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.

  • Letter
  • Published:

Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC

Nature Genetics volume 17, pages 79–83 (1997)Cite this article

Abstract

Approximately 130,000 cases of col ore eta I cancer (CRC) are diagnosed in the United States each year1, and about 15% of these have a hereditary component2,3. Two well-defined syndromes, familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC), account for up to 5% of the total new cases of CRC4. Truncating APC mutations are responsible for FAR5,6, and defective mismatch repair genes cause HNPCC4,7,8. However, the genes responsible for most of the familial cases are unknown. Here we report a mutation (T to A at APC nucleotide 3920) found in 6% of Ashkenazi Jews and about 28% of Ashkenazim with a family history of CRC. Rather than altering the function of the encoded protein, this mutation creates a small hypermutable region of the gene, indirectly causing cancer predisposition.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Similar content being viewed by others

References

  1. Parker, S.L., long, T., Bolden, S. & Wingo, P.A. Cancer statistics, 1997. CA Cancer J. Clin. 47, 5–27 1997).

    Article  CAS  Google Scholar 

  2. Cannon-Albright, L.A., Skolnick, M.H., Bishop, D.T., Lee, R.G & Burt, R.W. Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. N. Engl. J. Med. 319, 533–537 (1988).

    Article  CAS  Google Scholar 

  3. Houlston, R.S., Collins, A., Slack, J. & Morton, N.E. Dominant genes for colorectal cancer are not rare. Ann. Hum. Genet. 56, 99–103 (1992).

    Article  CAS  Google Scholar 

  4. Kinzler, K.W. & Vogelstein, B. Lessons from hereditary colorectal cancer. Cell 87, 159–170 (1996).

    Article  CAS  Google Scholar 

  5. Groden, J. et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66, 589–600 (1991).

    Article  CAS  Google Scholar 

  6. Nishisho, I. et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253, 665–669 (1991).

    Article  CAS  Google Scholar 

  7. Marra, G. & Boland, C.R. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J. Natl. Cancer Inst. USA 87, 1114–1125 (1995).

    Article  CAS  Google Scholar 

  8. Kolodner, R. Biochemistry and genetics of eukaryotic mismatch repair. Genes Dev. 10, 1433–1442 (1996).

    Article  CAS  Google Scholar 

  9. Liu, B. et al. Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nature Med. 2, 169–174 (1996).

    Article  CAS  Google Scholar 

  10. Powell, S.M. et al. Molecular diagnosis of familial adenomatous polyposis. N. Engl. J. Med. 329, 1982–1987 (1993).

    Article  CAS  Google Scholar 

  11. van der Luijt, R. et al. Rapid detection of translation-terminating mutations at the adenomatous polyposis coli (APC) gene by direct protein truncation test. Genomics 20, 1–4 (1994).

    Article  CAS  Google Scholar 

  12. Miyaki, M. et al. Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res. 54, 3011–3020 (1994).

    CAS  PubMed  Google Scholar 

  13. Nagase, H. & Nakamura, Y. Mutations of the APC (adenomatous polyposis coli) gene. Hum. Mutat. 2, 425–434 (1993).

    Article  CAS  Google Scholar 

  14. Sia, E.A., Kokoska, R.J., Dominska, M., Greenwell, P. & Petes, T.D. Microsatellite instability in yeast: dependence on repeat unit size and DNA mismatch repair genes. Mol. Cell. Biol. 17, 2851–2858 (1997).

    Article  CAS  Google Scholar 

  15. Shibata, D., Peinado, M.A. . lonov, Y., Malkhosyan, S. & Perucho, M. Genomic instability in repeated sequences is an early somatic event in colorectal tumorigenesisthat persists after transformation. Nature Genet. 6, 273–281 (1994).

    Article  CAS  Google Scholar 

  16. Minnick, D.T. & Kunkel, T.A. DNA synthesis errors, mutators and cancer. Cancer Surv. 28, 3–20 (1996).

    CAS  PubMed  Google Scholar 

  17. Roa, B.B., Boyd, A.A., Volcik, K. & Richards, C.S., Jewish population frequencies for common mutations in BRCA1 and BRCA2 . Nature Genet. 14, 185–187 (1996).

    Article  CAS  Google Scholar 

  18. Greenwald, P., Korns, R.F., Nasca, P.C. & Wolfgang, P.E. Cancer in United States Jews. Cancer Res. 35,, 3507–3512 (1975).

    Google Scholar 

  19. Bat, L. et al. Colorectal adenomatous polyps and carcinoma in Ashkenazi and non-Ashkenazi Jews in Israel. Cancer 58, 1167–1171 (1986).

    Article  CAS  Google Scholar 

  20. Kune, S., Kune, G.A. & Watson, L., Incidence findings by age, sex, site, migrants and religion. Int. J. Epidemiol. 15, 483–493 (1986).

    Article  CAS  Google Scholar 

  21. Burt, R.W. & Petersen, G.M., Familial Colorectal Cancer: Diagnosis and Management 171–194 (Saunders, London, 1996).

    Google Scholar 

  22. Muller, H., Scott, R., Weber, W. & Meier, R. Colorectal cancer: lessons for genetic counselling and care for families. Clin. Genet. 46, 106–114 (1994).

    Article  CAS  Google Scholar 

  23. Hall, N.R., Bishop, D.T., Stephenson, B.M. & Finan, P.J. Hereditary susceptibility to colorectal cancer. Dis. Colon Rectum 39, 739–743 (1996).

    Article  CAS  Google Scholar 

  24. Winawer, S.J. et al. Risk of colorectal cancer in the families of patients with adenomatous polyps. N. Engl. J. Med. 334, 82–87 (1996).

    Article  CAS  Google Scholar 

  25. Jen, J. et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N. Engl. J. Med. 331, 213–221 (1994).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, Maryland, 21231, USA

    Steven J. Laken, Gloria M. Petersen, Stephen B. Gruber, Stanley R. Hamilton, Kenneth W. Kinzler & Bert Vogelstein

  2. Department of Epidemiology, Johns Hopkins School of Public Health, 615 North Wolfe Street, Baltimore, Maryland, 21205, USA

    Gloria M. Petersen

  3. Human Genetics Program, Department of Pediatrics, New York University Medical Center, New York, New York, 10016, USA

    Carole Oddoux & Harry Ostrer

  4. The Johns Hopkins Hospital, 935Blalock, 600North WolfeStreet, Baltimore, Maryland, 21287, USA

    Francis M. Giardiello

  5. Department of Pathology, Johns Hopkins Hospital, University School of Medicine, 720 Rutland Avenue, Baltimore, Maryland, 21205, USA

    Stanley R. Hamilton

  6. Clinical Genetics Service, Department of Human Genetics, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York, 10021, USA

    Heather Hampel & Kenneth Offit

  7. Gastroenterology and Nutrition Service, Department of Medicine, MSKCC, New York, New York, 10021, USA

    Arnold Markowitz & Sidney Winawer

  8. Surgical Pathology Service, Department of Pathology, MSKCC, New York, New York, 10021, USA

    David Klimstra

  9. Cytogenetics Service, Department of Human Genetics, MSKCC, New York, New York, 10021, USA

    Suresh Jhanwar

  10. Laboratory Corporation of America, Research Triangle Park, North Carolina, 27709, USA

    Michael C. Luce

  11. The Howard Hughes Medical Institute, Baltimore, Maryland, 21231, USA

    Bert Vogelstein

Authors
  1. Steven J. Laken
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Gloria M. Petersen
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Stephen B. Gruber
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Carole Oddoux
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Harry Ostrer
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Francis M. Giardiello
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Stanley R. Hamilton
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Heather Hampel
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Arnold Markowitz
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. David Klimstra
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Suresh Jhanwar
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Sidney Winawer
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Kenneth Offit
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Michael C. Luce
    View author publications

    You can also search for this author inPubMed Google Scholar

  15. Kenneth W. Kinzler
    View author publications

    You can also search for this author inPubMed Google Scholar

  16. Bert Vogelstein
    View author publications

    You can also search for this author inPubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Laken, S., Petersen, G., Gruber, S. et al. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat Genet 17, 79–83 (1997). https://doi.org/10.1038/ng0997-79

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0997-79

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing