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Exclusion of PTEN and 10q22–24 As the Susceptibility Locus for Juvenile Polyposis Syndrome¹

Department of Adult Oncology and Human Cancer Genetics Unit [D. J. M., P. L. M. D., Z. Z., S. C., C. E.], Program in Population Sciences [D. J. M., P. L. M. D., Z. Z., S. C., S. S., C. E.], and Department of Biostatistical Science [K. L. L.], Dana-Farber Cancer Institute, Boston, Massachusetts 02115; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115 [D. J. M., P. L. M. D., Z. Z., S. C., N. J. v. O., S. S., J. V., C. E.]; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115 [K. L. L.]; Haartman Institute, Department of Medical Genetics, FIN-00014, University of Helsinki, Helsinki, Finland [S. R., A. H., L. A. A.]; Finnish Red Cross Transfusion Service, FIN-00014 Helsinki, Finland [P. S.]; Second Department of Surgery, Helsinki University Central Hospital, FIN-00014 Helsinki, Finland [H. J., I. K.]; Institute of Molecular Medicine, John Radcliffe Hospital, ICRF Cancer and Immunogenetics Laboratory, Oxford OX3 9DU, United Kingdom [W. F. B.]; ICRF Cancer Genetics Laboratory, London WC2A 3PX, United Kingdom [W. F. B., S. E. C., D. M., I. P. M. T.]; Department of Surgery, University of Edinburgh Royal Infirmary, Midlothian, Scotland [M. G. D.]; Wessex Regional Genetics Service, Princess Anne Hospital, Southampton SO16 5YA, United Kingdom [D. E.]; Department of Medical Genetics, United Medical and Dental School of Guy's and St. Thomas' Hospitals, London SE1 9RT, United Kingdom [S. V. H., D. M.]; Polyposis Registry, St Mark's Hospital, Harrow, Middlesex HA1 3UJ, United Kingdom [K. N., R. P.]; Division of Gastroenterology, Brigham and Women's Hospital, Boston Massachusetts 02115 [S. S.]; Molecular Genetics Section, Gerontology Division, Department of Medicine, Beth Israel Deaconess Medical Centre, Boston, Massachusetts 02115 [N. J. v. O., J. V.]; Department of Gastroenterology, Tel Aviv Medical Center and School of Medicine, IL-64239 Tel Aviv, Israel [P. R.]; Institute of Cancer Research, Royal Marsden Hospital, Sutton, Surrey SM2 5PT, United Kingdom [I. P. M. T.]; and Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge, Cambridge CB2 2QQ, United Kingdom [C. E.]

Juvenile polyposis syndrome (JPS; MIM 174900) is an autosomal dominant condition with incomplete penetrance characterized by hamartomatous polyps of the gastrointestinal tract and a risk of gastrointestinal cancer. Gastrointestinal hamartomatous polyps are also present in Cowden syndrome (CS; MIM 158350) and Bannayan-Zonana syndrome (BZS; also called Ruvalcaba-Myhre-Smith syndrome; MIM 153480). The susceptibility locus for both CS and BZS has recently been identified as the novel tumor suppressor gene PTEN, encoding a dual specificity phosphatase, located at 10q23.3. A putative JPS locus, JP1, which most likely functions as a tumor suppressor, had previously been mapped to 10q22–24 in both familial and sporadic juvenile polyps. Given the shared clinical features of gastrointestinal hamartomatous polyps among the three syndromes and the coincident mapping of JP1 to the region of PTEN, we sought to determine whether JPS was allelic to CS and BZS by mutation analysis of PTEN and linkage approaches. Microsatellite markers spanning the CS/BZS locus (D10S219, D10S551, D10S579, and D10S541) were used to compute multipoint lod scores in eight informative families with JPS. lod scores of < -2.0 were generated for the entire region, thus excluding PTEN and any genes within the flanking 20-cM interval as candidate loci for familial JPS under our statistical models. In addition, analysis of PTEN using a combination of denaturing gradient gel electrophoresis and direct sequencing was unable to identify a germline mutation in 14 families with JPS and 11 sporadic cases. Therefore, at least a proportion of JPS cases are not caused by germline PTEN alteration or by an alternative locus at 10q22–24.

¹ This work was supported by the Dana-Farber Partners Cancer Center Women's Cancer Program, the Lawrence and Susan Marx Investigatorship, the Barr Investigatorship, the Markey Charitable Trust, and the Charles A. Dana Foundation (to C. E.), the Finnish Cancer Society (to L. A. A.), The Academy of Finland and Special State Allowance (to S. R. and L. A. A.), and the Imperial Cancer Research Fund and the Institute of Cancer Research (to I. P. M. T.).

² The first two authors contributed equally to this work.

³ To whom requests for reprints should be addressed: C. E. at Dana-Farber Cancer Institute, 44 Binney Street Boston, MA 02115-6084. Phone: (617) 632-5632; Fax: (617) 632-4280; E-mail: charis_eng@macmailgw.dfci.harvard.edu.; L. A. A. at Harttman Institute, Department of Medical Genetics, University of Helsinki, FIN-00014 Helsinki, Finland, E-mail: lauri.aaltonen@helsinki.fi; and I. P. M. T. at Department of Clinical Genetics, Churchill Hospital, Oxford OX 3 7LJ, UK, E-mail: iptomlin@hgmp.mrc.ac.uk.

Received 9/ 2/97. Accepted 10/ 2/97.

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