TY - JOUR
T1 - Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas
AU - On behalf of The Intracranial Germ Cell Tumor Genome Analysis Consortium (The iGCTConsortium)
AU - Fukushima, Shintaro
AU - Yamashita, Satoshi
AU - Kobayashi, Hisato
AU - Takami, Hirokazu
AU - Fukuoka, Kohei
AU - Nakamura, Taishi
AU - Yamasaki, Kai
AU - Matsushita, Yuko
AU - Nakamura, Hiromi
AU - Totoki, Yasushi
AU - Kato, Mamoru
AU - Suzuki, Tomonari
AU - Mishima, Kazuhiko
AU - Yanagisawa, Takaaki
AU - Mukasa, Akitake
AU - Saito, Nobuhito
AU - Kanamori, Masayuki
AU - Kumabe, Toshihiro
AU - Tominaga, Teiji
AU - Nagane, Motoo
AU - Iuchi, Toshihiko
AU - Yoshimoto, Koji
AU - Mizoguchi, Masahiro
AU - Tamura, Kaoru
AU - Sakai, Keiichi
AU - Sugiyama, Kazuhiko
AU - Nakada, Mitsutoshi
AU - Yokogami, Kiyotaka
AU - Takeshima, Hideo
AU - Kanemura, Yonehiro
AU - Matsuda, Masahide
AU - Matsumura, Akira
AU - Kurozumi, Kazuhiko
AU - Ueki, Keisuke
AU - Nonaka, Masahiro
AU - Asai, Akio
AU - Kawahara, Nobutaka
AU - Hirose, Yuichi
AU - Takayama, Tatusya
AU - Nakazato, Yoichi
AU - Narita, Yoshitaka
AU - Shibata, Tatsuhiro
AU - Matsutani, Masao
AU - Ushijima, Toshikazu
AU - Nishikawa, Ryo
AU - Ichimura, Koichi
N1 - Publisher Copyright:
© 2017, Springer-Verlag Berlin Heidelberg.
PY - 2017/3/1
Y1 - 2017/3/1
N2 - 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.
AB - 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.
KW - Germinoma
KW - Global low DNA methylation
KW - LINE1 hypomethylation
KW - Primordial germ cell
KW - iGCT
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U2 - 10.1007/s00401-017-1673-2
DO - 10.1007/s00401-017-1673-2
M3 - Article
C2 - 28078450
AN - SCOPUS:85009253012
SN - 0001-6322
VL - 133
SP - 445
EP - 462
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 3
ER -