Abstract
Cyclin D1 is frequently overexpressed in human neoplasias by gene rearrangement and amplification, but no mutations in the CCND1 gene have so far been reported. However, in vitro mutagenesis of CCND1 has shown that substitutions affecting threonine 286 residue produced cyclin D1 nuclear accumulation, by interfering with protein degradation and induced neoplastic transformation in murine fibroblasts. To test whether similar genetic changes may occur in vivo, we analysed a series of 60 endometrioid endometrial carcinomas (EECs) for cyclin D1 expression and gene amplification by immunohistochemistry and FISH, respectively. Two of 17 carcinomas showing cyclin D1 expression in more than 5% of neoplastic cells, but without gene amplification, were found to harbor single-base substitutions in CCND1 that changed proline 287 into threonine and serine, respectively. Both cases expressed cyclin D1 in more than 50% of neoplastic cells. Additionally, seven tumors with cyclin D1 overexpression of an independent series of 59 EECs were also analysed, and a 12-bp in-frame deletion that eliminated amino acids 289–292 was detected in one case with cylin D1 expression in more than 50% of neoplastic cells. In contrast, no mutations of the CCND1 gene were detected in a set of breast carcinomas with cyclin D1 overexpression without gene amplification. In summary, our data indicate that mutations of CCND1, which probably render the protein insensitive to degradation, represent a previously unreported mechanism of cyclin D1 overexpression in human tumors in vivo.
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Acknowledgements
We are grateful to Raúl Cassia and Alicia Barroso for excellent technical assistance. The study is supported in part by Grants FIS PI020355, FIS 01/1656 and SAF2001-0065. GM-B is the recipient of a postdoctoral research grant for de CNIO Spain. SR-P is a recipient of a research grant from the CNIO, Spain. DS is a recipient of a research grant from FIS (BEFI, 1/9132).
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Moreno-Bueno, G., Rodríguez-Perales, S., Sánchez-Estévez, C. et al. Cyclin D1 gene (CCND1) mutations in endometrial cancer. Oncogene 22, 6115–6118 (2003). https://doi.org/10.1038/sj.onc.1206868
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DOI: https://doi.org/10.1038/sj.onc.1206868
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