for Juvenile Polyposis Syndrome 24 As the Susceptibility Locus − and 10 q 22 PTEN Exclusion of Updated Version

Introduction Gastrointestinal polyps are components of a number of syndromes with autosomal dominant inheritance and variable penetrance. The inherited polyposis syndromes are broadly divided into two groups, the adenomatous and the hamartomatous polyposes (1). The presence of hundreds to thousands of colorectal adenomatous polyps are char acteristic of familial APC. â€•The hamartomatous polyposis syndromes comprise four main disorders, CS, BZS (also known as Ruvalcaba Riley-Smith syndrome), PJS (MIM 175200), and JPS. Juvenile polyps represent the vast majority of all colorectal polyps in childhood and adolescence, accounting for 90% of all polyps in this age group (2). Although up to 2% of children and adolescents develop juvenile polyps, these polyps are usually solitary and unlikely to be premalig nant (3). A small proportion, however, occurs as part of JPS and is characterized by multiple hamartomatous polyps, which may occur throughout the gastrointestinal tract. Unlike isolated cases, with sol itary juvenile polyps, JPS patients have a 2â€”4-foldincreased risk of gastrointestinal malignancy compared to the general population (4â€”9). The genetic etiologies of the gastrointestinal polyposis syndromes are known in a number of cases. Familial APC has been shown to be caused by germline mutations in the APC gene located at 5q2l (10). Tumor suppressor, or putative tumor suppressor, genes have been implicated in the etiology of three of the four hamartomatous polyp osis syndromes, CS, BZS, and PJS. A susceptibility locus for PJS was mapped to 19p13.3 (1 1). Recently, germline mutations in PTEN [alternatively named MMACJ and TEPJ by independent groups (12, 13)} have been found in both CS and BZS (12, 14). PTEN, encoding a dual-specificity phosphatase, maps to 10q23.3 and has also been implicated in a number of sporadic cancers, including those of the breast, brain, prostate, and kidney (13, 15â€”17). The etiology of JPS has remained elusive until recently. Cytoge netic analysis of a single patient with JPS and congenital abnormal ities of the head, extremities, and abdomen revealed a de novo interstitial deletion at 10q22. 3â€”24. 1 that spans a 25-cM interval en 4 The abbreviations used are: APC, adenomatous polyposis coli; CS, Cowden syn drome;JPS,juvenilepolyposisyndrome; BZS,Bannayan-Zonana syndrome; PJS,Peutz Jegher syndrome; DGGE, denaturing gradient gel electrophoresis. Juvenile polyposis syndrome (JPS; MIM 174900) Is an autosomal dom itsant condition with incomplete penetrance characterized by hamartoma tons polyps of the gastrointestinal tract and a risk of gastrOIntestinal cancer. Gastrointestinal hamartomatous polyps are also present in Cow den syndrome (CS; MIM 158350) and Bannayan-Zonana syndrome (BZS; also called Ruvalcaba-Myhre-Smith syndrome MIM 153480). The ma ceptiblilty locus for both CS and BZS has recently been identified as the novel tumor suppressor gene PTEN, encoding a dual specificity phospha tam, located at 10q233. A putative JPS locus, JP1, which most likely functions as a tumor suppressor, had previously been mapped to 10q22. -24 in both fnmillal and sporadic juvenile polyps. Given the shared clinical features of gastrointestinal hamartomatous polyps among the three syn dramas and the coincident mapping of JPJ 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 span ning the CS/BZS locus (D10S219, DJOSS5J, D10S579, and DJOSS41) were used to compute multipoint led scores In eight informative families with ips. lodscoros of < â€”2.0 weregenerated for theentireregion, thus excluding PTEN and any genes within the flanldng 20-cM Interval as candidate loci for familial 31'S under our Statistical models. In addition, analysis oIPTEN using a combination of denaturing gradient gel electro phoresis and direct sequencing was unable to Identify a germllne mutation In 14 famIlies with JPS and 11 sporadIc cases. Therefore, at least a proportion ofJPS cases are not caused by germilne PTEN alteration or by an alternative locus at 10q22-24. Received 9t2/97; accepted 10/2/97. The costs of publication of this article were defrayed in part by the payment of page charges This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 â€ ̃fltis work was supported by the Dana-Farber Partners Cancer Center Women's Cancer Program, the Lawrence and Susan Marx Investigatorship, the Barr investigator ship, the Mackey Charitable Treat, and the Charles A. Dana Foundation (to C. E.), the Fsnnish Cancer Society (to L A. A.), The Academy of Finland and Special State Allow ance (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 â€ ̃@â€ ̃@ 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 021 15-6084. Phone: (617) 632-5632; Fax: (617) 632-4280; E-mail: charis.eng@macmailgw.dfci. harvaed.edu. ; L A. A. at Harttman Institute, Department of Medical Genetics, University of Helsinki, FIN-00014 Helsinki, Fmland,E-mail:lauti.aaltonen@helsinki.fl; and I. P. M.T. at Departmentof Clinical Genetics, Churchill Hospital. Oxford OX 3 lU, UK, E-mail: iptomlin@hgmp.mrc. ac.uk.