RT Journal Article
SR Electronic
T1 Aberrant intestinal stem cell lineage dynamics in Peutz–Jeghers syndrome and familial adenomatous polyposis consistent with protracted clonal evolution in the crypt
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 839
OP 846
DO 10.1136/gutjnl-2011-300622
VO 61
IS 6
A1 Danielle Langeveld
A1 Marnix Jansen
A1 D V de Boer
A1 Mariska van Sprundel
A1 Lodewijk A A Brosens
A1 Folkert H Morsink
A1 Francis M Giardiello
A1 G Johan A Offerhaus
A1 Wendy W J de Leng
YR 2012
UL http://gut.bmj.com/content/61/6/839.abstract
AB 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.Design 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.