Skip to main content
PMC home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2000 May;37(5):336–341. doi: 10.1136/jmg.37.5.336

Novel germline mutations in the PTEN tumour suppressor gene found in women with multiple cancers

I De Vivo 1, D Gertig 1, S Nagase 1, S Hankinson 1, R O'Brien 1, F Speizer 1, R Parsons 1, D Hunter 1
PMCID: PMC1734596  PMID: 10807691

Abstract

Germline mutations in PTEN can predispose people to Cowden syndrome (CS) and Bannayan-Ruvalcaba-Riley (BRR) syndrome, rare, autosomal dominantly inherited neoplastic disorders. To determine whether germline mutations in PTEN contribute to genetic predisposition to multiple primary tumours within the general population, we conducted a nested case-control study, among 32 826 members of the prospective Nurses' Health Study cohort; cases were women with more than one primary tumour at different anatomical sites. We screened all nine exons of PTEN and flanking intronic splice sites for all 103 eligible cases using SSCP and sequencing. We observed two novel germline heterozygous missense mutations in exon 5 in five of the cases; three were V119L and two were V158L. Neither mutation was observed in 115 controls free of diagnosed cancer (p=0.02). Both mutants showed partial tumour suppressor activity when compared to wild type PTEN when transfected into a PTEN null breast cancer cell line. The phenotype was cell line specific suggesting that genetic background affects growth suppression activity of the mutants. These data provide evidence that germline mutations in PTEN may be a more frequent predisposing factor for cancers in women than previously suggested.


Keywords: population based; tumour suppressor; multiple cancers; germline mutations

Full Text

The Full Text of this article is available as a PDF (163.0 KB).

Selected References

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

  1. Cairns P., Okami K., Halachmi S., Halachmi N., Esteller M., Herman J. G., Jen J., Isaacs W. B., Bova G. S., Sidransky D. Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res. 1997 Nov 15;57(22):4997–5000. [PubMed] [Google Scholar]
  2. Di Cristofano A., Pesce B., Cordon-Cardo C., Pandolfi P. P. Pten is essential for embryonic development and tumour suppression. Nat Genet. 1998 Aug;19(4):348–355. doi: 10.1038/1235. [DOI] [PubMed] [Google Scholar]
  3. Duerr E. M., Rollbrocker B., Hayashi Y., Peters N., Meyer-Puttlitz B., Louis D. N., Schramm J., Wiestler O. D., Parsons R., Eng C. PTEN mutations in gliomas and glioneuronal tumors. Oncogene. 1998 Apr 30;16(17):2259–2264. doi: 10.1038/sj.onc.1201756. [DOI] [PubMed] [Google Scholar]
  4. Easton D. Breast cancer genes--what are the real risks? Nat Genet. 1997 Jul;16(3):210–211. doi: 10.1038/ng0797-210. [DOI] [PubMed] [Google Scholar]
  5. Eng C. Genetics of Cowden syndrome: through the looking glass of oncology. Int J Oncol. 1998 Mar;12(3):701–710. doi: 10.3892/ijo.12.3.701. [DOI] [PubMed] [Google Scholar]
  6. Feilotter H. E., Coulon V., McVeigh J. L., Boag A. H., Dorion-Bonnet F., Duboué B., Latham W. C., Eng C., Mulligan L. M., Longy M. Analysis of the 10q23 chromosomal region and the PTEN gene in human sporadic breast carcinoma. Br J Cancer. 1999 Feb;79(5-6):718–723. doi: 10.1038/sj.bjc.6690115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Feilotter H. E., Nagai M. A., Boag A. H., Eng C., Mulligan L. M. Analysis of PTEN and the 10q23 region in primary prostate carcinomas. Oncogene. 1998 Apr 2;16(13):1743–1748. doi: 10.1038/sj.onc.1200205. [DOI] [PubMed] [Google Scholar]
  8. FitzGerald M. G., Marsh D. J., Wahrer D., Bell D., Caron S., Shannon K. E., Ishioka C., Isselbacher K. J., Garber J. E., Eng C. Germline mutations in PTEN are an infrequent cause of genetic predisposition to breast cancer. Oncogene. 1998 Aug 13;17(6):727–731. doi: 10.1038/sj.onc.1201984. [DOI] [PubMed] [Google Scholar]
  9. Fodor F. H., Weston A., Bleiweiss I. J., McCurdy L. D., Walsh M. M., Tartter P. I., Brower S. T., Eng C. M. Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients. Am J Hum Genet. 1998 Jul;63(1):45–51. doi: 10.1086/301903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Furnari F. B., Lin H., Huang H. S., Cavenee W. K. Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain. Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12479–12484. doi: 10.1073/pnas.94.23.12479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Lee J. O., Yang H., Georgescu M. M., Di Cristofano A., Maehama T., Shi Y., Dixon J. E., Pandolfi P., Pavletich N. P. Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell. 1999 Oct 29;99(3):323–334. doi: 10.1016/s0092-8674(00)81663-3. [DOI] [PubMed] [Google Scholar]
  13. Li D. M., Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res. 1997 Jun 1;57(11):2124–2129. [PubMed] [Google Scholar]
  14. Li J., Simpson L., Takahashi M., Miliaresis C., Myers M. P., Tonks N., Parsons R. The PTEN/MMAC1 tumor suppressor induces cell death that is rescued by the AKT/protein kinase B oncogene. Cancer Res. 1998 Dec 15;58(24):5667–5672. [PubMed] [Google Scholar]
  15. Li J., Yen C., Liaw D., Podsypanina K., Bose S., Wang S. I., Puc J., Miliaresis C., Rodgers L., McCombie R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997 Mar 28;275(5308):1943–1947. doi: 10.1126/science.275.5308.1943. [DOI] [PubMed] [Google Scholar]
  16. Longy M., Coulon V., Duboué B., David A., Larrègue M., Eng C., Amati P., Kraimps J. L., Bottani A., Lacombe D. Mutations of PTEN in patients with Bannayan-Riley-Ruvalcaba phenotype. J Med Genet. 1998 Nov;35(11):886–889. doi: 10.1136/jmg.35.11.886. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. Marsh D. J., Dahia P. L., Caron S., Kum J. B., Frayling I. M., Tomlinson I. P., Hughes K. S., Eeles R. A., Hodgson S. V., Murday V. A. Germline PTEN mutations in Cowden syndrome-like families. J Med Genet. 1998 Nov;35(11):881–885. doi: 10.1136/jmg.35.11.881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. Myers M. P., Pass I., Batty I. H., Van der Kaay J., Stolarov J. P., Hemmings B. A., Wigler M. H., Downes C. P., Tonks N. K. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13513–13518. doi: 10.1073/pnas.95.23.13513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Myers M. P., Stolarov J. P., Eng C., Li J., Wang S. I., Wigler M. H., Parsons R., Tonks N. K. P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9052–9057. doi: 10.1073/pnas.94.17.9052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nelen M. R., Kremer H., Konings I. B., Schoute F., van Essen A. J., Koch R., Woods C. G., Fryns J. P., Hamel B., Hoefsloot L. H. Novel PTEN mutations in patients with Cowden disease: absence of clear genotype-phenotype correlations. Eur J Hum Genet. 1999 Apr;7(3):267–273. doi: 10.1038/sj.ejhg.5200289. [DOI] [PubMed] [Google Scholar]
  23. Podsypanina K., Ellenson L. H., Nemes A., Gu J., Tamura M., Yamada K. M., Cordon-Cardo C., Catoretti G., Fisher P. E., Parsons R. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1563–1568. doi: 10.1073/pnas.96.4.1563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. 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]
  26. Risinger J. I., Hayes A. K., Berchuck A., Barrett J. C. PTEN/MMAC1 mutations in endometrial cancers. Cancer Res. 1997 Nov 1;57(21):4736–4738. [PubMed] [Google Scholar]
  27. Sander C., Schneider R. Database of homology-derived protein structures and the structural meaning of sequence alignment. Proteins. 1991;9(1):56–68. doi: 10.1002/prot.340090107. [DOI] [PubMed] [Google Scholar]
  28. Singh B., Ittmann M. M., Krolewski J. J. Sporadic breast cancers exhibit loss of heterozygosity on chromosome segment 10q23 close to the Cowden disease locus. Genes Chromosomes Cancer. 1998 Feb;21(2):166–171. [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. Struewing J. P., Hartge P., Wacholder S., Baker S. M., Berlin M., McAdams M., Timmerman M. M., Brody L. C., Tucker M. A. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997 May 15;336(20):1401–1408. doi: 10.1056/NEJM199705153362001. [DOI] [PubMed] [Google Scholar]
  31. Suzuki A., de la Pompa J. L., Stambolic V., Elia A. J., Sasaki T., del Barco Barrantes I., Ho A., Wakeham A., Itie A., Khoo W. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol. 1998 Oct 22;8(21):1169–1178. doi: 10.1016/s0960-9822(07)00488-5. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. Tsou H. C., Teng D. H., Ping X. L., Brancolini V., Davis T., Hu R., Xie X. X., Gruener A. C., Schrager C. A., Christiano A. M. The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases. Am J Hum Genet. 1997 Nov;61(5):1036–1043. doi: 10.1086/301607. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES