title: The 5' region of the MSH2 gene involved in hereditary non-polyposis colorectal cancer contains a high density of recombinogenic sequences.
abstract: MSH2 rearrangements are involved in approximately 10% of hereditary non-polyposis colorectal cancer (HNPCC) families, and in most of the rearrangements, exon 1 is deleted. We scanned by quantitative multiplex polymerase chain reaction (PCR) of short fluorescent fragments (QMPSF) 200 kb of genomic sequences upstream of the MSH2 transcription initiation site in 21 HNPCC families with exon 1 deletions. This QMPSF scan revealed 12 distinct 5' breakpoints located up to 200 kb upstream of the MSH2 transcription initiation site. Sequencing analysis of the rearranged allele in 17 families revealed that most of the deletions (15/17) resulted from homologous Alu-mediated recombination. QMPSF and sequencing analysis in these 21 families led us to detect the presence of 20 distinct 5' breakpoints. In 14 out of 15 Alu-mediated recombinations, we found, either within the identical region in which the recombination had probably occurred or in its vicinity, the 26-bp Alu core sequence containing the recombinogenic Chi-like motif. Compared to the equivalent regions of other human genes, the MSH2 upstream region was found to contain a high density of Alu repeats (30% within 228 kb and 43% within 50 kb), most of which belong to the old Alu S subfamilies. In conclusion, this study demonstrates the heterogeneity of the breakpoints within the MSH2 upstream region and reveals the remarkable density of recombinogenic Alu sequences in this region.
authors.affiliation: Inserm U614-IFRMP, Faculty of Medicine, Rouen, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Charbonnier
authors.forename: Stephanie
authors.initials: S
authors.lastname: Baert-Desurmont
authors.forename: Ping
authors.initials: P
authors.lastname: Liang
authors.forename: Frederic
authors.initials: F
authors.lastname: Di Fiore
authors.forename: Cosette
authors.initials: C
authors.lastname: Martin
authors.forename: Stephanie
authors.initials: S
authors.lastname: Frerot
authors.forename: Sylviane
authors.initials: S
authors.lastname: Olschwang
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Buisine
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gilbert
authors.forename: Mef
authors.initials: M
authors.lastname: Nilbert
authors.forename: Annika
authors.initials: A
authors.lastname: Lindblom
authors.forename: Thierry
authors.initials: T
authors.lastname: Frebourg
mesh_terms: D000328:Adult; D020087:Alu Elements; D001483:Base Sequence; D015179:Colorectal Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons; D017353:Gene Deletion; D006801:Humans; D008875:Middle Aged; D008957:Models, Genetic; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D011995:Recombination, Genetic; D012689:Sequence Homology, Nucleic Acid
chemical_list: C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein