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Background  Depending on the population studied, large genomic rearrangements (LGRs) of the mismatch repair ( MMR ) genes constitute various proportions of the germline mutations that predispose to hereditary non-polyposis colorectal cancer (HNPCC). It has been reported that loss of heterozygosity (LOH) at the LGR region occurs through a gene conversion mechanism in tumors from  MLH1 / MSH2  deletion carriers; however, the converted tracts were delineated only by extragenic microsatellite markers. We sought to determine the frequency of LGRs in Slovak HNPCC patients and to study LOH in tumors from LGR carriers at the LGR region, as well as at other heterozygous markers within the gene to more precisely define conversion tracts.    Methods  The main  MMR  genes responsible for HNPCC,  MLH1 ,  MSH2 ,  MSH6 , and  PMS2 , were analyzed by MLPA (multiplex ligation-dependent probe amplification) in a total of 37 unrelated HNPCC-suspected patients whose  MLH1/MSH2  genes gave negative results in previous sequencing experiments. An LOH study was performed on six tumors from LGR carriers by combining MLPA to assess LOH at LGR regions and sequencing to examine LOH at 28 SNP markers from the  MLH1  and  MSH2  genes.    Results  We found six rearrangements in the  MSH2  gene (five deletions and dup5-6), and one aberration in the  MLH1  gene (del5-6). The  MSH2  deletions were of three types (del1, del1-3, del1-7). We detected LOH at the LGR region in the single  MLH1  case, which was determined in a previous study to be LOH-negative in the intragenic D3S1611 marker. Three tumors displayed LOH of at least one SNP marker, including two cases that were LOH-negative at the LGR region.    Conclusion  LGRs accounted for 25% of germline  MMR  mutations identified in 28 Slovakian HNPCC families. A high frequency of LGRs among the  MSH2  mutations provides a rationale for a MLPA screening of the Slovakian HNPCC families prior scanning by DNA sequencing. LOH at part of the informative loci confined to the  MLH1  or  MSH2  gene (heterozygous LGR region, SNP, or microsatellite) is a novel finding and can be regarded as a partial LOH. The conversion begins within the gene, and the details of conversion tracts are discussed for each case.

Partial loss of heterozygosity events at the mutated gene in tumors from MLH1/MSH2 large genomic rearrangement carriers