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Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human

Nature Genetics volume 34, pages 403–412 (2003)Cite this article

Abstract

Linkage analysis and haplotype mapping in interspecific mouse crosses (Mus musculus × Mus spretus) identified the gene encoding Aurora2 (Stk6 in mouse and STK15 in human) as a candidate skin tumor susceptibility gene. The Stk6 allele inherited from the susceptible M. musculus parent was overexpressed in normal cells and preferentially amplified in tumor cells from F1 hybrid mice. We identified a common genetic variant in STK15 (resulting in the amino acid substitution F31I) that is preferentially amplified and associated with the degree of aneuploidy in human colon tumors. The Ile31 variant transforms rat1 cells more potently than the more common Phe31 variant. The E2 ubiquitin-conjugating enzyme UBE2N was a preferential binding partner of the 'weak' STK15 Phe31 variant form in yeast two-hybrid screens and in human cells. This interaction results in colocalization of UBE2N with STK15 at the centrosomes during mitosis. These results are consistent with an important role for the Ile31 variant of STK15 in human cancer susceptibility.

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Figure 1: lod score plots for Skts13 on distal mouse chromosome 2.
Figure 2: Mouse and human physical maps surrounding Stk6/STK15.
Figure 3: Allelic expression of Stk6.
Figure 4: Colon tumor amplification of STK15 alleles.
Figure 5: CGH array analysis of colon cancer and STK15 genotype.
Figure 6: Effect of STK15 Phe31 and Ile31 on cell growth and tumorigenicity.
Figure 7: In vitro and in vivo interaction between STK15 and UBE2N.

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Acknowledgements

We thank C. Collins and S. Volik for sharing unpublished data on mouse chromosome 2, D. Albertson and D. Pinkel for assistance with array CGH analysis, D. Albertson for help in interpretation of CGH arrays, R. del Rosario and R. Contreras for assistance with animal husbandry, the UCSF Cancer Center Genome Core for the sequencing and study design of allelic discrimination and A.H. Trainer for ascertainment of the paired colon samples for this study. S.L. thanks A. Ashworth, P. Workman and colleagues in the laboratory for discussions and support, M. Lelekakis for help in animal studies and D. Robertson for assistance with confocal microscopy. The UCSF School of Medicine Research Evaluation and Allocation Committee Fund, a US National Cancer Institute Mouse Models of Human Cancer Consortium Grant, the Stewart Trust, the UCSF Prostate Spore and a UCSF Prostate Cancer Center Award supported this work. J.P.d.K. was supported by a research fellowship through the Dutch Cancer Society. A.E.-T. was supported by a US National Institutes of Health training grant. B.A.J.P. is a Gibb Fellow of the Cancer Research UK. Studies carried out in S.L.'s laboratory were funded by the Breakthrough Breast Cancer Fund.

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Author notes

  1. John P de Koning

    Present address: Department of Physiological Chemistry, University Medical Center Utrecht, P.O. Box 85060, 3508 AB, Utrecht, The Netherlands

  2. Sarah Ball

    Present address: University Hospitals of Leicester NHS Trust, Leicester Royal Infirmatory, Leicester, LE1 5WW, UK

  3. Amanda Ewart-Toland, Paraskevi Briassouli and John P de Koning: These authors contributed equally to this work.

Authors and Affiliations

  1. UCSF Comprehensive Cancer Center, University of California, San Francisco, 94115, California, USA

    Amanda Ewart-Toland, John P de Koning, Jian-Hua Mao, Jinwei Yuan & Allan Balmain

  2. The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK

    Paraskevi Briassouli, Lucy MacCarthy-Morrogh & Spiros Linardopoulos

  3. Cancer Research UK, Centre for Cancer Therapeutics, The Institute of Cancer Research Haddow's Laboratories, 15 Cotswold Road, Sutton, SM2 5NG, UK

    Florence Chan & Spiros Linardopoulos

  4. University Department of Oncology, Cancer Research UK, Human Cancer Genetics Group, Strangeways Research Laboratories, Worts Causeway, Cambridge, CB1 8RN, UK

    Bruce A J Ponder

  5. Roswell Park Cancer Center, Buffalo, New York, USA

    Hiroki Nagase

  6. Institute of Human Genetics, Newcastle Upon Tyne, NE1 3B2, UK

    John Burn, Sarah Ball & Maria Almeida

  7. Department of Biochemistry and Biophysics, University of California, San Francisco, 94143, California, USA

    Allan Balmain

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Correspondence to Spiros Linardopoulos or Allan Balmain.

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Ewart-Toland, A., Briassouli, P., de Koning, J. et al. Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human. Nat Genet 34, 403–412 (2003). https://doi.org/10.1038/ng1220

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