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KIT gene mutation and amplification in dysgerminoma of the ovary

2011-05-01 15:43:24

Cancer; 2011 May; 117(10):2096-103


Liang Cheng, Lawrence M. Roth, Shaobo Zhang, Mingsheng Wang, Michael J. Morton, Wenxin Zheng, Fadi W. Abdul Karim, Rodolfo Montironi, and Antonio Lopez-Beltran



Abstract



BACKGROUND:



Dysgerminoma, the ovarian counterpart of seminoma, is the most common type of malignant ovarian germ cell tumor. The role of KIT mutation and amplification in the development of dysgerminoma is not currently established. The purpose of this study was to analyze alterations of the KIT gene in a large series of dysgerminomas and correlate the findings with clinicopathological parameters.



METHODS:



Dysgerminoma cells from 22 patients were analyzed for KIT mutations at exon 17 codon 816. KIT amplification and chromosome 12p anomalies were investigated by way of dual color fluorescence in situ hybridization. KIT protein expression was also examined by way of immunohistochemistry.



RESULTS:



KIT exon 17 codon 816 mutations and KIT amplification were each detected in 6 cases of dysgerminoma (27%); however, there was no correlation between these 2 factors. KIT expression was detected in 87% of dysgerminomas. The KIT mutation was associated with advanced pathological stage (P < .05), and KIT amplification was associated with elevated KIT protein expression (P < .05). Chromosome 12p anomalies were found in 82% of the dysgerminomas and did not correlate with KIT abnormalities.



CONCLUSIONS:



KIT mutations occur in approximately one-third of cases of dysgerminomas and are associated with advanced stage at presentation. KIT is a potential therapeutic target for those dysgerminomas that have the mutation.



Introduction



KIT is a growth factor receptor important for normal germ cell migration and development. The KIT gene has been mapped to chromosome 4q12, which spans approximately 89 kb and consists of 21 exons. The gene encodes the human homolog of the protooncogene that was identified as the cellular homolog of the feline sarcoma viral oncogene v-kit. The KIT protein is a type 3 receptor tyrosine kinase containing 5 immunoglobulin-like loops (exons 1-9), a transmembrane domain (exon 10), a juxtamembrane domain (exon 11), and an intracellular domain (exons 13-21). The majority of KIT mutations are clustered in a relatively small region at exons 11 and 17, or less frequently, in KIT extracellular domain (exons 2, 8, and 9) or KIT TK1 (exons 13 and 14). Activating mutations typically confer constitutional KIT phosphorylation and downstream activation independent of ligand binding. The activated KIT further activates the Ras/MEK/MAPK pathway. The results of activation mutation of KIT include support of cell proliferation, sustained survival, differentiation, adhesion, and motility.



KIT mutations are frequently identified in testicular seminoma, having been reported in up to 30% of cases. In contrast to gastrointestinal stromal tumors, which frequently harbor KIT activating mutations in exon 11, the majority of these mutations affect codon 816, leading to substitution D816V/H/Y. Sakuma et al.15 analyzed the entire coding region of KIT DNA along with 4 mutational hot spots (exons 9, 11, 13, and 17) in 34 testicular germ cell tumors containing a seminoma component by PCR and direct sequencing and found KIT mutations in four pure seminomas. Mutation were found in exons 11 (W557R) and 17 (D816H and D816V) although there were no differences in any clinicopathological factors or outcome between patients with and without mutations.15 Willmore-Payne et al. found KIT-activating mutations in 22 testicular seminomas using high-resolution melting amplicon analysis. Four cases (18%) had exon 17-activating mutations, including D816Y, D816V, and Y823N, and 1 case contained both D816E and D820H. A single case (5%) had an exon 11-activating mutation (L576P).



Dysgerminoma is the most common type of malignant germ cell tumor of the ovary. It typically occurs in adolescents and young women and is bilateral in 10-15% of patients. Dysgerminoma is morphologically and immunophenotypically similar to testicular seminoma. Due to its rarity, only a few studies on KIT mutation in dysgerminoma have been reported. In the current study, we characterized KIT abnormalities by way of mutation, fluorescence in situ hybridization (FISH), and immunohistochemical analysis and correlated the findings with various clinicopathological parameters and other known genetic abnormalities frequently found in tumors of germ origin.



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