c‐kit gene mutations in intracranial germinomas

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. he c-kit proto-oncogene encodes a receptor tyrosine kinase (KIT) that is a member of the same subfamily as the receptors for platelet-derived growth factor and colony-stimulating factor-1. KIT consists of an extracellular domain with five immunoglobulin-like repeats, a transmembrane domain, a juxtamembrane domain, and tyrosine kinase (TK) I and II domains split by a kinase insert. The ligand for KIT is stem cell factor (SCF). The SCF-KIT system is critical for the normal development and survival of melanocytes, erythrocytes, germ cells, mast cells, and interstitial cells of Cajal (ICCs).1-3) On the other hand, gain-of-function mutations of the c-kit gene and the expression of phosphorylated KIT have been reported in tumors arising from these cell lineages, such as mast cell tumors, 4,5) gastrointestinal stromal tumors (GISTs), [6][7][8][9][10][11][12][13] which are thought to originate from ICCs in the gastrointestinal tract, and germ cell tumors (GCTs).14-18) Four mutational hot spots in different regions of the c-kit gene have been identified: in exons 9, 11, 13, and 17. More recently, an additional activating c-kit gene mutation has been detected at exon 10 encoding the transmembrane domain. 19) Imatinib mesylate (STI571; Gleevec; Novartis Pharma, Basel, Switzerland) is a selective inhibitor of certain tyrosine kinases including KIT, and has proven very effective in the treatment of patients with advanced GISTs, which are resistant to conventional chemotherapy, especially those harboring c-kit mutations at exon 11. 20) However, mutant KIT with Asp816Val at exon 17, which is the most common type of c-kit mutation in adult mastocytosis, is resistant to ...

Detection of c-kit exons 11- and 17-activating mutations in testicular seminomas by high-resolution melting amplicon analysis

“…[10][11][12][13][14][15] To investigate this discrepancy and to further characterize the types of c-kit mutations in semi- c-kit mutations in seminoma C Willmore-Payne et al nomas, we used a new methodology referred to as high-resolution melting amplicon analysis, to screen 22 pure testicular seminomas for c-kit-activating mutations. After PCR amplification of genomic DNA from a tumor with a c-kit-activating mutation, a mixture of DNA molecules is obtained.…”

“…10,11 Most reports describe point mutations in exon 17, but occasional exon 11 mutations have also been noted. [12][13][14][15] The frequency of these mutations in seminomas has been reported to range up to 41%. 14 The majority of the exon 17 mutations reported (D816V) code for a c-kit protein that is probably imatinib resistant.…”

Elucidating human male germ cell development by studying germ cell cancer

“…Therefore, it is conceivable that auto-activating mutations of the cKIT gene (exon 17: D816V, D816H, N822K, Y823D; exon 11: L576P, W557C), rendering cKIT expression independent of SCF, might cause erroneous migration of PGCs, eventually leading to formation of intracranial germinomas (Przygodzki et al 2002, Kemmer et al 2004, WillmorePayne et al 2006, Biermann et al 2007). Sakuma and coworkers and Kamakura and coworkers demonstrated cKIT expression in all germinomas or germinomatous components of mixed non-germinomas (Sakuma et al 2004, Kamakura et al 2006. Additionally, Sakuma and coworkers found that 25% of all germinomas analyzed harbored an autoactivating cKIT mutation at exon 11 or 17, while Kamakura and co-workers detected mutated cKIT in 23% of germinomas (exon 2 (E73K, T96M), 11 (V560D), 13 (A636V), 17 (D816Y)) (Sakuma et al 2004, Kamakura et al 2006).…”

“…Sakuma and coworkers and Kamakura and coworkers demonstrated cKIT expression in all germinomas or germinomatous components of mixed non-germinomas (Sakuma et al 2004, Kamakura et al 2006. Additionally, Sakuma and coworkers found that 25% of all germinomas analyzed harbored an autoactivating cKIT mutation at exon 11 or 17, while Kamakura and co-workers detected mutated cKIT in 23% of germinomas (exon 2 (E73K, T96M), 11 (V560D), 13 (A636V), 17 (D816Y)) (Sakuma et al 2004, Kamakura et al 2006). These mutation rates are very similar to the cKIT mutation rates found in classical seminoma (24.1%) (Sakuma et al 2003, Kemmer et al 2004.…”

Pineal region tumors: a simplified management scheme

“…The importance of these findings is that molecular targeting agents, such as imatinib, which is an inhibitor of specific tyrosine kinases, including KIT, can be used in the management of GGCTs that harbor KIT mutations. These alternative management options can help avoid long-term adverse effects associated with radiotherapy which include neurocognitive impairment, secondary neoplasms, radiation-induced occlusive vasculopathy, and endocrinological dysfunctions [29,30]. The relationship between KIT mutations and the prognosis of GGCTs is controversial [31].…”