Abstract
Gains of 1q21-q23 have been associated with metastasis and chemotherapy response, particularly in bladder cancer, hepatocellular carcinomas and sarcomas. By positional cloning of amplified genes by yeast artificial chromosome-mediated cDNA capture using magnetic beads, we have identified three candidate genes (COAS1, -2 and -3) in the amplified region in sarcomas. COAS1 and -2 showed higher amplification levels than COAS3. Most notably, amplification was very common in osteosarcomas, where in particular COAS2 was highly expressed. COAS1 has multiple repeats and shows no homology to previously described genes, whereas COAS2 is a novel member of the cyclosporin-binding peptidyl-prolyl isomerase family, very similar to cyclophilin A. COAS2 was overexpressed almost exclusively in aggressive metastatic or chemotherapy resistant tumours. Although COAS2 was generally more amplified than COAS1, it was not expressed in well-differentiated liposarcomas, where amplification of this region is very common. All three genes were found to be amplified and over-expressed also in breast carcinomas. The complex nature of the 1q21-23 amplicons and close proximity of the genes make unequivocal determination of the gene responsible difficult. Quite likely, the different genes may give selective advantages to different subsets of tumours.
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Acknowledgements
We are grateful to J Høie and P Helgerud for supplying clinical samples and AE Stenwig and B Bjerkehagen for the histological classification of tumours. Additional recognition to The Sanger Center for providing PACs identified by sequence homology during this study, and to Phil Rye and TJ Meza for critical reading of the manuscript. This work was supported by The Norwegian Research Council, the Norwegian Cancer Society, The Nordic Cancer Union, the European Union (through the Biomedicine and Health grant BMH4-CT96-0319), the Cancer Research Campaign, UK (SP 2475/0101) (Nizetic, South), Leiras Research Foundation (Knuutila, Tarkkanen) and Associazione Italiana per la Ricerca sul Cancro (AIRC) and of the Istituti Ortopedici Rizzoli (Ricerca Corrente and Ricerca Finalizzata) (Serra). The Celera Human Genome Sequence was kindly made available by Celera (www.celera.com) (Venter et al. (2001) Science, 291, 1304–1351).
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COAS1, BG154169; COAS2, GI:4826471; COAS3, AF345651; KIAA1245, AB033071; Hypothetical gene spanning COAS1, AL117237.
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Meza-Zepeda, L., Forus, A., Lygren, B. et al. Positional cloning identifies a novel cyclophilin as a candidate amplified oncogene in 1q21. Oncogene 21, 2261–2269 (2002). https://doi.org/10.1038/sj.onc.1205339
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DOI: https://doi.org/10.1038/sj.onc.1205339
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