title: Prevalence of germline PTEN, BMPR1A, SMAD4, STK11, and ENG mutations in patients with moderate-load colorectal polyps.
abstract: OBJECTIVE
  Gastrointestinal polyposis is a common clinical problem, yet there is no consensus on how to best manage patients with moderate-load polyposis. Identifying genetic features of this disorder could improve management and especially surveillance of these patients. We sought to determine the prevalence of hamartomatous polyposis-associated mutations in the susceptibility genes PTEN, BMPR1A, SMAD4, ENG, and STK11 in individuals with ≥5 gastrointestinal polyps, including at least 1 hamartomatous or hyperplastic/serrated polyp.
  
  
  METHODS
  We performed a prospective, referral-based study of 603 patients (median age: 51 years; range, 2-89 years) enrolled from June 2006 through January 2012. Genomic DNA was extracted from peripheral lymphocytes and analyzed for specific mutations and large rearrangements in PTEN, BMPR1A, SMAD4, and STK11, as well as mutations in ENG. Recursive partitioning analysis was used to determine cutoffs for continuous variables. The prevalence of mutations was compared using Fisher's exact test. Logistic regression analyses were used to determine univariate and multivariate risk factors.
  
  
  RESULTS
  Of 603 patients, 119 (20%) had a personal history of colorectal cancer and most (n = 461 [76%]) had <30 polyps. Seventy-seven patients (13%) were found to have polyposis-associated mutations, including 11 in ENG (1.8%), 13 in PTEN (2.2%), 13 in STK11 (2.2%), 20 in BMPR1A (3.3%), and 21 in SMAD4 (3.5%). Univariate clinical predictors for risk of having these mutations included age at presentation younger than 40 years (19% vs 10%; P = .008), a polyp burden of ≥30 (19% vs 11%; P = .014), and male sex (16% vs 10%; P = .03). Patients who had ≥1 ganglioneuroma (29% vs 2%; P < .001) or presented with polyps of ≥3 histologic types (20% vs 2%; P = .003) were more likely to have germline mutations in PTEN.
  
  
  CONCLUSIONS
  Age younger than 40 years, male sex, and specific polyp histologies are significantly associated with risk of germline mutations in hamartomatous-polyposis associated genes. These associations could guide clinical decision making and further investigations.
authors: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors: Joanne
authors: J
authors: Ngeow
authors: Brandie
authors: B
authors: Heald
authors: Lisa A
authors: LA
authors: Rybicki
authors: Mohammed S
authors: MS
authors: Orloff
authors: Jin Lian
authors: JL
authors: Chen
authors: Xiuli
authors: X
authors: Liu
authors: Lisa
authors: L
authors: Yerian
authors: Joseph
authors: J
authors: Willis
authors: Heli J
authors: HJ
authors: Lehtonen
authors: Rainer
authors: R
authors: Lehtonen
authors: Jessica L
authors: JL
authors: Mester
authors: Jessica
authors: J
authors: Moline
authors: Carol A
authors: CA
authors: Burke
authors: James
authors: J
authors: Church
authors: Lauri A
authors: LA
authors: Aaltonen
authors: Charis
authors: C
authors: Eng
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003111:Colonic Polyps / Q000235:genetics*; D000071063:Endoglin; D005260:Female; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D010580:Peutz-Jeghers Syndrome / Q000235:genetics; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*; D051901:Smad4 Protein / Q000235:genetics*; D055815:Young Adult
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
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