Aberrant intestinal stem cell lineage dynamics in Peutz–Jeghers syndrome and familial adenomatous polyposis consistent with protracted clonal evolution in the crypt

• Published in: Gut Vol. 61; no. 6; pp. 839 - 846
• Main Authors: Langeveld, Danielle, Jansen, Marnix, de Boer, D V, van Sprundel, Mariska, Brosens, Lodewijk A A, Morsink, Folkert H, Giardiello, Francis M, Offerhaus, G Johan A, de Leng, Wendy W J
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01.06.2012; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: adenocarcinoma; Adenomatous Polyposis Coli - etiology; Adenomatous Polyposis Coli - genetics; Adolescent; Adult; Aged; Biological and medical sciences; cancer; cancer prevention; cancer syndromes; Case-Control Studies; Cell Lineage - genetics; Child; clonal expansion; Cloning; Colorectal cancer; colorectal cancer genes; colorectal cancer screening; colorectal neoplasia; colorectal neoplasm; CSX; Dermatology; DNA Methylation; Evolution; Gastroenterology. Liver. Pancreas. Abdomen; gastrointestinal cancer; gastrointestinal neoplasia; gastrointestinal pathology; Genetic diversity; Humans; Intestinal Mucosa - physiology; LGR5; LKB1; Medical sciences; methylation pattern diversity; Middle Aged; molecular genetics; Mutation; Mutation - genetics; Peutz-Jeghers Syndrome - etiology; Peutz-Jeghers Syndrome - genetics; Peutz–Jeghers syndrome; Pigmentary diseases of the skin; polyp; polyposis; Population; Protein-Serine-Threonine Kinases - genetics; Stem cell; Stem cells; Stem Cells - physiology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Studies; Tumors; Young Adult; Skin disease; Pigmentation disorder; Lentiginosis; Stem cell; Gut; Familial adenomatous polyposis coli; Peutz-Jeghers syndrome; Genetic disease; Gastroenterology; Digestive diseases; Intestinal disease; Evolution; Benign neoplasm
• ISSN: 0017-5749; 1468-3288; 1468-3288
• DOI: 10.1136/gutjnl-2011-300622

ObjectiveGenetic 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.DesignTo 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.ResultsThe 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.ConclusionsMonoallelic 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.