Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis

JAMA. 2005 Nov 16;294(19):2465-73. doi: 10.1001/jama.294.19.2465.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • Adolescent
  • Adult
  • Antigens, CD
  • Bone Morphogenetic Protein Receptors, Type I / genetics
  • Child
  • Endoglin
  • Genetic Predisposition to Disease
  • Germ-Line Mutation
  • Hamartoma Syndrome, Multiple / classification
  • Hamartoma Syndrome, Multiple / genetics*
  • Hamartoma Syndrome, Multiple / pathology
  • Humans
  • Intestinal Polyposis / classification
  • Intestinal Polyposis / genetics*
  • Intestinal Polyposis / pathology
  • Intestinal Polyps / classification
  • Intestinal Polyps / genetics*
  • Intestinal Polyps / pathology
  • Middle Aged
  • Mutation
  • PTEN Phosphohydrolase / genetics
  • Peutz-Jeghers Syndrome / classification
  • Peutz-Jeghers Syndrome / genetics*
  • Peutz-Jeghers Syndrome / pathology
  • Prospective Studies
  • Protein Serine-Threonine Kinases / genetics
  • Proteins / genetics
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins B-raf / genetics
  • Receptors, Cell Surface
  • Smad4 Protein / genetics
  • Syndrome
  • Tumor Suppressor Proteins
  • Vascular Cell Adhesion Molecule-1 / genetics


  • Antigens, CD
  • ENG protein, human
  • Endoglin
  • FLCN protein, human
  • Proteins
  • Proto-Oncogene Proteins
  • Receptors, Cell Surface
  • Smad4 Protein
  • Tumor Suppressor Proteins
  • Vascular Cell Adhesion Molecule-1
  • BRAF protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins B-raf
  • STK11 protein, human
  • AMP-Activated Protein Kinase Kinases
  • BMPR1A protein, human
  • Bone Morphogenetic Protein Receptors, Type I
  • PTEN Phosphohydrolase
  • PTEN protein, human