title: Identification and characterization of a novel MLH1 genomic rearrangement as the cause of HNPCC in a Tunisian family: evidence for a homologous Alu-mediated recombination.
abstract: High rates of early colorectal cancers are observed in Tunisia suggesting high genetic susceptibility. Nevertheless, up to now no molecular studies have been performed. Hereditary nonpolyposis colorectal cancer (HNPCC) is the most frequent cause of inherited colorectal cancer. It is caused by constitutional mutations in the DNA mismatch repair (MMR) genes. Here, we investigated a Tunisian family highly suspected of hereditary nonpolyposis colorectal cancer (HNPCC). Six patients were diagnosed with a colorectal or an endometrial cancer at an early age, including one young female who developed a colorectal cancer at 22 years and we tested for germline mutations in MMR genes. MMR genes were tested for rearrangements by MLPA (MLH1, MSH2) and the presence of point mutations by sequencing (MLH1, MSH2, MSH6). Moreover, tumors were analyzed for microsatellite instability and expression of MMR proteins, as well as for somatic rearrangements in MLH1 and MSH2 by MLPA. MMR gene analysis by MLPA revealed the presence of a large deletion in MLH1 removing exon 6. Sequence analysis of the breakpoint region showed that this rearrangement resulted from a homologous unequal recombination mediated by a repetitive Alu sequence. Moreover, tumors harbored biallelic deletion of MLH1 exon 6 and loss of heterozygosity at MLH1 intragenic markers, suggesting duplication of the rearranged allele in the tumor. This germline MLH1 rearrangement was associated to a severe phenotype in this family. This is the first report of a molecular analysis in a Tunisian family with HNPCC.
authors.affiliation: Laboratoire de Biochimie et Biologie Moléculaire, Faculté des Sciences de Tunis, Tunis, Tunisia.
authors.forename: Sana
authors.initials: S
authors.lastname: Aissi-Ben Moussa
authors.forename: Amel
authors.initials: A
authors.lastname: Moussa
authors.forename: Tonio
authors.initials: T
authors.lastname: Lovecchio
authors.forename: Nadia
authors.initials: N
authors.lastname: Kourda
authors.forename: Taoufik
authors.initials: T
authors.lastname: Najjar
authors.forename: Sarra
authors.initials: S
authors.lastname: Ben Jilani
authors.forename: Amel
authors.initials: A
authors.lastname: El Gaaied
authors.forename: Nicole
authors.initials: N
authors.lastname: Porchet
authors.forename: Mohamed
authors.initials: M
authors.lastname: Manai
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Buisine
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D020087:Alu Elements / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D015321:Gene Rearrangement / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D014416:Tunisia; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1
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