title: MSH2 in contrast to MLH1 and MSH6 is frequently inactivated by exonic and promoter rearrangements in hereditary nonpolyposis colorectal cancer.
abstract: To estimate the relative frequency of mismatch repair genes, rearrangements in hereditary nonpolyposis colorectal cancer (HNPCC) families without detectable mutations in MSH2 or MLH1, we have analyzed by multiplex PCR of short fluorescent fragments MSH2, MLH1, and MSH6 in 61 families, either fulfilling Amsterdam criteria or including cases of multiple primary cancers belonging to the HNPCC spectrum. We detected 13 different genomic rearrangements of MSH2 in 14 families (23%), whereas we found no rearrangement of MLH1 and MSH6. Analysis of 31 other families, partially meeting Amsterdam criteria, revealed no additional rearrangement of MSH2. All of the MSH2 rearrangements, except one, corresponded to genomic deletions involving one or several exons. In 8 of 13 families with a MSH2 genomic deletion, the MSH2 promoter was also deleted, and the 5' breakpoint was located either within or upstream the MSH2 gene. This study demonstrates the heterogeneity of MSH2 exonic and promoter rearrangements and shows that, in HNPCC families without detectable MSH2 or MLH1 point mutation, one must consider the presence of MSH2 genomic rearrangements before the involvement of other mismatch repair genes. The simplicity and rapidity of their detection, using fluorescent multiplex PCR, led us to recommend to begin the molecular analysis in HNPCC by screening for MSH2 rearrangements.
authors.affiliation: Laboratoire de Génétique Moléculaire, CHU de Rouen et Institut National de la Santé et de la Recherche Médicale EMI 9906, Faculté de Médecine et de Pharmacie, IFRMP, 22 Boulevard de Gambetta, 76183 Rouen, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Charbonnier
authors.forename: Sylviane
authors.initials: S
authors.lastname: Olschwang
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Cécile
authors.initials: C
authors.lastname: Boisson
authors.forename: Cosette
authors.initials: C
authors.lastname: Martin
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Buisine
authors.forename: Alain
authors.initials: A
authors.lastname: Puisieux
authors.forename: Thierry
authors.initials: T
authors.lastname: Frebourg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D020868:Gene Silencing; D006801:Humans; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D017354:Point Mutation; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein