title: 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.
authors.affiliation: Pathology/Lab. for Exp. Patho-Oncology, Erasmus MC/Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
authors.forename: Leendert H J
authors.initials: LH
authors.lastname: Looijenga
authors.forename: Gaetano
authors.initials: G
authors.lastname: Zafarana
authors.forename: Beata
authors.initials: B
authors.lastname: Grygalewicz
authors.forename: Brenda
authors.initials: B
authors.lastname: Summersgill
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.forename: Joris
authors.initials: J
authors.lastname: Veltman
authors.forename: Eric F P M
authors.initials: EF
authors.lastname: Schoenmakers
authors.forename: Sandrine
authors.initials: S
authors.lastname: Rodriguez
authors.forename: Osman
authors.initials: O
authors.lastname: Jafer
authors.forename: Jeremy
authors.initials: J
authors.lastname: Clark
authors.forename: Ad Geurts
authors.initials: AG
authors.lastname: van Kessel
authors.forename: Janet
authors.initials: J
authors.lastname: Shipley
authors.forename: Ruud J H L M
authors.initials: RJ
authors.lastname: van Gurp
authors.forename: Ad J M
authors.initials: AJ
authors.lastname: Gillis
authors.forename: J Wolter
authors.initials: JW
authors.lastname: Oosterhuis
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D002278:Carcinoma in Situ / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D015536:Down-Regulation; D020869:Gene Expression Profiling; D018237:Germinoma / Q000235:genetics*; D006031:Glycosylation; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011544:Pseudogenes; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D018239:Seminoma / Q000235:genetics; D012708:Sertoli Cells; D013736:Testicular Neoplasms / Q000196:embryology / Q000235:genetics*
chemical_list: C409423:DAD1P1 protein, human; D012097:Repressor Proteins