SNOMEDCT: 1162858007, 74751003; ORPHA: 206484; DO: 3301;
An increased risk for gonadoblastoma in phenotypic females with dysgenetic gonads and the presence of Y-chromosomal material is well established (Verp and Simpson, 1987). Page (1987) postulated the existence of a gene (GBY) on the Y chromosome with an undefined physiologic function in normal males but with the ability to predispose dysgenetic gonads to develop malignancy when present in females. On the basis of 2 reported cases of females with dysgenetic gonads, deleted Y chromosomes, and gonadoblastoma, Page (1987) argued that the GBY gene is located either near the centromere or on the long arm of the Y chromosome and is distinct from the testis-determining factor. Petrovic et al. (1992) described a 12-year-old girl who was referred for chromosome analysis because of short stature and was found to have a mosaic karyotype 45,X/46,X,+mar. The marker chromosome was found in 58% of the blood lymphocytes. DNA analysis using Y-specific probes showed absence of the testis-determining region and the presence of some short arm and centromeric Y-chromosomal material. In situ hybridization confirmed that the Y-chromosomal material was associated with the marker chromosome. At laparotomy the patient was found to have streak gonads with a dysgerminoma arising from a gonadoblastoma in the left gonad. The case demonstrated that even very small Y-derived marker chromosomes with pericentric material can predispose the phenotypic female to gonadal neoplasia.
Tsuchiya et al. (1995) used sequence tagged sites to perform deletion mapping of the Y chromosome in sex-reversed female patients with a Y chromosome and gonadoblastoma. The GBY gene was sublocalized to a small region near the centromere. They estimated the size of the GBY critical region to be approximately 1-2 Mb. Their analysis indicated that copies of the 2 dispersed Y-linked gene families, TSPY (480100) and YRRM (Y-chromosome RNA recognition motif; 400006) were present in all patients. Copies of TSPY but not YRRM fall within the GBY critical region as formally defined by deletion mapping. Two tumor samples showed expression of both genes and in one patient this expression was limited to a unilateral gonadoblastoma but absent in the contralateral streak gonad. Although the results of Tsuchiya et al. (1995) did not directly implicate TSPY or YRRM in the etiology of the tumor, they raised the issue of whether there is one GBY gene in the critical region or possibly multiple GBY loci dispersed on the Y chromosome.
Salo et al. (1995) attempted to map GBY by making use of a dense map of Y-chromosome sequence tagged sites (STSs). In 2 female patients with gonadoblastoma, small marker chromosomes contained portions of the Y chromosome, and a single region of overlap could be defined extending from probe pDP97 in interval 4B, which contains the centromere, to marker sY182 in interval 5E of the proximal long arm. This interval is contained in a YAC contig that comprises approximately 4 Mb of DNA. Their result confirmed the previous localization of GBY and greatly refined it. The localization overlaps with the region to which GCY (475000), a putative growth determinant, had been assigned.
By PCR, Gravholt et al. (2000) examined 114 females with Turner syndrome for the presence of Y-chromosomal material and found 14 who had Y-chromosomal material. The karyotype in 7 of these patients did not suggest the presence of Y-chromosomal material. Seven of the patients had been ovariectomized before entering the study due to verified Y-chromosomal material, whereas 3 patients were operated upon after the DNA analysis. The histopathologic evaluations showed that 1 of the 10 ovariectomized patients actually had a gonadoblastoma. The authors concluded that the frequency of Y-chromosomal material is high in Turner syndrome (12.2%), but the occurrence of gonadoblastoma among Y-positive patients seems to be low (7-10%), and the risk may have been overestimated in previous studies, perhaps due to problems with selection bias.
Gravholt, C. H., Fedder, J., Naeraa, R. W., Muller, J. Occurrence of gonadoblastoma in females with Turner syndrome and Y chromosome material: a population study. J. Clin. Endocr. Metab. 85: 3199-3202, 2000. [PubMed: 10999808] [Full Text: https://doi.org/10.1210/jcem.85.9.6800]
Page, D. C. Hypothesis: a Y-chromosomal gene causes gonadoblastoma in dysgenetic gonads. Development 101 (suppl.): 151-155, 1987. [PubMed: 3503713] [Full Text: https://doi.org/10.1242/dev.101.Supplement.151]
Petrovic, V., Nasioulas, S., Chow, C. W., Voullaire, L., Schmidt, M., Dahl, H. Minute Y chromosome derived marker in a child with gonadoblastoma: cytogenetic and DNA studies. J. Med. Genet. 29: 542-546, 1992. [PubMed: 1518023] [Full Text: https://doi.org/10.1136/jmg.29.8.542]
Salo, P., Kaariainen, H., Petrovic, V., Peltomaki, P., Page, D. C., de la Chapelle, A. Molecular mapping of the putative gonadoblastoma locus on the Y chromosome. Genes Chromosomes Cancer 14: 210-214, 1995. [PubMed: 8589038] [Full Text: https://doi.org/10.1002/gcc.2870140309]
Tsuchiya, K., Reijo, R., Page, D. C., Disteche, C. M. Gonadoblastoma: molecular definition of the susceptibility region on the Y chromosome. Am. J. Hum. Genet. 57: 1400-1407, 1995. [PubMed: 8533770]
Verp, M. S., Simpson, J. L. Abnormal sexual differentiation and neoplasia. Cancer Genet. Cytogenet. 25: 191-218, 1987. [PubMed: 3548944] [Full Text: https://doi.org/10.1016/0165-4608(87)90180-4]