Skip to main content
PMC home page
Gut logoLink to Gut
. 2000 May;46(5):656–660. doi: 10.1136/gut.46.5.656

Analysis of genetic and phenotypic heterogeneity in juvenile polyposis

K Woodford-Richens 1, S Bevan 1, M Churchman 1, B Dowling 1, D Jones 1, C Norbury 1, S Hodgson 1, D Desai 1, K Neale 1, R Phillips 1, J Young 1, B Leggett 1, M Dunlop 1, P Rozen 1, C Eng 1, D Markie 1, M Rodriguez-Bigas 1, E Sheridan 1, T Iwama 1, D Eccles 1, G Smith 1, J Kim 1, K Kim 1, J Sampson 1, G Evans 1, S Tejpar 1, W Bodmer 1, I Tomlinson 1, R Houlston 1
PMCID: PMC1727907  PMID: 10764709

Abstract

BACKGROUND—Juvenile polyposis syndrome (JPS) is characterised by gastrointestinal (GI) hamartomatous polyposis and an increased risk of GI malignancy. Juvenile polyps also occur in the Cowden (CS), Bannayan-Ruvalcaba-Riley (BRRS) and Gorlin (GS) syndromes. Diagnosing JPS can be problematic because it relies on exclusion of CS, BRRS, and GS. Germline mutations in the PTCH, PTEN and DPC4 (SMAD4) genes can cause GS, CS/BRRS, and JPS, respectively.
AIMS—To examine the contribution of mutations in PTCH, PTEN, and DPC4 (SMAD4) to JPS.
METHODS—Forty seven individuals from 15 families and nine apparently sporadic cases with JPS were screened for germline mutations in DPC4, PTEN, and PTCH.
RESULTS—No patient had a mutation in PTEN or PTCH. Five different germline mutations were detected in DPC4; three of these were deletions, one a single base substitution creating a stop codon, and one a missense change. None of these patients had distinguishing clinical features.
CONCLUSIONS—Mutations in PTEN and PTCH are unlikely to cause juvenile polyposis in the absence of clinical features indicative of CS, BRRS, or GS. A proportion of JPS patients harbour DPC4 mutations (21% in this study) but there remains uncharacterised genetic heterogeneity in JPS.


Keywords: juvenile polyposis syndrome; germline mutations

Full Text

The Full Text of this article is available as a PDF (113.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arch E. M., Goodman B. K., Van Wesep R. A., Liaw D., Clarke K., Parsons R., McKusick V. A., Geraghty M. T. Deletion of PTEN in a patient with Bannayan-Riley-Ruvalcaba syndrome suggests allelism with Cowden disease. Am J Med Genet. 1997 Sep 5;71(4):489–493. [PubMed] [Google Scholar]
  2. Bevan S., Woodford-Richens K., Rozen P., Eng C., Young J., Dunlop M., Neale K., Phillips R., Markie D., Rodriguez-Bigas M. Screening SMAD1, SMAD2, SMAD3, and SMAD5 for germline mutations in juvenile polyposis syndrome. Gut. 1999 Sep;45(3):406–408. doi: 10.1136/gut.45.3.406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Carethers J. M., Furnari F. B., Zigman A. F., Lavine J. E., Jones M. C., Graham G. E., Teebi A. S., Huang H. J., Ha H. T., Chauhan D. P. Absence of PTEN/MMAC1 germ-line mutations in sporadic Bannayan-Riley-Ruvalcaba syndrome. Cancer Res. 1998 Jul 1;58(13):2724–2726. [PubMed] [Google Scholar]
  4. Dahia P. L., Marsh D. J., Zheng Z., Zedenius J., Komminoth P., Frisk T., Wallin G., Parsons R., Longy M., Larsson C. Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res. 1997 Nov 1;57(21):4710–4713. [PubMed] [Google Scholar]
  5. Eng C., Ji H. Molecular classification of the inherited hamartoma polyposis syndromes: clearing the muddied waters. Am J Hum Genet. 1998 May;62(5):1020–1022. doi: 10.1086/301847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Giardiello F. M., Hamilton S. R., Kern S. E., Offerhaus G. J., Green P. A., Celano P., Krush A. J., Booker S. V. Colorectal neoplasia in juvenile polyposis or juvenile polyps. Arch Dis Child. 1991 Aug;66(8):971–975. doi: 10.1136/adc.66.8.971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Guldberg P., thor Straten P., Birck A., Ahrenkiel V., Kirkin A. F., Zeuthen J. Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res. 1997 Sep 1;57(17):3660–3663. [PubMed] [Google Scholar]
  8. Hahn H., Wicking C., Zaphiropoulous P. G., Gailani M. R., Shanley S., Chidambaram A., Vorechovsky I., Holmberg E., Unden A. B., Gillies S. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996 Jun 14;85(6):841–851. doi: 10.1016/s0092-8674(00)81268-4. [DOI] [PubMed] [Google Scholar]
  9. Hahn S. A., Bartsch D., Schroers A., Galehdari H., Becker M., Ramaswamy A., Schwarte-Waldhoff I., Maschek H., Schmiegel W. Mutations of the DPC4/Smad4 gene in biliary tract carcinoma. Cancer Res. 1998 Mar 15;58(6):1124–1126. [PubMed] [Google Scholar]
  10. Heldin C. H., Miyazono K., ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997 Dec 4;390(6659):465–471. doi: 10.1038/37284. [DOI] [PubMed] [Google Scholar]
  11. Houlston R., Bevan S., Williams A., Young J., Dunlop M., Rozen P., Eng C., Markie D., Woodford-Richens K., Rodriguez-Bigas M. A. Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases. Hum Mol Genet. 1998 Nov;7(12):1907–1912. doi: 10.1093/hmg/7.12.1907. [DOI] [PubMed] [Google Scholar]
  12. Howe J. R., Mitros F. A., Summers R. W. The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann Surg Oncol. 1998 Dec;5(8):751–756. doi: 10.1007/BF02303487. [DOI] [PubMed] [Google Scholar]
  13. Howe J. R., Ringold J. C., Summers R. W., Mitros F. A., Nishimura D. Y., Stone E. M. A gene for familial juvenile polyposis maps to chromosome 18q21.1. Am J Hum Genet. 1998 May;62(5):1129–1136. doi: 10.1086/301840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Howe J. R., Roth S., Ringold J. C., Summers R. W., Järvinen H. J., Sistonen P., Tomlinson I. P., Houlston R. S., Bevan S., Mitros F. A. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science. 1998 May 15;280(5366):1086–1088. doi: 10.1126/science.280.5366.1086. [DOI] [PubMed] [Google Scholar]
  15. Jacoby R. F., Schlack S., Cole C. E., Skarbek M., Harris C., Meisner L. F. A juvenile polyposis tumor suppressor locus at 10q22 is deleted from nonepithelial cells in the lamina propria. Gastroenterology. 1997 Apr;112(4):1398–1403. doi: 10.1016/s0016-5085(97)70156-2. [DOI] [PubMed] [Google Scholar]
  16. Jass J. R., Williams C. B., Bussey H. J., Morson B. C. Juvenile polyposis--a precancerous condition. Histopathology. 1988 Dec;13(6):619–630. doi: 10.1111/j.1365-2559.1988.tb02093.x. [DOI] [PubMed] [Google Scholar]
  17. Ko F. Y., Wu T. C., Hwang B. Intestinal polyps in children and adolescents--a review of 103 cases. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1995 May-Jun;36(3):197–202. [PubMed] [Google Scholar]
  18. Liaw D., Marsh D. J., Li J., Dahia P. L., Wang S. I., Zheng Z., Bose S., Call K. M., Tsou H. C., Peacocke M. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997 May;16(1):64–67. doi: 10.1038/ng0597-64. [DOI] [PubMed] [Google Scholar]
  19. Lynch E. D., Ostermeyer E. A., Lee M. K., Arena J. F., Ji H., Dann J., Swisshelm K., Suchard D., MacLeod P. M., Kvinnsland S. Inherited mutations in PTEN that are associated with breast cancer, cowden disease, and juvenile polyposis. Am J Hum Genet. 1997 Dec;61(6):1254–1260. doi: 10.1086/301639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Marsh D. J., Coulon V., Lunetta K. L., Rocca-Serra P., Dahia P. L., Zheng Z., Liaw D., Caron S., Duboué B., Lin A. Y. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet. 1998 Mar;7(3):507–515. doi: 10.1093/hmg/7.3.507. [DOI] [PubMed] [Google Scholar]
  21. Marsh D. J., Dahia P. L., Zheng Z., Liaw D., Parsons R., Gorlin R. J., Eng C. Germline mutations in PTEN are present in Bannayan-Zonana syndrome. Nat Genet. 1997 Aug;16(4):333–334. doi: 10.1038/ng0897-333. [DOI] [PubMed] [Google Scholar]
  22. Marsh D. J., Roth S., Lunetta K. L., Hemminki A., Dahia P. L., Sistonen P., Zheng Z., Caron S., van Orsouw N. J., Bodmer W. F. Exclusion of PTEN and 10q22-24 as the susceptibility locus for juvenile polyposis syndrome. Cancer Res. 1997 Nov 15;57(22):5017–5021. [PubMed] [Google Scholar]
  23. Murday V., Slack J. Inherited disorders associated with colorectal cancer. Cancer Surv. 1989;8(1):139–157. [PubMed] [Google Scholar]
  24. Nelen M. R., Padberg G. W., Peeters E. A., Lin A. Y., van den Helm B., Frants R. R., Coulon V., Goldstein A. M., van Reen M. M., Easton D. F. Localization of the gene for Cowden disease to chromosome 10q22-23. Nat Genet. 1996 May;13(1):114–116. doi: 10.1038/ng0596-114. [DOI] [PubMed] [Google Scholar]
  25. Olschwang S., Serova-Sinilnikova O. M., Lenoir G. M., Thomas G. PTEN germ-line mutations in juvenile polyposis coli. Nat Genet. 1998 Jan;18(1):12–14. doi: 10.1038/ng0198-12. [DOI] [PubMed] [Google Scholar]
  26. Rasheed B. K., Stenzel T. T., McLendon R. E., Parsons R., Friedman A. H., Friedman H. S., Bigner D. D., Bigner S. H. PTEN gene mutations are seen in high-grade but not in low-grade gliomas. Cancer Res. 1997 Oct 1;57(19):4187–4190. [PubMed] [Google Scholar]
  27. Rhei E., Kang L., Bogomolniy F., Federici M. G., Borgen P. I., Boyd J. Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. Cancer Res. 1997 Sep 1;57(17):3657–3659. [PubMed] [Google Scholar]
  28. Schutte M., Hruban R. H., Hedrick L., Cho K. R., Nadasdy G. M., Weinstein C. L., Bova G. S., Isaacs W. B., Cairns P., Nawroz H. DPC4 gene in various tumor types. Cancer Res. 1996 Jun 1;56(11):2527–2530. [PubMed] [Google Scholar]
  29. Steck P. A., Pershouse M. A., Jasser S. A., Yung W. K., Lin H., Ligon A. H., Langford L. A., Baumgard M. L., Hattier T., Davis T. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997 Apr;15(4):356–362. doi: 10.1038/ng0497-356. [DOI] [PubMed] [Google Scholar]
  30. Tashiro H., Blazes M. S., Wu R., Cho K. R., Bose S., Wang S. I., Li J., Parsons R., Ellenson L. H. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res. 1997 Sep 15;57(18):3935–3940. [PubMed] [Google Scholar]
  31. Thomas H. J., Whitelaw S. C., Cottrell S. E., Murday V. A., Tomlinson I. P., Markie D., Jones T., Bishop D. T., Hodgson S. V., Sheer D. Genetic mapping of hereditary mixed polyposis syndrome to chromosome 6q. Am J Hum Genet. 1996 Apr;58(4):770–776. [PMC free article] [PubMed] [Google Scholar]
  32. Tsuchiya K. D., Wiesner G., Cassidy S. B., Limwongse C., Boyle J. T., Schwartz S. Deletion 10q23.2-q23.33 in a patient with gastrointestinal juvenile polyposis and other features of a Cowden-like syndrome. Genes Chromosomes Cancer. 1998 Feb;21(2):113–118. doi: 10.1002/(sici)1098-2264(199802)21:2<113::aid-gcc6>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
  33. Whitelaw S. C., Murday V. A., Tomlinson I. P., Thomas H. J., Cottrell S., Ginsberg A., Bukofzer S., Hodgson S. V., Skudowitz R. B., Jass J. R. Clinical and molecular features of the hereditary mixed polyposis syndrome. Gastroenterology. 1997 Feb;112(2):327–334. doi: 10.1053/gast.1997.v112.pm9024286. [DOI] [PubMed] [Google Scholar]
  34. Wicking C., Shanley S., Smyth I., Gillies S., Negus K., Graham S., Suthers G., Haites N., Edwards M., Wainwright B. Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident. Am J Hum Genet. 1997 Jan;60(1):21–26. [PMC free article] [PubMed] [Google Scholar]

Articles from Gut are provided here courtesy of BMJ Publishing Group

RESOURCES