title: Restricted 12p amplification and RAS mutation in human germ cell tumors of the adult testis.
abstract: Human testicular germ-cell tumors of young adults (TGCTs), both seminomas and nonseminomas, are characterized by 12p overrepresentation, mostly as isochromosomes, of which the biological and clinical significance is still unclear. A limited number of TGCTs has been identified with an additional high-level amplification of a restricted region of 12p including the K-RAS proto-oncogene. Here we show that the incidence of these restricted 12p amplifications is approximately 8% in primary TGCTs. Within a single cell formation of i(12p) and restricted 12p amplification is mutually exclusive. The borders of the amplicons cluster in short regions, and the amplicon was never found in the adjacent carcinoma in situ cells. Seminomas with the restricted 12p amplification virtually lacked apoptosis and the tumor cells showed prolonged in vitro survival like seminoma cells with a mutated RAS gene. However, no differences in proliferation index between these different groups of seminomas were found. Although patients with a seminoma containing a homogeneous restricted 12p amplification presented at a significantly younger age than those lacking it, the presence of a restricted 12p amplification/RAS mutation did not predict the stage of the disease at clinical presentation and the treatment response of primary seminomas. In 55 primary and metastatic tumors from 44 different patients who failed cisplatinum-based chemotherapy, the restricted 12p amplification and RAS mutations had the same incidence as in the consecutive series of responding patients. These data support the model that gain of 12p in TGCTs is related to invasive growth. It allows tumor cells, in particular those showing characteristics of early germ cells (ie, the seminoma cells), to survive outside their specific microenvironment. Overexpression of certain genes on 12p probably inhibits apoptosis in these tumor cells. However, the copy numbers of the restricted amplification of 12p and K-RAS mutations do not predict response to therapy and survival of the patients.
authors.affiliation: Pathology/Laboratory for Experimental Patho-Oncology, University Hospital Rotterdam/Daniel, Josephine Nefkens Institute, Rotterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Roelofs
authors.forename: M C
authors.initials: MC
authors.lastname: Mostert
authors.forename: K
authors.initials: K
authors.lastname: Pompe
authors.forename: G
authors.initials: G
authors.lastname: Zafarana
authors.forename: M
authors.initials: M
authors.lastname: van Oorschot
authors.forename: R J
authors.initials: RJ
authors.lastname: van Gurp
authors.forename: A J
authors.initials: AJ
authors.lastname: Gillis
authors.forename: H
authors.initials: H
authors.lastname: Stoop
authors.forename: B
authors.initials: B
authors.lastname: Beverloo
authors.forename: J W
authors.initials: JW
authors.lastname: Oosterhuis
authors.forename: C
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: L H
authors.initials: LH
authors.lastname: Looijenga
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000235:genetics; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D005784:Gene Amplification; D011905:Genes, ras / Q000235:genetics*; D014644:Genetic Variation; D018237:Germinoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009367:Neoplasm Staging; D000090063:Proto-Oncogene Mas; D013736:Testicular Neoplasms / Q000235:genetics* / Q000473:pathology