title: Prevalence of c-KIT mutations in gonadoblastoma and dysgerminomas of patients with disorders of sex development (DSD) and ovarian dysgerminomas.
abstract: Activating c-KIT mutations (exons 11 and 17) are found in 10-40% of testicular seminomas, the majority being missense point mutations (codon 816). Malignant ovarian dysgerminomas represent ~3% of all ovarian cancers in Western countries, resembling testicular seminomas, regarding chromosomal aberrations and c-KIT mutations. DSD patients with specific Y-sequences have an increased risk for Type II Germ Cell Tumor/Cancer, with gonadoblastoma as precursor progressing to dysgerminoma. Here we present analysis of c-KIT exon 8, 9, 11, 13 and 17, and PDGFRA exon 12, 14 and 18 by conventional sequencing together with mutational analysis of c-KIT codon 816 by a sensitive and specific LightCycler melting curve analysis, confirmed by sequencing. The results are combined with data on TSPY and OCT3/4 expression in a series of 16 DSD patients presenting with gonadoblastoma and dysgerminoma and 15 patients presenting pure ovarian dysgerminomas without DSD. c-KIT codon 816 mutations were detected in five out of the total of 31 cases (all found in pure ovarian dysgerminomas). A synonymous SNP (rs 5578615) was detected in two patients, one DSD patient (with bilateral disease) and one patient with dysgerminoma. Next to these, three codon N822K mutations were detected in the group of 15 pure ovarian dysgerminomas. In total activating c-KIT mutations were found in 53% of ovarian dysgerminomas without DSD. In the group of 16 DSD cases a N505I and D820E mutation was found in a single tumor of a patient with gonadoblastoma and dysgerminoma. No PDGFRA mutations were found. Positive OCT3/4 staining was present in all gonadoblastomas and dysgerminomas investigated, TSPY expression was only seen in the gonadoblastoma/dysgerminoma lesions of the 16 DSD patients. This data supports the existence of two distinct but parallel pathways in the development of dysgerminoma, in which mutational status of c-KIT might parallel the presence of TSPY.
authors.affiliation: Department of Pathology, Erasmus MC - University Medical Center Rotterdam, Josephine Nefkens Institute, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
authors.forename: Remko
authors.initials: R
authors.lastname: Hersmus
authors.forename: Hans
authors.initials: H
authors.lastname: Stoop
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: van de Geijn
authors.forename: Ronak
authors.initials: R
authors.lastname: Eini
authors.forename: Katharina
authors.initials: K
authors.lastname: Biermann
authors.forename: J Wolter
authors.initials: JW
authors.lastname: Oosterhuis
authors.forename: Catharina
authors.initials: C
authors.lastname: Dhooge
authors.forename: Dominik T
authors.initials: DT
authors.lastname: Schneider
authors.forename: Isabelle C
authors.initials: IC
authors.lastname: Meijssen
authors.forename: Winand N M
authors.initials: WN
authors.lastname: Dinjens
authors.forename: Hendrikus Jan
authors.initials: HJ
authors.lastname: Dubbink
authors.forename: Stenvert L S
authors.initials: SL
authors.lastname: Drop
authors.forename: Leendert H J
authors.initials: LH
authors.lastname: Looijenga
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D012734:Disorders of Sex Development / Q000150:complications / Q000235:genetics* / Q000473:pathology; D004407:Dysgerminoma / Q000150:complications / Q000235:genetics* / Q000473:pathology; D005260:Female; D018238:Gonadoblastoma / Q000150:complications / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D013736:Testicular Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D050814:Octamer Transcription Factor-3; C497749:TSPY1 protein, human; D019009:Proto-Oncogene Proteins c-kit