Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis

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

Research output: Contribution to journalArticle

186 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2465-2473
Number of pages9
JournalJournal of the American Medical Association
Volume294
Issue number19
DOIs
Publication statusPublished - Nov 16 2005

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Mutation
Germ-Line Mutation
Histology
Peutz-Jeghers Syndrome
Hereditary Hemorrhagic Telangiectasia
Sequence Deletion
Polyps
Genes
Exons
Referral and Consultation
Outcome Assessment (Health Care)
Neoplasms
Endoglin
Pathologists

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Sweet, K., Willis, J., Zhou, X. P., Gallione, C., Sawada, T., Alhopuro, P., ... Eng, C. (2005). Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. Journal of the American Medical Association, 294(19), 2465-2473. https://doi.org/10.1001/jama.294.19.2465

Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. / Sweet, Kevin; Willis, Joseph; Zhou, Xiao Ping; Gallione, Carol; Sawada, Takeshi; Alhopuro, Pia; Khoo, Sok Kean; Patócs, A.; Martin, Cossette; Bridgeman, Scott; Heinz, John; Pilarski, Robert; Lehtonen, Rainer; Prior, Thomas W.; Frebourg, Thierry; Teh, Bin Tean; Marchuk, Douglas A.; Aaltonen, Lauri A.; Eng, Charis.

In: Journal of the American Medical Association, Vol. 294, No. 19, 16.11.2005, p. 2465-2473.

Research output: Contribution to journalArticle

Sweet, K, Willis, J, Zhou, XP, Gallione, C, Sawada, T, Alhopuro, P, Khoo, SK, Patócs, A, Martin, C, Bridgeman, S, Heinz, J, Pilarski, R, Lehtonen, R, Prior, TW, Frebourg, T, Teh, BT, Marchuk, DA, Aaltonen, LA & Eng, C 2005, 'Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis', Journal of the American Medical Association, vol. 294, no. 19, pp. 2465-2473. https://doi.org/10.1001/jama.294.19.2465
Sweet, Kevin ; Willis, Joseph ; Zhou, Xiao Ping ; Gallione, Carol ; Sawada, Takeshi ; Alhopuro, Pia ; Khoo, Sok Kean ; Patócs, A. ; Martin, Cossette ; Bridgeman, Scott ; Heinz, John ; Pilarski, Robert ; Lehtonen, Rainer ; Prior, Thomas W. ; Frebourg, Thierry ; Teh, Bin Tean ; Marchuk, Douglas A. ; Aaltonen, Lauri A. ; Eng, Charis. / Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. In: Journal of the American Medical Association. 2005 ; Vol. 294, No. 19. pp. 2465-2473.
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AU - Sweet, Kevin

AU - Willis, Joseph

AU - Zhou, Xiao Ping

AU - Gallione, Carol

AU - Sawada, Takeshi

AU - Alhopuro, Pia

AU - Khoo, Sok Kean

AU - Patócs, A.

AU - Martin, Cossette

AU - Bridgeman, Scott

AU - Heinz, John

AU - Pilarski, Robert

AU - Lehtonen, Rainer

AU - Prior, Thomas W.

AU - Frebourg, Thierry

AU - Teh, Bin Tean

AU - Marchuk, Douglas A.

AU - Aaltonen, Lauri A.

AU - Eng, Charis

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N2 - 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.

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