Alterations of the c‐kit gene in testicular germ cell tumors

Abstract

Expression and gain-of-function mutation of the c-kit gene, that encodes a receptor tyrosine kinase (KIT), have been reported in mast cell tumors and gastrointestinal stromal tumors (GISTs). Among human testicular germ cell tumors (GCTs), seminomas and seminoma components of mixed GCTs have also been shown to express KIT, but only one study has found the c-kit gene mutation at exon 17 in seminoma. To elucidate the frequency and location of the c-kit gene mutation of testicular GCTs, we analyzed the whole coding region of the c-kit complementary DNA along with 4 mutational hot spots (exons 9, 11, 13 and 17) of the c-kit genomic DNA by polymerase chain reaction and direct sequencing. Somatic mutations were found in 4 pure seminomas of 34 testicular GCTs (11.8%). One mutation was found in exon 11 (W557R) and the others were observed in exon 17 (D816H and D816V). These types of mutations were reported in GISTs (W557R), seminoma (D816H) and mastocytosis (D816V) and were considered to be gain-of-function mutations, although there were no differences of any clinicopathological factors or outcome between patients with and without mutations. Additionally, we also demonstrated coexpression of Gly-Asn-Asn-Lys 510-513

c‐kit gene mutations in intracranial germinomas

“…This result is similar to that in the case of testicular seminomas. 16,22,23) Moreover, we revealed the presence of c-kit gene mutations in 4 of the 16 (25.0%) intracranial germinomas. This frequency is higher than that of testicular GCTs (4 of 34, 11.8%) in our previous report, 16) but almost equal to that reported by Kemmer et al, 18) who found activating point mutations at exon 17 in 24.1% (13 of 54) of the pure testicular seminomas studied.…”

“…The amplified fragments were purified using a GFX PCR DNA and Gel Band Purification Kit (Amersham Biosciences, Piscataway, NJ) and direct sequencing was performed as described previously. 16) Statistical analysis. Values are shown as the mean±SD.…”

“…14-18) To date, c-kit gene mutations have been reported in testicular seminomas, 14,[16][17][18] an ovarian dysgerminoma, 14) and mediastinal seminomas. 15) However, only one report describes KIT expression in intracranial germinomas 24) and it is still unknown whether c-kit gene mutations are also present in intracranial germinomas.…”

“…[1][2][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][15][16][17][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.…”

“…The most common type of mutation is an isolated point mutation at the TK II domain (exon 17), whereas we also found a point mutation at the juxtamembrane domain (exon 11). [14][15][16][17][18] To date, c-kit gene mutations have been reported in testicular seminomas, 14,[16][17][18] an ovarian dysgerminoma, 14) and mediastinal seminomas. 15) However, only one report describes KIT expression in intracranial germinomas 24) and it is still unknown whether c-kit gene mutations are also present in intracranial germinomas.…”