title: Intensity-dependent constitutional MLH1 promoter methylation leads to early onset of colorectal cancer by affecting both alleles.
abstract: Constitutional epimutation is one of the causes for MLH1 gene inactivation associated with hereditary non-polyposis colon cancer (HNPCC) syndrome. Here we investigate MLH1 promoter hypermethylation in 110 sporadic early-onset colorectal cancer patients. Variable levels of hypermethylation were detected in 55 patients (50%). Importantly a reduced MLH1 gene expression was found in patients with high-level methylation, with the association of microsatellite instability (MSI) in their tumor cells. Such high-level methylation accounts for 7.4% of all patients included in this study. Furthermore, we found that in one case constitutional methylation affected both alleles, indicating a post-zygotic methylation dysregulation. Our findings suggest that constitutional epimutation is a mechanism underlying early-onset colorectal cancer, although it is involved in only a small proportion of patients, who require appropriate surveillance. Our findings provide further insight into the role of aberrant constitutional methylation in colon carcinogenesis and raise the question of whether prevalent low-level methylation constitutes a potential risk factor for cancer development.
authors.affiliation: Centre Léon Bérard, Laboratoire de Recherche Translationnelle, Lyon, France.
authors.forename: Jessie
authors.initials: J
authors.lastname: Auclair
authors.forename: Thomas
authors.initials: T
authors.lastname: Vaissière
authors.forename: Françoise
authors.initials: F
authors.lastname: Desseigne
authors.forename: Christine
authors.initials: C
authors.lastname: Lasset
authors.forename: Valérie
authors.initials: V
authors.lastname: Bonadona
authors.forename: Sophie
authors.initials: S
authors.lastname: Giraud
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Saurin
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Joly
authors.forename: Dominique
authors.initials: D
authors.lastname: Leroux
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.forename: Carole
authors.initials: C
authors.lastname: Audoynaud
authors.forename: Gilles
authors.initials: G
authors.lastname: Montmain
authors.forename: Eric
authors.initials: E
authors.lastname: Ruano
authors.forename: Zdenko
authors.initials: Z
authors.lastname: Herceg
authors.forename: Alain
authors.initials: A
authors.lastname: Puisieux
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053842:Microsatellite Instability; D008875:Middle Aged; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1