Mutually exclusive mutations of KIT and RAS are associated with KIT mRNA expression and chromosomal instability in primary intracranial pure germinomas
Intracranial germ cell tumors (iGCTs) are the second most common brain tumors among children under 15 in Japan. The pathogenesis of iGCTs is largely unexplored. Although a subset of iGCTs is known to have KIT mutation, its impact on the biology and patients’ survival has not been established. In thi...
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Veröffentlicht in: | Acta neuropathologica 2014-06, Vol.127 (6), p.911-925 |
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Zusammenfassung: | Intracranial germ cell tumors (iGCTs) are the second most common brain tumors among children under 15 in Japan. The pathogenesis of iGCTs is largely unexplored. Although a subset of iGCTs is known to have
KIT
mutation, its impact on the biology and patients’ survival has not been established. In this study, we investigated genes involved in the KIT signaling pathway. 65 iGCTs (30 pure germinomas, 14 teratomas, 18 mixed GCTs, 2 yolk sac tumors, 1 choriocarcinoma) were screened for mutation of
KIT
,
KRAS
,
NRAS
,
HRAS
,
BRAF
,
PDGFRA
, and
IDH1
by direct sequencing. KIT expression was examined by immunohistochemistry and quantitative PCR. Chromosomal status was analyzed by array-comparative genomic hybridization (aCGH). Somatic mutations were detected only in
KIT
and
RAS
, which were frequently observed in pure germinomas (60.0 %), but rare in non-germinomatous GCTs (NGGCTs) (8.6 %). All
KIT
/
RAS
mutations were mutually exclusive. Regardless of the mutation status or mRNA expression, the KIT protein was expressed in all germinomas, while only in 54.3 % of NGGCTs. Amplification of
KIT
was found in one pure germinoma by aCGH. In pure germinomas, high expression of
KIT
mRNA was associated with the presence of
KIT
/
RAS
alterations and severe chromosomal instability. Our results indicate that alterations of the KIT signaling pathway play an important role in the development of germinomas. Pure germinomas may develop through two distinct pathogeneses: one with
KIT
/
RAS
alterations, elevated
KIT
mRNA expression and severe chromosomal instability, and the other through yet an unidentified mechanism without any of the above abnormalities. |
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ISSN: | 0001-6322 1432-0533 |
DOI: | 10.1007/s00401-014-1247-5 |