This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Roelofs, H. Articles by Looijenga, L. H. J. Search for Related Content PubMed PubMed Citation Articles by Roelofs, H. Articles by Looijenga, L. H. J.

(American Journal of Pathology. 2000;157:1155-1166.)
© 2000 American Society for Investigative Pathology

Regular Articles

Restricted 12p Amplification and RAS Mutation in Human Germ Cell Tumors of the Adult Testis

Helene Roelofs^*, Marijke C. Mostert^*, Kirsten Pompe^*, Gaetano Zafarana^*, Monique van Oorschot^*, Ruud J. H. L. M. van Gurp^*, Ad J. M. Gillis^*, Hans Stoop^*, Berna Beverloo, J. Wolter Oosterhuis^*, Carsten Bokemeyer and Leendert H. J. Looijenga^*

From the Pathology/Laboratory for Experimental Patho-Oncology,^*
University Hospital Rotterdam/Daniel, Josephine Nefkens Institute, Rotterdam, The Netherlands; the Department of Hematology and Oncology,
University of Tübingen, Tübingen, Germany; and the Department of Cell Biology and Genetics,
Erasmus University Rotterdam, Rotterdam, The Netherlands

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 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.

This article has been cited by other articles:

				E. RAJPERT-DE MEYTS and C. E. HOEI-HANSEN From Gonocytes to Testicular Cancer: The Role of Impaired Gonadal Development Ann. N.Y. Acad. Sci., December 1, 2007; 1120(1): 168 - 180. [Abstract] [Full Text] [PDF]

				L. H. J. LOOIJENGA, AD. J. M. GILLIS, H. J. STOOP, R. HERSMUS, and J. W. OOSTERHUIS Chromosomes and Expression in Human Testicular Germ-Cell Tumors: Insight into Their Cell of Origin and Pathogenesis Ann. N.Y. Acad. Sci., December 1, 2007; 1120(1): 187 - 214. [Abstract] [Full Text] [PDF]

				K. Biermann and K. Steger Epigenetics in Male Germ Cells J Androl, July 1, 2007; 28(4): 466 - 480. [Full Text] [PDF]

				E. Rajpert-De Meyts Developmental model for the pathogenesis of testicular carcinoma in situ: genetic and environmental aspects Hum. Reprod. Update, May 1, 2006; 12(3): 303 - 323. [Abstract] [Full Text] [PDF]

				J. Ishikawa, T. Taniguchi, H. Higashi, K. Miura, K. Suzuki, A. Takeshita, and M. Maekawa High Lactate Dehydrogenase Isoenzyme 1 in a Patient with Malignant Germ Cell Tumor Is Attributable to Aberrant Methylation of the LDHA Gene Clin. Chem., October 1, 2004; 50(10): 1826 - 1828. [Full Text] [PDF]

				F. Mayer, F. Honecker, L. H. J. Looijenga, and C. Bokemeyer Towards an understanding of the biological basis of response to cisplatin-based chemotherapy in germ-cell tumors Ann. Onc., June 1, 2003; 14(6): 825 - 832. [Abstract] [Full Text] [PDF]

				V. Bourdon, F. Naef, P. H. Rao, V. Reuter, S. C. Mok, G. J. Bosl, S. Koul, V. V. V. S. Murty, R. S. Kucherlapati, and R. S. K. Chaganti Genomic and Expression Analysis of the 12p11-p12 Amplicon Using EST Arrays Identifies Two Novel Amplified and Overexpressed Genes Cancer Res., November 1, 2002; 62(21): 6218 - 6223. [Abstract] [Full Text] [PDF]

				R. I. Skotheim, O. Monni, S. Mousses, S. D. Fossa, O.-P. Kallioniemi, R. A. Lothe, and A. Kallioniemi New Insights into Testicular Germ Cell Tumorigenesis from Gene Expression Profiling Cancer Res., April 1, 2002; 62(8): 2359 - 2364. [Abstract] [Full Text] [PDF]

				G. Zafarana, A. J. M. Gillis, R. J. H. L. M. van Gurp, P. G. Olsson, F. Elstrodt, H. Stoop, J. L. Millan, J. W. Oosterhuis, and L. H. J. Looijenga Coamplification of DAD-R, SOX5, and EKI1 in Human Testicular Seminomas, with Specific Overexpression of DAD-R, Correlates with Reduced Levels of Apoptosis and Earlier Clinical Manifestation Cancer Res., March 1, 2002; 62(6): 1822 - 1831. [Abstract] [Full Text] [PDF]