Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Oncogenomics
  • Published:

Convergence of congenic mapping and allele-specific alterations in tumors for the resolution of the Skts1 skin tumor susceptibility locus

Abstract

Although several familial cancer genes with high-penetrance mutations have been identified, the major genetic component of susceptibility to sporadic cancers is attributable to low-penetrance alleles. These ‘weak’ tumor susceptibility genes do not segregate as single Mendelian traits and are therefore difficult to find in studies of human populations. Previously, we have proposed that a combination of germline mapping and analysis of allele-specific imbalance in tumors may be used to refine the locations of susceptibility genes using mouse models of cancer. Here, we have used linkage analysis and congenic mouse strains to map the major skin tumor susceptibility locus Skts1 within a genetic interval of 0.9 cM on proximal chromosome 7. This interval lies in an apparent recombination cold spot, and corresponds to a physical distance of about 15 Mb. We therefore, used patterns of allele-specific imbalances in tumors from backcross and congenic mice to refine the location of Skts1. We demonstrate that this single tumor modifier locus has a dramatic effect on the allelic preference for imbalance on chromosome 7, with at least 90% of tumors from the congenics showing preferential gain of markers on the chromosome carrying the susceptibility variant. Importantly, these alterations enabled us to refine the location of Skts1 at higher resolution than that attained using the congenic mice. We conclude that low-penetrance susceptibility genes can have strong effects on patterns of allele-specific somatic genetic changes in tumors, and that analysis of the directionality of these somatic events provides an important and rapid route to identification of germline genetic variants that confer increased cancer risk.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Balmain A . (2002). Cancer as a complex genetic trait: tumor susceptibility in humans and mouse models. Cell 108: 145–152.

    Article  CAS  Google Scholar 

  • Balmain A, Gray J, Ponder BA . (2003). The genetics and genomics of cancer. Nat Genet 33: 238–244.

    Article  CAS  Google Scholar 

  • Cormier RT, Bilger A, Lillich AJ, Halberg RB, Hong KH, Gould KA et al. (2000). The Mom1AKR intestinal tumor resistance region consists of Pla2g2a and a locus distal to D4Mit64. Oncogene 19: 3182–3192.

    Article  CAS  Google Scholar 

  • Demant P . (2003). Cancer susceptibility in the mouse: genetics, biology and implications for human cancer. Nat Rev Genet 4: 721–734.

    Article  CAS  Google Scholar 

  • Dietrich WF, Lander ES, Smith JS, Moser AR, Gould KA, Luongo C et al. (1993). Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell 75: 631–639.

    Article  CAS  Google Scholar 

  • Dragani TA . (2003). 10 years of mouse cancer modifier loci: human relevance. Cancer Res 63: 3011–3018.

    CAS  PubMed  Google Scholar 

  • Ewart-Toland A, Briassouli P, de Koning JP, Mao JH, Yuan J, Chan F et al. (2003). Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human. Nat Gene 34: 403–412.

    Article  CAS  Google Scholar 

  • Ewart-Toland A, Dai Q, Gao YT, Nagase H, Dunlop MG, Farrington SM et al. (2005). Aurora-A/STK15 T+91A is a general low penetrance cancer susceptibility gene: a meta-analysis of multiple cancer types. Carcinogenesis 26: 1368–1373.

    Article  CAS  Google Scholar 

  • Fijneman RJ, de Vries SS, Jansen RC, Demant P . (1996). Complex interactions of new quantitative trait loci, Sluc1, Sluc2, Sluc3, and Sluc4, that influence the susceptibility to lung cancer in the mouse. Nat Genet 14: 465–467.

    Article  CAS  Google Scholar 

  • Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM et al. (1986). A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323: 643–646.

    Article  CAS  Google Scholar 

  • Hienonen T, Salovaara R, Mecklin JP, Jarvinen H, Karhu A, Aaltonen LA . (2006). Preferential amplification of AURKA 91A (Ile31) in familial colorectal cancers. Int J Cancer 118: 505–508.

    Article  CAS  Google Scholar 

  • Kemp CJ, Fee F, Balmain A . (1993). Allelotype analysis of mouse skin tumors using polymorphic microsatellites: sequential genetic alterations on chromosomes 6, 7, and 11. Cancer Res 53: 6022–6027.

    CAS  PubMed  Google Scholar 

  • Knudson AG . (1971). Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68: 820–823.

    Article  Google Scholar 

  • Legare ME, Frankel WN . (2000). Multiple seizure susceptibility genes on chromosome 7 in SWXL-4 congenic mouse strains. Genomics 70: 62–65.

    Article  CAS  Google Scholar 

  • Mao JH, Balmain A . (2003). Genomic approaches to identification of tumour-susceptibility genes using mouse models. Curr Opin Genet Dev 13: 14–19.

    Article  CAS  Google Scholar 

  • Mao JH, Saunier EF, de Koning JP, McKinnon MM, Higgins MN, Nicklas K et al. (2006). Genetic variants of Tgfb1 act as context-dependent modifiers of mouse skin tumor susceptibility. Proc Natl Acad Sci USA 103: 8125–8130.

    Article  CAS  Google Scholar 

  • Nagase H, Bryson S, Cordell H, Kemp CJ, Fee F, Balmain A . (1995). Distinct genetic loci control development of benign and malignant skin tumours in mice. Nat Genet 10: 424–429.

    Article  CAS  Google Scholar 

  • Nagase H, Mao JH, Balmain A . (1999). A subset of skin tumor modifier loci determines survival time of tumor-bearing mice. Proc Natl Acad Sci USA 96: 15032–15037.

    Article  CAS  Google Scholar 

  • Nagase H, Mao JH, Balmain A . (2003). Allele-specific Hras mutations and genetic alterations at tumor susceptibility loci in skin carcinomas from interspecific hybrid mice. Cancer Res 63: 4849–4853.

    CAS  PubMed  Google Scholar 

  • Peto J . (2001). Cancer epidemiology in the last century and the next decade. Nature 411: 390–395.

    Article  CAS  Google Scholar 

  • Ponder BA . (2001). Cancer genetics. Nature 411: 336–341.

    Article  CAS  Google Scholar 

  • Ruivenkamp CA, van Wezel T, Zanon C, Stassen AP, Vlcek C, Csikos T et al. (2002). Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers. Nat Genet 31: 295–300.

    Article  CAS  Google Scholar 

  • Saran A, Spinola M, Pazzaglia S, Peissel B, Tiveron C, Tatangelo L et al. (2004). Loss of tyrosinase activity confers increased skin tumor susceptibility in mice. Oncogene 23: 4130–4135.

    Article  CAS  Google Scholar 

  • Silver LM . (1995). Mouse Genetics: Concepts and Applications. Oxford University Press: Oxford.

    Google Scholar 

  • To MD, Perez-Losada J, Mao JH, Hsu J, Jacks T, Balmain A . (2006). A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice. Nat Genet 38: 926–930.

    Article  CAS  Google Scholar 

  • Vogel SN, Wax JS, Perera PY, Padlan C, Potter M, Mock BA . (1994). Construction of a BALB/c congenic mouse, C.C3H-Lpsd, that expresses the Lpsd allele: analysis of chromosome 4 markers surrounding the Lps gene. Infect Immun 62: 4454–4459.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P et al. Mouse Genome Sequencing Consortium. (2002). Initial sequencing and comparative analysis of the mouse genome. Nature 420: 520–562.

    Article  CAS  Google Scholar 

  • Yu A, Zhao C, Fan Y, Jang W, Mungall AJ, Deloukas P et al. (2001). Comparison of human genetic and sequence-based physical maps. Nature 409: 951–953.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R del Rosario and R Contreras for assistance with animal husbandry. This work was supported by an NCI Mouse Models of Human Cancer Consortium Grant (U01 CA84244). The early development of the congenic lines was funded by Cancer Research UK at the Beatson Institute (Glasgow, Scotland). JPdK was supported by a research fellowship through the Dutch Cancer Society. JHM is the recipient of a Leukemia & Lymphoma Society Fellowship. AB acknowledges support of the Barbara Bass Bakar Endowed Chair of Cancer Genetics.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A Balmain.

Additional information

Competing interests statement

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

de Koning, J., Wakabayashi, Y., Nagase, H. et al. Convergence of congenic mapping and allele-specific alterations in tumors for the resolution of the Skts1 skin tumor susceptibility locus. Oncogene 26, 4171–4178 (2007). https://doi.org/10.1038/sj.onc.1210206

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210206

Keywords

This article is cited by

Search

Quick links