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Alternative splicing and mutation status of CHEK2 in stage III breast cancer

Oncogene volume 23, pages 8535–8544 (2004)Cite this article

Abstract

The DNA damage checkpoint kinase, CHK2, promotes growth arrest or apoptosis through phosphorylating targets such as Cdc25A, Cdc25C, BRCA1, and p53. Both germline and somatic loss-of-function CHEK2 mutations occur in human tumours, the former linked to the Li–Fraumeni syndrome, and the latter found in diverse types of sporadic malignancies. Here we examined the status of CHK2 by genetic and immunohistochemical analyses in 53 breast carcinomas previously characterized for TP53 status. We identified two CHEK2 mutants, 470T>C (Ile157Thr), and a novel mutation, 1368insA leading to a premature stop codon in exon 13. The truncated protein encoded by CHEK2 carrying the 1368insA was stable yet mislocalized to the cytoplasm in tumour sections and when ectopically expressed in cultured cells. Unexpectedly, we found CHEK2 to be subject to extensive alternative splicing, with some 90 splice variants detected in our tumour series. While all cancers expressed normal-length CHEK2 mRNA together with the spliced transcripts, we demonstrate and/or predict some of these splice variants to lack CHK2 function and/or localize aberrantly. We conclude that cytoplasmic sequestration may represent a novel mechanism to disable CHK2, and propose to further explore the significance of the complex splicing patterns of this tumour suppressor gene in oncogenesis.

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Acknowledgements

This work was supported by grants from the Norwegian Cancer Society, Nordic Cancer Union, Danish Cancer Society, and the European Union.

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Authors and Affiliations

  1. Department of Molecular Biology, University of Bergen, Bergen, Norway

    Vidar Staalesen & Johan Richard Lillehaug

  2. Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark

    Jacob Falck, Jirina Bartkova, Jiri Lukas & Jiri Bartek

  3. Section of Oncology, Institute of Medicine, Haukeland University Hospital, Bergen, Norway

    Stephanie Geisler & Per Eystein Lønning

  4. Department of genetics, The Norwegian Radiumhospital, Oslo, Norway

    Anne-Lise Børresen-Dale

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  1. Vidar Staalesen
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  2. Jacob Falck
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Correspondence to Per Eystein Lønning.

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Staalesen, V., Falck, J., Geisler, S. et al. Alternative splicing and mutation status of CHEK2 in stage III breast cancer. Oncogene 23, 8535–8544 (2004). https://doi.org/10.1038/sj.onc.1207928

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