Role of gain of 12p in germ cell tumour development

Abstract

Within the human testis, three entities of germ cell tumours are distinguished: the teratomas and yolk sac tumors of newborn and infants, the seminomas and nonseminomas of adolescents and young adults, referred to as testicular germ cell tumours (TGCT), and the spermatocytic seminomas. Characteristic chromosomal anomalies have been reported for each group, supporting their distinct pathogenesis. TGCT are the most common cancer in young adult men. The initiating pathogenetic event of these tumours occurs during embryonal development, affecting a primordial germ cell or gonocyte. Despite this intra-uterine initiation, the tumour will only be clinically manifest after puberty, with carcinoma in situ (IS) as the precursor. All invasive TGCT, both seminomas and nonseminomas, as well as CIS cells are aneuploid. The only consistent (structural) chromosomal abnormalities in invasive TGCT are gains of the short arm of chromosome 12, mostly due to isochromosome (i(12p)) formation. This suggests that an increase in copy number of a gene(s) on 12p is associated with the development of a clinically manifest TGCT. Despite the numerous (positional) candidate gene approaches that have been undertaken thus far, identification of a causative gene(s) has been hampered by the fact that most 12p gains involve rather large genomic intervals, containing unmanageable numbers of candidate genes. Several years ago, we initiated a search for 12p candidate genes using TGCT with a restricted 12p-amplification, cytogenetically identified as 12p11.2-p12.1. This approach is mainly based on identification of candidate genes mapped within the shortest region of overlap of amplification (SROA). In this review, data will be presented, which support the model that gain of 12p-sequences is associated with suppression of apoptosis and Sertoli cell-independence of CIS cells. So far, DAD-R is one of the most likely candidate genes involved in this process, possibly via N-glycosylation. Preliminary results on high through-put DNA- and cDNA array analyses of 12p-sequences will be presented.

Mixed germ cell sex cord–stromal tumors of the testis and ovary. Morphological, immunohistochemical, and molecular genetic study of seven cases

“…Overrepresentation of l2p renders the tumor cells independent from the supporting Sertoli cells. Cells of intratubular germ cell neoplasia therefore lack overrepresentation of l2p [20]. The presence of gain in the short arm of chromosome 12 in our case 7 is in accordance with the well-documented ability of ovarian MGSCTs to produce invasive dysgerminoma and other neoplastic germ cell components [13,18,19,37].…”

Diagnostic markers for germ cell neoplasms: from placental-like alkaline phosphatase to micro-RNAs

“…The GCT genome is characterised by polyploidisation and the presence of genomic gain of the short arm of chromosome 12p, often in the form of an isochromosome, i(12p) and a relative excess of the X chromosome (reviewed in [1,3,17]. The presence of i(12p) is considered pathognomonic for the germ cell origin of a tumour and is useful in differential diagnosis [18,19].…”

Chromosome 12p abnormalities in dysgerminoma of the ovary: a FISH analysis

“…[2][3][4][5] The hallmark genetic marker of testicular germ cell tumor is the presence of an isochromosome of the short arm of chromosome 12 (i(12p)), first recognized using karyotypic analysis by Atkin and Baker 6,7 who described a small metacentric marker in a small series of seminomas and subsequently in nonseminomatous germ cell tumors. Very little is known about the genetic abnormalities of dysgerminoma.…”