title: Aberrant intestinal stem cell lineage dynamics in Peutz-Jeghers syndrome and familial adenomatous polyposis consistent with protracted clonal evolution in the crypt.
abstract: OBJECTIVE
  Genetic predisposition to cancer in Peutz-Jeghers syndrome (PJS) and the role of germline serine-threonine kinase (LKB1) mutations are poorly understood. The authors studied the effect of germline LKB1 mutations on intestinal stem cell dynamics in unaffected flat PJS mucosa. Recent research has documented that the intestinal crypt houses multiple equipotent stem cell lineages. Lineages continuously compete through random drifts, while somatically inherited methylation patterns record clonal diversity.
  
  
  METHODS
  To study the effect of germline LKB1 mutations on clonal expansion, the authors performed quantitative analyses of cardiac-specific homeobox methylation pattern diversity in crypts isolated from unaffected colonic mucosa obtained from archival PJS patient material. The authors compared methylation density and methylation pattern diversity in patients with PJS to those in patients with familial adenomatous polyposis and age-matched controls.
  
  
  RESULTS
  The percentage of total methylation is comparable between groups, but the number of unique methylation patterns is significantly increased for patients with familial adenomatous polyposis and patients with PJS compared to control subjects.
  
  
  CONCLUSIONS
  Monoallelic LKB1 loss is not silent and provokes a protracted clonal evolution in the crypt. The increased methylation pattern diversity observed in unaffected PJS mucosa predicts that premalignant lesions will arise at an accelerated pace compared to the general population.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Danielle
authors.initials: D
authors.lastname: Langeveld
authors.forename: Marnix
authors.initials: M
authors.lastname: Jansen
authors.forename: D V
authors.initials: DV
authors.lastname: de Boer
authors.forename: Mariska
authors.initials: M
authors.lastname: van Sprundel
authors.forename: Lodewijk A A
authors.initials: LA
authors.lastname: Brosens
authors.forename: Folkert H
authors.initials: FH
authors.lastname: Morsink
authors.forename: Francis M
authors.initials: FM
authors.lastname: Giardiello
authors.forename: G Johan A
authors.initials: GJ
authors.lastname: Offerhaus
authors.forename: Wendy W J
authors.initials: WW
authors.lastname: de Leng
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D011125:Adenomatous Polyposis Coli / Q000209:etiology* / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D019070:Cell Lineage / Q000235:genetics*; D002648:Child; D019175:DNA Methylation; D006801:Humans; D007413:Intestinal Mucosa / Q000502:physiology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010580:Peutz-Jeghers Syndrome / Q000209:etiology* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D013234:Stem Cells / Q000502:physiology*; D055815:Young Adult
chemical_list: D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases