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Updated: Sep 25, 2026
Deficient Pms2, ERCC1, Ku86, CcOI in Field Defects During Progression to Colon Cancer
Published on: July 28, 2010
Little evidence for involvement of MLH3 in colorectal cancer predisposition
Tuija Hienonen1, Päivi Laiho, Reijo Salovaara
1Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Abstract:
Mutations in the DNA MMR genes MSH2, MLH1, MSH6 and PMS2 underlie a large subset of HNPCC cases, and a hallmark of the tumors is MSI. In many HNPCC families, however, a causative mutation has not been found. Therefore, the involvement of additional, thus far unknown, genes in MSI as well as MSS colorectal tumor predisposition is possible. The role of a relatively recently cloned MMR gene, MLH3, in familial CRC has been studied; but the results appear somewhat conflicting. To further evaluate the role of MLH3 in CRC predisposition, we analyzed 30 Finnish CRC cases for germline mutations by sequencing. These cases were selected from a large series of Finnish CRC patients, to match features previously proposed to associate with MLH3 germline defects. We found 5 missense variants, 4 of which were also found in Finnish cancer-free controls. The only remaining variant does not appear to be an attractive candidate for a disease-associated mutation because the amino acid change is located outside the conserved residues. We also screened for the previously reported variants, including a frameshift change, the most likely pathogenic MLH3 mutation observed so far. The frameshift was not present in the 30 CRC cases or in 700 cancer-free controls. While it is a difficult task to exclude a role of MLH3 in HNPCC, our study could not confirm a role for MLH3 in CRC predisposition.
Insights
This study investigated the MLH3 gene
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- DNA mismatch repair (MMR) gene mutations (MSH2, MLH1, MSH6, PMS2) are linked to Lynch syndrome (HNPCC) and microsatellite instability (MSI).
- Unidentified genes may contribute to hereditary colorectal cancer (CRC) predisposition, including microsatellite stable (MSS) tumors.
- The role of the MMR gene MLH3 in familial CRC predisposition remains unclear due to conflicting findings.
Purpose of the Study:
- To evaluate the role of MLH3 germline mutations in colorectal cancer (CRC) predisposition.
- To analyze MLH3 variants in Finnish CRC cases selected for features associated with MLH3 defects.
Main Methods:
- Germline mutation analysis by sequencing 30 Finnish CRC cases.
- Screening for previously reported MLH3 variants, including a frameshift mutation.
- Comparison of identified variants with cancer-free control populations.
Main Results:
- Five missense variants in MLH3 were identified; four were also present in controls.
- The single remaining variant was not considered a strong candidate for disease association due to its location.
- A previously reported frameshift MLH3 mutation was absent in both CRC cases and controls.
Conclusions:
- This study did not find evidence to support a role for MLH3 in colorectal cancer predisposition.
- While a definitive exclusion of MLH3's involvement in HNPCC is challenging, current findings do not confirm its role.
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