Short communicationNo association between two MLH3 variants (S845G and P844L)and colorectal cancer risk
Introduction
The DNA mismatch repair system plays a critical role in genomic stability by correcting errors caused during DNA replication. Germline mutations in mismatch repair genes (MLH1, MSH2, and MSH6) have been found to be associated with hereditary nonpolyposis colorectal cancer (HNPCC) susceptibility.
In 12 out of 327 Dutch patients suspected of HNPCC, 10 different possibly disease causing germline MLH3 variants were detected: 1 frameshift (2578delA, which results in a premature stop codon) and 9 missense variants [1]. None of these variants were observed in the 188 controls; another variant (S845G) was detected seven times in the patientsand once in the controls. None of the families of the patients carrying this variant fulfilled the revised Amsterdam criteria for HNPCC [2]. Hence, it was hypothesized that this MLH3 variant might well play a role in causing apparently sporadic colorectal cancer. In the present study, therefore, we analyzed a part of exon 1, including the S845G variant, in DNA of 467 white sporadic colorectal cancer patients and 497 white controls.
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Patients and control individuals
The controls were spouses of the colorectal cancer pa-tients tested and spouses of breast cancer patients. Both patients and controls participated in population-based stud-ies to detect low-penetrance genes and gene variants predisposing to sporadic colorectal or breast cancer. As of writing,these studies were still being conducted in the north of the Netherlands. Both incident and prevalent cases were included, irrespective of family history. The patients completed a form regarding their
Results and discussion
The truncating mutation described by Wu et al. [1] was not found. The S845G variant, however, was detected in five patients and eight controls; thus, the results indicate that this variant does not confer an increased colorectal cancer risk (Table 1). Four other missense variants were observed: M809V, S817G, S817R, and P844L. Three of these variants were rare; the M809V variant was detected in two patients and three controls, the S817G variant in three patients and two controls, and the S817R
Acknowledgements
This work was supported by grants RUG-1998-1665 and RUG-2002-2678 of the Dutch Cancer Society.
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