title: MYH biallelic mutation can inactivate the two genetic pathways of colorectal cancer by APC or MLH1 transversions.
abstract: MYH associated polyposis is a hereditary syndrome responsible for early colorectal cancer with a distinct genetic pathway from the Familial Adenomatous Polyposis or the Hereditary Non Polyposis Colorectal Cancer syndrome. We have studied a family with three members bearing a biallelic mutation in MYH at c.1185_1186dup. One patient who developed colon cancer had loss of expression of MLH1 on tumoral tissue and microsatellite instability (MSI) phenotype. Analysis of MLH1 based on his blood sample revealed no germline mutation or large genomic deletion. No methylation of the promoter was identified in tumoral DNA. No transversion mutations were identified in APC or KRAS in tumor DNA of this patient. Loss of expression of MLH1 was due to a transversion in intron 7 at position +5 (c.588 + 5G > T) leading to a complete deletion of exon 7 at the RNA level. This observation demonstrates that MLH1 can be a target of MYH transversions leading to MSI phenotype.
authors.affiliation: Department of Digestive Surgery, Hôpital Saint-Antoine AP-HP, University Pierre et Marie Curie Paris VI, 184 rue du Faubourg Saint-Antoine, 75571 Paris, France. jeremie.lefevre@sat.aphp.fr
authors.forename: Jérémie H
authors.initials: JH
authors.lastname: Lefevre
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Colas
authors.forename: Florence
authors.initials: F
authors.lastname: Coulet
authors.forename: Carolina
authors.initials: C
authors.lastname: Bonilla
authors.forename: Najat
authors.initials: N
authors.lastname: Mourra
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Flejou
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Tiret
authors.forename: Walter
authors.initials: W
authors.lastname: Bodmer
authors.forename: Florent
authors.initials: F
authors.lastname: Soubrier
authors.forename: Yann
authors.initials: Y
authors.lastname: Parc
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000236:Adenoma / Q000175:diagnosis / Q000235:genetics*; D011125:Adenomatous Polyposis Coli / Q000175:diagnosis / Q000235:genetics*; D000483:Alleles; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D000070957:MutL Protein Homolog 1