Germ cell tumours (GCT) are thought to arise as the result of a defect in early development, probably shortly after arrival of the migrating primordial germ cells (PGC) in the genital ridge when, if in a male genital ridge, the germ cells arrest in mitosis, but in a female genital ridge they enter meiosis. We suggest that dysfunction of the mitotic:meiotic switch, with cells aberrantly co-expressing functions pertinent to both states, might provide the genetic instability that could initiate tumour development. If this hypothesis is correct, GCT could arise because of disruption in the function of any one of a number of different genes involved in controlling mitosis and meiosis, rather than being dependent upon a single prominent susceptibility gene. The Notch signalling system is one candidate system for controlling the switch and we have identified expression of Notch2 and Notch4 in seminomas and carcinoma in situ. Thus those two members of the Notch family are candidates for proto-oncogenes that could play a role in GCT development. We have also identified a human homologue of the synaptonemal complex protein, SCP3, and have found its apparently aberrant expression in some established EC cell lines. One possibility is that abnormal regulation of such proteins involved in the synaptonemal complex could also lead to genetic instability in PGC and so also initiate tumour development.

CAG/CTG repeat expansions in genomic DNA of testicular tumour cell lines, and germline DNA from members of families predisposed to this malignancy, have been previously described. In order to identify genes possibly concerned by this alteration, we attempted to clone all possible human testis cDNA containing at least ®ve CAG/CTG repeats. Thirty-four di erent transcripts were identi®ed. By using PCR and non denaturing gel electrophoresis, we determined the size of their repeats, as well as their polymorphisms in a collection of human testicular germ cell tumours and the normal surrounding tissues. For all tested genes, we detected the presence of several species of the same mRNA for each person. Nine genes exhibited speci®c patterns of expression among di erent groups of individuals, indicative of polymorphism. None of these polymorphisms was related to human testicular tumours. Oncogene (2001) 20, 5548 ± 5553.