c-kit gene mutations in intracranial germinomas
Yuji Sakuma1, Shinji Sakurai, Sachiko Oguni
1Department of Pathology, Jichi Medical School, Minamikawachi-machi, Kawachi-gun, Tochigi 329-0498, Japan.
Abstract:
Gain-of-function mutations of the c-kit gene and the expression of phosphorylated KIT are found in most gastrointestinal stromal tumors and mastocytosis. Further, almost all gonadal seminomas/dysgerminomas exhibit KIT membranous staining, and several reports have clarified that some (10-25%) have a c-kit gene mutation. But, whether intracranial germinomas also have a c-kit gene mutation remains unsolved. To elucidate the presence, frequency, and location of c-kit gene mutations in intracranial germinomas, we analyzed five mutational hot spots (exons 9, 10, 11, 13, and 17) in the c-kit genomic DNA of 16 germinomas using polymerase chain reaction and direct sequencing. We found c-kit gene mutations at exon 11 (W557C) or 17 (D816V, D820V, and N822Y) in four germinomas (25.0%), although no statistically significant difference in any clinicopathological factor was found between patients with or without mutations. These results are similar to those seen in gonadal seminoma/dysgerminoma patients, and confirm that intracranial germinomas are exact counterparts of gonadal seminomas/dysgerminomas, as would be expected on histological and immunohistochemical grounds. Moreover, molecular targeting drugs such as imatinib mesylate (STI571), which is a selective inhibitor of KIT, might be promising agents for the treatment of intracranial germinomas with c-kit gene mutations.
Insights
Intracranial germinomas, rare brain tumors, harbor c-kit gene mutations in 25% of cases, similar to gonadal germ cell tumors. These findings suggest potential therapeutic strategies targeting KIT mutations.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gain-of-function mutations in the c-kit gene are prevalent in gastrointestinal stromal tumors and mastocytosis.
- KIT mutations are identified in a subset of gonadal germinomas, but their presence in intracranial germinomas is unknown.
Purpose of the Study:
- To investigate the occurrence, frequency, and specific locations of c-kit gene mutations within intracranial germinomas.
Main Methods:
- Analysis of five c-kit gene mutational hotspots (exons 9, 10, 11, 13, and 17) in genomic DNA from 16 intracranial germinomas.
- Utilized polymerase chain reaction and direct sequencing techniques.
Main Results:
- c-kit gene mutations were detected in four (25.0%) intracranial germinomas, specifically at exon 11 (W557C) or exon 17 (D816V, D820V, N822Y).
- No significant correlation was observed between c-kit mutations and clinicopathological factors.
- The mutation profile in intracranial germinomas mirrors that of gonadal germinomas.
Conclusions:
- Intracranial germinomas share molecular similarities with gonadal germinomas, supporting their classification as counterparts.
- The presence of c-kit mutations suggests that molecularly targeted therapies, such as imatinib mesylate, may offer a promising treatment avenue for intracranial germinomas harboring these mutations.
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