Restricted 12p amplification and RAS mutation in human germ cell tumors ofthe adult testis

Human testicular germ-cell tumors of young adults (TGCTs), both seminomas a nd nonseminomas, are characterized by 12p overrepresentation, mostly as iso chromosomes, of which the biological and clinical significance is still unc lear. A limited number of TGCTs has been identified with an additional high -level amplification of a restricted region of 12p including the K-RAS prot o-oncogene. Here we show that the incidence of these restricted 12p amplifi cations is similar to 8% in primary TGCTs, Within a single cell formation o f i(12p) and restricted 12p amplification is mutually exclusive. The border s of the amplicons cluster in short regions, and the amplicon was never fou nd in the adjacent carcinoma in situ cells. Seminomas with the restricted 1 2p amplification virtually lacked apoptosis and the tumor cells showed prol onged in vitro survival like seminoma cells with a mutated RAS gene. Howeve r, no differences in proliferation index between these different groups of seminomas were found. Although patients with a seminoma containing a homoge neous 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 metastat ic tumors from 44 different patients who failed cisplatinum-based chemother apy, the restricted 12p amplification and RAS mutations had the same incide nce 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 allo ws tumor cells, in particular those showing characteristics of early germ c ells tie, the seminoma cells), to survive outside their specific microenvir onment, Overexpression of certain genes on 12p probably inhibits apoptosis in these tumor cells. However, the copy numbers of the restricted amplifica tion of 12p and K-RAS mutations do not predict response to therapy and surv ival of the patients.