Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer

Abstract

The mechanism by which germline mutations of DNA mismatch repair genes cause susceptibility to tumour formation is not yet understood. Studies in vitro indicate that heterozygosity for these mutations, unlike homozygosity, does not affect mismatch repair. Surprisingly, no loss of heterozygosity at the predisposing loci has so far been described in hereditary nonpolyposis colorectal cancers. Here, we show that loss of heterozygosity (LOH) of markers within or adjacent to the MLH1 gene on chromosome 3p occurs nonrandomly in tumours from members of families in which the disease phenotype cosegregates with MLH1. In every informative case, the loss affects the wild type allele. These results suggest that DNA mismatch repair genes resemble tumour suppressor genes in that two hits are required to cause a phenotypic effect.

Immunohistochemical analysis of expression and allelotype of mismatch repair genes (hMLH1 and hMSH2) in bladder cancer

“…This second mutational step may be revealed as LOH, which was previously reported at the hMLH1 locus in HNPCC (Hemminki et al, 1994) as well as at hMLH1 and hMSH2 loci in sporadic colorectal cancers (Tomlinson et al, 1996;Benachenhou et al, 1998b), in non-small cell lung cancer (Benachenhou et al, 1998a) and in breast cancer (Benachenhou et al, 1999). Christensen et al (1998) reported the occurrence of LOH at microsatellites located close to hMSH2 and hMLH1 and suggested a possible role of these genes in causing profound MSI in bladder cancer.…”

“…Tumour suppressor and MMR genes share the requirement for homozygosity at the cellular level and somatic deletion is a common event in both (Hemminki et al, 1994). This second mutational step may be revealed as LOH, which was previously reported at the hMLH1 locus in HNPCC (Hemminki et al, 1994) as well as at hMLH1 and hMSH2 loci in sporadic colorectal cancers (Tomlinson et al, 1996;Benachenhou et al, 1998b), in non-small cell lung cancer (Benachenhou et al, 1998a) and in breast cancer (Benachenhou et al, 1999).…”

No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer

“…The majority of the HNPCC patients have mutations in MLH1 or MSH2 genes (Peltoma¨ki and Vasen, 2004). MMR genes are considered as caretaker genes, and inactivation of both alleles is believed to be required for tumor development Hemminki et al, 1994). Deficiency in MMR machinery creates genomic instability that can be observed as frequently mutated microsatellite sequences (microsatellite instability (MSI)) in tumor cells of the HNPCC patients (Aaltonen et al, 1993).…”

“…MLH1 promoter hypermethylation has been detected in 17-46% of the HNPCC tumors (Cunningham et al, 1998;Herman et al, 1998;Kuismanen et al, 2000;Potocnik et al, 2001). Loss of the wild-type allele in HNPCC tumors was proposed by Hemminki et al (1994) and it has been found to be the major mechanism for somatic second hits in most of the studies. Frequency of LOH in published studies varies between 33 and 86% (Hemminki et al, 1994;Lu et al, 1996;Tannerga˚rd et al, 1997;Kuismanen et al, 2000;Potocnik et al, 2001;Yuen et al, 2002), although the lost allele has not always been specified.…”

“…Loss of the wild-type allele in HNPCC tumors was proposed by Hemminki et al (1994) and it has been found to be the major mechanism for somatic second hits in most of the studies. Frequency of LOH in published studies varies between 33 and 86% (Hemminki et al, 1994;Lu et al, 1996;Tannerga˚rd et al, 1997;Kuismanen et al, 2000;Potocnik et al, 2001;Yuen et al, 2002), although the lost allele has not always been specified. In contrast, sporadic MMR-deficient tumors are most commonly due to bi-allelic inactivation of MLH1 by promoter hypermethylation, and these tumors rarely show LOH or somatic mutations in MLH1 (Kane et al, 1997;Cunningham et al, 1998;Herman et al, 1998;Veigl et al, 1998;Wheeler et al, 1999;Kuismanen et al, 2000).…”