differentiation and cisplatin resistance. J Pathol 221:433–442PubMed
43.
Yang AS, Estecio MR, Doshi K, Kondo Y, Tajara EH, Issa JP (2004) A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res 32:e38CrossRefPubMedPubMedCentral
44.
Yoshida T, Yamashita S, Takamura-Enya T, Niwa T, Ando T, Enomoto S, Maekita T, Nakazawa K, Tatematsu M, Ichinose M, Ushijima T (2011) Alu and Satalpha hypomethylation in Helicobacter pylori-infected gastric mucosae. Int J Cancer 128:33–39CrossRefPubMed
45.
Zong L, Hattori N, Yoda Y, Yamashita S, Takeshima H, Takahashi T, Maeda M, Katai H, Nanjo S, Ando T, Seto Y, Ushijima T (2016) Establishment of a DNA methylation marker to evaluate cancer cell fraction in gastric cancer. Gastric Cancer 19:361–369CrossRefPubMed
Metadata
Title
Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas
Authors
Shintaro Fukushima
Satoshi Yamashita
Hisato Kobayashi
Hirokazu Takami
Kohei Fukuoka
Taishi Nakamura
Kai Yamasaki
Yuko Matsushita
Hiromi Nakamura
Yasushi Totoki
Mamoru Kato
Tomonari Suzuki
Kazuhiko Mishima
Takaaki Yanagisawa
Akitake Mukasa
Nobuhito Saito
Masayuki Kanamori
Toshihiro Kumabe
Teiji Tominaga
Motoo Nagane
Toshihiko Iuchi
Koji Yoshimoto
Masahiro Mizoguchi
Kaoru Tamura
Keiichi Sakai
Kazuhiko Sugiyama
Mitsutoshi Nakada
Kiyotaka Yokogami
Hideo Takeshima
Yonehiro Kanemura
Masahide Matsuda
Akira Matsumura
Kazuhiko Kurozumi
Keisuke Ueki
Masahiro Nonaka
Akio Asai
Nobutaka Kawahara
Yuichi Hirose
Tatusya Takayama
Yoichi Nakazato
Yoshitaka Narita
Tatsuhiro Shibata
Masao Matsutani
Toshikazu Ushijima
Ryo Nishikawa
Koichi Ichimura
On behalf of The Intracranial Germ Cell Tumor Genome Analysis Consortium (The iGCTConsortium)
Publication date
01-03-2017
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 3/2017
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-017-1673-2

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