Familial Cancer

, Volume 8, Issue 2, pp 119–126 | Cite as

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

  • Sana Aissi-Ben Moussa
  • Amel Moussa
  • Tonio Lovecchio
  • Nadia Kourda
  • Taoufik Najjar
  • Sarra Ben Jilani
  • Amel El Gaaied
  • Nicole Porchet
  • Mohamed Manai
  • Marie-Pierre BuisineEmail author


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.


HNPCC MLH1 MLPA Microsatellite instability Alu Recombination 



Colorectal cancer


Hereditary nonpolyposis colorectal cancer


Loss of heterozygosity


Multiplex ligation dependent probe amplification


Mismatch repair gene


Microsatellite instability





This study was the result of collaboration between the universities of Tunis-El Manar and Lille 2. S.A.B. was supported in part by a grant from the Tunisian government. We would like to thank Dr. A. Wacrenier for her help in immunohistochemical studies and our colleagues for their participation to this study. We also thank the “Plateau Commun de Biologie Moléculaire du Centre de Biologie-Pathologie” of the CHRU of Lille.


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Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Sana Aissi-Ben Moussa
    • 1
    • 2
  • Amel Moussa
    • 3
  • Tonio Lovecchio
    • 4
    • 5
  • Nadia Kourda
    • 6
  • Taoufik Najjar
    • 3
  • Sarra Ben Jilani
    • 6
  • Amel El Gaaied
    • 7
  • Nicole Porchet
    • 2
    • 4
    • 5
    • 8
  • Mohamed Manai
    • 1
  • Marie-Pierre Buisine
    • 2
    • 4
    • 5
    • 8
    Email author
  1. 1.Laboratoire de Biochimie et Biologie MoléculaireFaculté des Sciences de TunisTunisTunisia
  2. 2.Equipe n°5Centre de Recherche Jean-Pierre Aubert, INSERM U837Lille CedexFrance
  3. 3.Service de Gastro-EntérologieHôpital Charles Nicolle de TunisTunisTunisia
  4. 4.Laboratoire de Biochimie et Biologie MoléculaireCHRU de LilleLilleFrance
  5. 5.Cancéropôle Nord-OuestLilleFrance
  6. 6.Laboratoire d’AnatomopathologieHôpital Charles Nicolle de TunisTunisTunisia
  7. 7.Laboratoire de Génétique et Immunologie des Pathologies HumainesFaculté des Sciences de TunisTunisTunisia
  8. 8.Faculté de Médecine H. WarembourgUniversité de Lille 2LilleFrance

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