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Kevin Sweet, MS, CGC; Joseph Willis, MD; Xiao-Ping Zhou, MD, PhD; Carol Gallione, PhD; Takeshi Sawada, MD, PhD; Pia Alhopuro, MD; Sok Kean Khoo, PhD; Attila Patocs, MD, PhD; Cossette Martin, PhD; Scott Bridgeman, BSc; John Heinz, PhD; Robert Pilarski, MS, CGC; Rainer Lehtonen, BSc; Thomas W. Prior, PhD; Thierry Frebourg, MD, PhD; Bin Tean Teh, MD, PhD; Douglas A. Marchuk, PhD; Lauri A. Aaltonen, MD, PhD; Charis Eng, MD, PhD

JAMA. 2005;294:2465-2473.

Context  Significant proportions of patients with hamartomatous polyposis or with hyperplastic/mixed polyposis remain without specific clinical and molecular diagnosis or present atypically. Assigning a syndromic diagnosis is important because it guides management, especially surveillance and prophylactic surgery.

Objective  To systematically classify patients with unexplained hamartomatous or hyperplastic/mixed polyposis by extensive molecular analysis in the context of central rereview of histopathology results.

Design, Setting, and Patients  Prospective, referral-based study of 49 unrelated patients from outside institutions (n = 28) and at a comprehensive cancer center (n = 21), conducted from May 2, 2002, until December 15, 2004. Germline analysis of PTEN, BMPR1A, STK11 (sequence, deletion), SMAD4, and ENG (sequence), specific exon screening of BRAF, MYH, and BHD, and rereview of polyp histology results were performed.

Main Outcome Measures  Molecular, clinical, and histopathological findings in patients with unexplained polyposis.

Results  Of the 49 patients, 11 (22%) had germline mutations. Of 14 patients with juvenile polyposis, 2 with early-onset disease had mutations in ENG, encoding endoglin, previously only associated with hereditary hemorrhagic telangiectasia; 1 had hemizygous deletion encompassing PTEN and BMPR1A; and 1 had an SMAD4 mutation. One individual previously classified with Peutz-Jeghers syndrome had a PTEN deletion. Among 9 individuals with an unknown hamartomatous polyposis, 4 had mutations in STK11 (1), BMPR1A (2), and SMAD4 (1). Of the 23 patients with hyperplastic/mixed polyposis, 2 had PTEN mutations. Substantial discrepancies in histopathology results were seen.

Conclusions  Systematic molecular classification of 49 patients with unexplained hamartomatous or hyperplastic polyposis uncovered a potential novel susceptibility gene, ENG, for juvenile polyposis. Importantly, given the substantial proportion of patients found to have germline mutations, more extensive analysis of the known susceptibility genes is indicated. Rereview of histology results by a dedicated gastrointestinal pathologist should be considered routinely, as organ-specific surveillance rests on defining syndromic diagnosis.

Author Affiliations: Clinical Cancer Genetics Program, Human Cancer Genetics Program, Comprehensive Cancer Center (Drs Zhou, Sawada, Patocs, and Eng and Mssrs Sweet and Pilarski), Division of Human Genetics, Department of Internal Medicine (Dr Eng and Mssrs Sweet and Pilarski), and Department of Pathology (Drs Prior and Heinz and Mr Bridgeman), The Ohio State University, Columbus; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (Drs Patocs and Eng); Department of Pathology, University Hospitals Health System (Dr Willis) and Department of Genetics, Case Western Reserve University School of Medicine (Dr Eng), Cleveland; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC (Drs Gallione and Marchuk); Biomedicum Helsinki, Department of Medical Genetics and Molecular and Cancer Biology Research Program, University of Helsinki, Helsinki, Finland (Drs Alhopuro and Aaltonen and Mr Lehtonen); Cancer Genetics Laboratory, Van Andel Research Institute, Grand Rapids, Mich (Drs Khoo and Teh); Department of Genetics, Faculty of Medicine University Hospital of Rouen, Rouen, France (Drs Martin and Frebourg); and Cancer Research UK Human Cancer Genetics Research Group, University of Cambridge, Cambridge, England (Dr Eng).

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