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Abstract

Only a small proportion of cancers result from familial cancer syndromes with Mendelian inheritance. Nonfamilial, 'sporadic' cancers, which represent most cancer cases, also have a significant hereditary component1,2, but the genes involved have low penetrance and are extremely difficult to detect2,3. Therefore, mapping and cloning of quantitative trait loci (QTLs) for cancer susceptibility in animals could help identify homologous genes in humans. Several cancer-susceptibility QTLs have been mapped in mice and rats4,5, but none have been cloned so far. Here we report the positional cloning of the mouse gene Scc1 (Susceptibility to colon cancer 1)6 and the identification of Ptprj, encoding a receptor-type protein tyrosine phosphatase, as the underlying gene. In human colon, lung and breast cancers, we show frequent deletion of PTPRJ, allelic imbalance in loss of heterozygosity (LOH) and missense mutations. Our data suggest that PTPRJ is relevant to the development of several different human cancers.

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References

  1. 1.

    et al. Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N. Engl. J. Med. 343, 78–85 (2000).

  2. 2.

    Cancer genetics. Nature 411, 336–341 (2001).

  3. 3.

    & How many diseases does it take to map a gene with SNPs? Nature Genet. 26, 151–157 (2000).

  4. 4.

    & Cancer resistance genes in mice: models for the study of tumour modifiers. Trends Genet. 14, 139–144 (1998).

  5. 5.

    , & in Genotype to Phenotype (eds Malcolm, S. & Goodship, S.) 107–129 (BIOS Scientific Publishers, Oxford, 2001).

  6. 6.

    , , , & Fine mapping of colon tumor susceptibility (Scc) genes in the mouse, different from the genes known to be somatically mutated in colon cancer. Proc. Natl Acad. Sci. USA 93, 1082–1086 (1996).

  7. 7.

    et al. The sequence of the human genome. Science 291, 1304–1351 (2001).

  8. 8.

    et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

  9. 9.

    , , , & The protein tyrosine phosphatase DEP-1 is induced during differentiation and inhibits growth of breast cancer cells. Cancer Res. 56, 4236–4243 (1996).

  10. 10.

    et al. Rat protein tyrosine phosphatase η suppresses the neoplastic phenotype of retrovirally transformed thyroid cells through the stabilization of p27(Kip1). Mol. Cell. Biol. 20, 9236–9246 (2000).

  11. 11.

    et al. Molecular cloning and characterization of Byp, a murine receptor-type tyrosine phosphatase similar to human DEP-1. FEBS Lett. 378, 7–14 (1996).

  12. 12.

    et al. Expression of the membrane protein tyrosine phosphatase CD148 in human tissues. Tissue Antigens 54, 485–498 (1999).

  13. 13.

    & The p120 catenin family: complex roles in adhesion, signaling and cancer. J. Cell Sci. 113, 1319–1334 (2000).

  14. 14.

    , , & CD44 glycoproteins in colorectal cancer: expression, function, and prognostic value. Adv. Cancer Res. 77, 169–187 (2000).

  15. 15.

    , , , & Molecular cloning, characterization, and chromosomal localization of a novel protein-tyrosine phosphatase, HPTP η. Blood 84, 4186–4194 (1994).

  16. 16.

    , & Expression of DEP-1, a receptor-like protein-tyrosine-phosphatase, is enhanced with increasing cell density. Proc. Natl Acad. Sci. USA 91, 9680–9684 (1994).

  17. 17.

    et al. Assignment of the human p27Kip1 gene to 12p13 and its analysis in leukemias. Cancer Res. 55, 1206–1210 (1995).

  18. 18.

    , , , & The murine gene p27Kip1 is haplo-insufficient for tumour suppression. Nature 396, 177–180 (1998).

  19. 19.

    , , , & Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature 413, 83–86 (2001).

  20. 20.

    et al. Haploinsufficiency of the Pten tumor suppressor gene promotes prostate cancer progression. Proc. Natl Acad. Sci. USA 98, 11563–11568 (2001).

  21. 21.

    et al. Disruption of the ARF transcriptional activator DMP1 facilitates cell immortalization, Ras transformation, and tumorigenesis. Genes Dev. 14, 1797–1809 (2000).

  22. 22.

    et al. A high-resolution microsatellite map of the mouse genome. Genome Res. 8, 531–542 (1998).

  23. 23.

    et al. A novel, rapid method for the isolation of terminal sequences from yeast artificial chromosome (YAC) clones. Nucleic Acids Res. 18, 2887–2890 (1990).

  24. 24.

    et al. High-resolution DNA Fiber-FISH for genomic DNA mapping and colour bar-coding of large genes. Hum. Mol. Genet. 4, 831–836 (1995).

  25. 25.

    & Primer3 on the WWW for general users and for biologist programmers. Methods Mol. Biol. 132, 365–386 (2000).

  26. 26.

    et al. Laser capture microdissection. Science 274, 998–1001 (1996).

  27. 27.

    et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152–154 (1996).

  28. 28.

    , & CLUSTALW: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 22, 4673–4680 (1994).

  29. 29.

    , , , & Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).

  30. 30.

    et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).

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Acknowledgements

The authors thank V. Theodorou, E. Dijsselbloem, E. Anthony and M. Treur for technical assistance; J. de Moes, E. Delzenne-Goette and M. Timpico for help with breeding, tumor induction and autopsies; A. Berns, M. Snoek, J. Jonkers, H. Mikkers and A. Cleton-Jansen for helpful comments on the manuscript; E. Robanus for the human BAC filters; R. Pruntel for all the ABI runs; and S. Banus and H. van Kranen for their help with pyrosequencing. This work was supported by grants from the Dutch Cancer Society and the Dutch Basic Research Organization.

Author information

Author notes

    • Claudia A.L. Ruivenkamp
    •  & Tom van Wezel

    These authors contributed equally to this work.

Affiliations

  1. Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.

    • Claudia A.L. Ruivenkamp
    • , Tom van Wezel
    • , Carlo Zanon
    • , Alphons P.M. Stassen
    • , Tamás Csikós
    • , Anita M. Klous
    • , Nikos Tripodis
    • , Peter C. Groot
    •  & Peter Demant
  2. Division of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.

    • Lucie Boerrigter
    •  & Wolter J. Mooi
  3. Division of Clinical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.

    • Nico van Zandwijk
  4. Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.

    • Anastassis Perrakis
  5. Center for Genomics, Institute of Molecular Genetics Academy of Sciences of the Czech Republic, Prague, Czech Republic.

    • Cestmir Vlcek
    •  & Vaclav Paces
  6. Department of Pathology, Slotervaart Hospital, Amsterdam, the Netherlands.

    • Jan Lindeman
    •  & Gert Scholten
  7. Leiden University Medical Center, Department of Human and Clinical Genetics, Leiden, the Netherlands.

    • Hans Dauwerse
    •  & Gert Jan B. van Ommen
  8. Department of Pathology, Free University, Amsterdam, the Netherlands.

    • Gerrit A. Meijjer

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Peter Demant.

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DOI

https://doi.org/10.1038/ng903

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