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Recurrent point mutations in the kinetochore gene KNSTRN in cutaneous squamous cell carcinoma

Nature Genetics 46, 1060–1062 (2014) | Download Citation

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Abstract

Here we report the discovery of recurrent mutations concentrated at an ultraviolet signature hotspot in KNSTRN, which encodes a kinetochore protein, in 19% of cutaneous squamous cell carcinomas (SCCs). Cancer-associated KNSTRN mutations, most notably those encoding p.Ser24Phe, disrupt chromatid cohesion in normal cells, occur in SCC precursors, correlate with increased aneuploidy in primary tumors and enhance tumorigenesis in vivo. These findings suggest a role for KNSTRN mutagenesis in SCC development.

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Acknowledgements

We thank J.G. Rheinwald (Dana-Farber/Harvard Cancer Center) for his generous gift of SCC cell lines. We thank A.E. Oro, H.Y. Chang, M. Diehn, M.P. Scott, S.E. Artandi, G.R. Crabtree and T. Waldman as well as A. Zehnder, X. Bao, B.K. Sun, R.J. Flockhart and V. Lopez-Pajares for presubmission review and helpful comments. This work was supported by the US Veterans Affairs Office of Research and Development and by US National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS) grant AR43799 to P.A.K. C.S.L. is the recipient of career award K08 AR064732 from the NIH/NIAMS. A.S. is supported by NIH/National Institute of General Medical Science (NIGMS) grant GM074728 and American Cancer Society grant 120161-RSG. W.L.J. is the recipient of National Science Foundation (NSF) graduate research fellowship grant DGE-114747.

Author information

Affiliations

  1. Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.

    • Carolyn S Lee
    • , Aparna Bhaduri
    • , Angela Mah
    • , Alexander Ungewickell
    • , Cody J Aros
    • , Christie B Nguyen
    • , Eon J Rios
    • , Zurab Siprashvili
    • , Jinah Kim
    • , Sumaira Z Aasi
    •  & Paul A Khavari

  2. Department of Biochemistry, Stanford University School of Medicine, Stanford, California, USA.

    • Whitney L Johnson
    •  & Aaron Straight

  3. Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA.

    • Paul A Khavari

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Contributions

C.S.L. designed and executed experiments, analyzed data and wrote the manuscript. A.M., A.B., C.J.A., C.B.N., W.L.J., E.J.R., A.U. and Z.S. helped execute experiments, analyzed data and contributed to the design of experimentation. A.S. helped design experiments and analyzed data. J.K. and S.Z.A. performed tumor tissue acquisition and analysis. P.A.K. designed experiments, analyzed data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Paul A Khavari.

Integrated supplementary information

Supplementary figures

  1. 1.

    Comparison of mutation frequency in TP53, CDKN2A and HRAS between data in the COSMIC database and this study.

  2. 2.

    Expression of kinastrin in human skin and SCCs.

  3. 3.

    Somatic KNSTRN p.Ser24Phe mutations in SCC.

  4. 4.

    KNSTRN mutations in SCC compared to other cancer types.

  5. 5.

    Enforced expression of kinastrin p.Ser24Phe is stable in normal cells.

  6. 6.

    Kinastrin p.Ser24Phe disrupts chromatid cohesion in SCC-13 cells.

  7. 7.

    Cancer-associated KNSTRN mutations disrupt chromatid cohesion in normal cells.

  8. 8.

    Kinastrin p.Ser28Phe enhances aneuploidy in normal cells.

  9. 9.

    Kinastrin p.Ser28Phe does not affect cell growth or cell cycle kinetics.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–9

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  1. 1.

    Supplementary Tables 1–7

    Supplementary Tables 1–7

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DOI

https://doi.org/10.1038/ng.3091

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