Frequent amplifications and deletions of G₁/S-phase transition genes, CCND1 and MYC in early breast cancers: A potential role in G₁/S escape

Article type: Research Article

Authors: Jensen, L.B.^{a; b; c} | Bartlett, J.M.S.^a | Witton, C.J.^{b; d} | Kirkegaard, T.^{a; b; e} | Brown, S.^f | Müller, S.^b | Campbell, F.^a | Cooke, T.G.^c | Nielsen, K.V.^{b; *}

Affiliations: [a] Endocrine Cancer Group, Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK | [b] Dako A/S, Glostrup, Denmark | [c] Currently at University of Copenhagen, Faculty of Pharmaceutical Sciences, Copenhagen, Denmark | [d] Currently at LiPlasome Pharma A/S, Lyngby, Denmark | [e] Currently at Department of Tumour Endocrinology, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark | [f] Endocrine Cancer Group, University Department of Surgery, Glasgow Royal Infirmary, Glasgow, UK

Correspondence: [*] Corresponding author: Dr. Kirsten Vang Nielsen, Senior Principal Scientist, Department of Pathology, Dako A/S, DK-2600, Glostrup, Denmark. Tel.: +45 4485 9494; Fax: +45 4485 9500; E-mail: kirsten.vang@dako.com.

Abstract: Uncontrolled growth of cancer cells can be related to dysfunctional cell cycle control, including entry into S-phase, initiating cell division. Cyclin CCND3 and CCNE1 along with CDK2 and CDK6 regulate this checkpoint, and genetic changes, detectable by fluorescence in situ hybridization, are hypothesized to increase the aggressiveness of breast cancer, thereby influencing patient survival. Genomic change was investigated in 106 primary breast cancer samples, where the combined gene copy number changes in one of these four cell cycle regulatory factors was observed in 22% of the 98 tumors of successful analysis, distributed with 15 deletions and 7 amplifications. A trend towards decreased survival was observed with the aberrations, suggesting a prognostic potential of this set of markers, which was supported by an association with tumor grade. For validation of the new set of FISH probes for the G1/S-phase cell cycle factors, two additional markers, frequently amplified in breast cancers, were included in this study: The G1/S phase control gene CCND1 and the proliferation marker MYC. Both markers were amplified in 14% and deleted in 5% of the cases. This is the first report of genomic deletions of MYC in breast cancer.

Keywords: Amplification, breast cancer, CCND1, CCND3, CCNE1, CDK2, CDK6, deletion, fluorescence in situ hybridization, MYC

DOI: 10.3233/CBM-2009-0570

Journal: Cancer Biomarkers, vol. 5, no. 1, pp. 41-49, 2009