Genomic rearrangements of hMSH6 contribute to the genetic predisposition in suspected hereditary non-polyposis colorectal cancer syndrome.
BACKGROUND
Germline mutations in mismatch repair genes, mainly in hMLH1, hMSH2, and hMSH6, predispose to the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. A substantial fraction of these mutations exists in genomic rearrangements of hMSH2 and hMLH1. In contrast, genomic rearrangements have not been reported in hMSH6.


METHODS
Out of 15 HNPCC or HNPCC-like patients who developed tumours with loss of hMSH6 protein expression, we selected three patients who still had no germline mutations after gene sequencing. Genomic DNA of these patients was analysed using PCR based relative quantification of hMSH6 fragments. Indicated exon deletions and amplifications were characterised by long range PCR and sequencing.


RESULTS
Genomic rearrangements were identified in two of the three patients. Breakpoint analyses showed an Alu repeat mediated deletion of 13.0 kb affecting the promoter region, exon 1, and exon 2 in one patient, and a duplication of 4.9 kb containing 1.6 kb of the 3' end of exon 4 and exon 5, integrated into intron 5, in the other patient.


CONCLUSIONS
Although genomic rearrangements of hMSH6 only play a small role in the spectrum of all mutations predisposing to HNPCC, our results suggest that up to 10-20% of patients with hMSH6 negative tumours harbour germline rearrangements in this gene.
Plaschke
J
J
Department of Surgical Research, Carl Gustav Carus Klinikum, Dresden University of Technology, D-01307 Dresden, Germany. plaschke@rcs.urz.tu-dresden.de
Rüschoff
J
J
Schackert
H K
HK
D019457:Chromosome Breakage / Q000235:genetics; D002872:Chromosome Deletion; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D015321:Gene Rearrangement / Q000235:genetics*; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human; D018095:Germ-Line Mutation; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics
D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D005819:Genetic Markers