MLH3 mutation in endometrial cancer

Department of Obstetrics and Gynecology, Washington University in St. Louis, San Luis, Missouri, United States
Cancer Research (Impact Factor: 9.28). 09/2006; 66(15):7502-8. DOI: 10.1158/0008-5472.CAN-06-0248
Source: PubMed

ABSTRACT MLH3 is a recently described member of the DNA mismatch repair gene family. Based on its interaction with the MutL homologue MLH1, it was postulated that MLH3 might play a role in tumorigenesis. Germ line and somatic mutations in MLH3 have been identified in a small fraction of colorectal cancers, but the role of MLH3 in colorectal cancer tumorigenesis remains controversial. We investigated MLH3's role in endometrial tumorigenesis through analysis of tumor and germ line DNA from 57 endometrial cancer patients who were at increased risk for having inherited cancer susceptibility. Patients with known MSH2 or MSH6 mutations were excluded as well as those who had MLH1-methylated tumors. Sixteen different variants were identified by single-strand conformational variant analysis. Of the 12 missense changes identified, three were somatic mutations. One patient had a germ line missense variant and loss of heterozygosity (LOH) in her tumor specimen. There was no evidence of MLH3 promoter methylation based on combined bisulfite restriction analysis. The identification of inherited missense variants, somatic missense mutations (present in 3 of 57 tumors), and LOH in the tumor from a patient with a germ line missense change suggest a role for MLH3 in endometrial tumorigenesis.


Available from: Janet Rader, Dec 31, 2013
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    ABSTRACT: Background: Meiotic genes are very important candidates for genes contributing to female and male infertility. Mammalian MutL homologues have dual roles in DNA mismatch repair (MMR) after replication errors and meiotic reciprocal recombination. The MutL homologs, MLH1 and MLH3, are crucial for meiotic reciprocal recombination and human fertility. In this study the functional polymorphisms of MLH3 C2531T was investigated in Iranian women with unexplained infertility. Objective: Investigating the association between a common SNP (single nucleotide polymorphism) C2531T in the MLH3 gene and female infertility. Materials and Methods: In total, 105 women with unexplained infertility as case group and 100 women with at least one child and no history of infertility or abortion as controls were recruited for this association study. The MLH3 C2531T polymorphism was tested by tetra-amplification refractory mutation system-PCR (4P-ARMS-PCR) method. Results: The MLH3 2531C and T alleles frequencies were 43.33% and 56.67% among infertile patients, and 61.5% and 38.5% among normal controls, respectively. In the patient and control subjects the CC (Pro 844 Pro) genotype frequency of MLH3 C2531T was 4.76% and 25%, the CT (Pro 844 Leu) genotype was 77.15% and 73%, and the TT (Leu 844 Leu) genotype was 19% and 2%, respectively (p=0.0001). Conclusion: The presence of the polymorphic allele T leads to an increased risk of 2.09 times (OR=2.09, 95% CI=1.38-3.16; p=0.0001) for developing infertility in relation to the control group. Therefore, our data suggest that the MLH3 C2531T polymorphism can be associated with the risk of unexplained infertility in Iranian women.
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