title: The serrated neoplasia pathway of colorectal tumors: Identification of MUC5AC hypomethylation as an early marker of polyps with malignant potential.
abstract: The serrated neoplasia pathway accounts for 20-30% of colorectal cancers (CRC), which are characterized by extensive methylation (CpG island methylation phenotype, CIMP), frequent BRAF mutation and high microsatellite instability (MSI). We recently identified MUC5AC mucin gene hypomethylation as a specific marker of MSI CRC. The early identification of preneoplastic lesions among serrated polyps is currently challenging. Here, we performed a detailed pathological and molecular analysis of a large series of colorectal serrated polyps and evaluated the usefulness of mucin genes MUC2 and MUC5AC to differentiate serrated polyps and to identify lesions with malignant potential. A series of 330 colorectal polyps including 218 serrated polyps [42 goblet cell-rich hyperplastic polyps (GCHP), 68 microvesicular hyperplastic polyps (MVHP), 100 sessile serrated adenoma (SSA) and eight traditional serrated adenoma (TSA)] and 112 conventional adenomas was analyzed for BRAF/KRAS mutations, MSI, CIMP, MLH1 and MGMT methylation, and MUC2 and MUC5AC expression and methylation. We show that MUC5AC hypomethylation is an early event in the serrated neoplasia pathway, and specifically detects MVHP and SSA, arguing for a filiation between MVHP, SSA and CIMP-H/MSI CRC, whereas GCHP and TSA arise from a distinct pathway. Moreover, MUC5AC hypomethylation specifically identified serrated lesions with BRAF mutation, CIMP-H or MSI, suggesting that it may be useful to identify serrated neoplasia pathway-related precursor lesions. Our data suggest that MVHP should be recognized among HP and require particular attention.
authors.affiliation: Inserm, UMR-S1172, Team 'Mucins, Epithelial Differentiation and Carcinogenesis', Jean-Pierre Aubert Research Center, Lille, France.|Pathology Institute, Biology Pathology Center, Lille University Hospital, Lille, France.|North of France Lille 2 University, Lille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Renaud
authors.affiliation: Inserm, UMR-S1172, Team 'Mucins, Epithelial Differentiation and Carcinogenesis', Jean-Pierre Aubert Research Center, Lille, France.|North of France Lille 2 University, Lille, France.|Department of Digestive Surgery, Claude Huriez Hospital, Lille University Hospital, Lille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Mariette
authors.affiliation: Inserm, UMR-S1172, Team 'Mucins, Epithelial Differentiation and Carcinogenesis', Jean-Pierre Aubert Research Center, Lille, France.|North of France Lille 2 University, Lille, France.|Lille University Hospital, Lille, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Vincent
authors.affiliation: Pathology Institute, Biology Pathology Center, Lille University Hospital, Lille, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Wacrenier
authors.affiliation: Department of Gastroenterology, Claude Huriez Hospital, Lille University Hospital, Lille, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Maunoury
authors.affiliation: Inserm, UMR-S1172, Team 'Mucins, Epithelial Differentiation and Carcinogenesis', Jean-Pierre Aubert Research Center, Lille, France.|North of France Lille 2 University, Lille, France.|Department of Molecular Oncology and Genetics, Biochemistry and Molecular Biology Institute, Biology Pathology Center, Lille University Hospital, Lille, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Leclerc
authors.affiliation: Inserm, UMR-S1172, Team 'Mucins, Epithelial Differentiation and Carcinogenesis', Jean-Pierre Aubert Research Center, Lille, France.|North of France Lille 2 University, Lille, France.|Department of Molecular Oncology and Genetics, Biochemistry and Molecular Biology Institute, Biology Pathology Center, Lille University Hospital, Lille, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Coppin
authors.affiliation: Department of Molecular Oncology and Genetics, Biochemistry and Molecular Biology Institute, Biology Pathology Center, Lille University Hospital, Lille, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Crépin
authors.affiliation: Inserm, UMR-S1172, Team 'Mucins, Epithelial Differentiation and Carcinogenesis', Jean-Pierre Aubert Research Center, Lille, France.|North of France Lille 2 University, Lille, France.|Lille University Hospital, Lille, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van Seuningen
authors.affiliation: Inserm, UMR-S1172, Team 'Mucins, Epithelial Differentiation and Carcinogenesis', Jean-Pierre Aubert Research Center, Lille, France.|Pathology Institute, Biology Pathology Center, Lille University Hospital, Lille, France.|North of France Lille 2 University, Lille, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Leteurtre
authors.affiliation: Inserm, UMR-S1172, Team 'Mucins, Epithelial Differentiation and Carcinogenesis', Jean-Pierre Aubert Research Center, Lille, France.|North of France Lille 2 University, Lille, France.|Department of Molecular Oncology and Genetics, Biochemistry and Molecular Biology Institute, Biology Pathology Center, Lille University Hospital, Lille, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Buisine
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003111:Colonic Polyps / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D019175:DNA Methylation; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D055271:Mucin 5AC / Q000235:genetics*; D009154:Mutation; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D055271:Mucin 5AC; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins
keywords: colonic cancer; hyperplastic polyp; methylation; mucin; sessile serrated adenoma