title: An interstitial deletion at 3p21.3 results in the genetic fusion of MLH1 and ITGA9 in a Lynch syndrome family.
abstract: OBJECTIVE
  Germline mutations in DNA mismatch repair genes, mainly MLH1 or MSH2, have been shown to predispose with high penetrance for the development of the clinical phenotype of hereditary nonpolyposis colorectal cancer (Lynch syndrome). Here, we describe the discovery and first functional characterization of a novel germline MLH1 mutant allele.
  
  
  METHODS
  A large kindred including 54 potential carriers was investigated at the molecular level by using different types of PCR experiments, gene cloning, transfection studies, Western blot experiments, and mismatch repair assays to identify and characterize a novel MLH1 mutant allele. Twenty-two of 54 putative carriers developed colon cancer or other tumors, including breast cancer.
  
  
  RESULTS
  The identified MLH1 mutant allele emerged from an interstitial deletion on chromosome 3p21.3, leading to an in-frame fusion of MLH1 (exons 1-11) with ITGA9 (integrin alpha 9; exons 17-28). The deleted area has a size of about 400 kb; codes for LRRFIP2 (leucine-rich repeat in flightless interaction protein 2), GOLGA4 (Golgi autoantigen, golgin subfamily a, 4), and C3orf35/APRG1 (chromosome 3 open reading frame 35/AP20 region protein 1); and partly disrupts the AP20 region implicated in major epithelial malignancies. Tumor cells lost their second MLH1 allele. The MLH1*ITGA9 fusion protein provides no capability for DNA mismatch repair. Murine fibroblasts, expressing a doxycycline-inducible MLH1*ITGA9 fusion gene, exhibit a loss-of-contact inhibition phenotype.
  
  
  CONCLUSIONS
  This is the first description of a functional gene fusion of the human MLH1 gene, resulting in the loss of mismatch repair capabilities. The MLH1*ITGA9 fusion allele, together with deletions of the AP20 region, presumably defines a novel subclass of Lynch syndrome patients, which results in an extended tumor spectrum known from hereditary nonpolyposis colorectal cancer and Muir-Torre syndrome patients.
authors.affiliation: Institute of Pharmaceutical Biology/Diagnostic Center for Acute Leukemia/Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit/Cluster of Excellence Frankfurt, Biocenter, Goethe-University Frankfurt, Frankfurt/Main, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Meyer
authors.forename: Angela
authors.initials: A
authors.lastname: Brieger
authors.forename: Guido
authors.initials: G
authors.lastname: Plotz
authors.forename: Nicole
authors.initials: N
authors.lastname: Weber
authors.forename: Sandra
authors.initials: S
authors.lastname: Passmann
authors.forename: Theo
authors.initials: T
authors.lastname: Dingermann
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.forename: Joerg
authors.initials: J
authors.lastname: Trojan
authors.forename: Rolf
authors.initials: R
authors.lastname: Marschalek
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D053843:DNA Mismatch Repair; D005260:Female; D050939:Gene Fusion; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics*; D016023:Integrins / Q000235:genetics*; D008297:Male; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D017384:Sequence Deletion
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C541973:ITGA9 protein, human; D039001:Integrin alpha Chains; D016023:Integrins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1