We investigated a possible role of the mismatch-repair gene MLH3 in hereditary nonpolyposis colorectal cancer by scanning for mutations in 39 HNPCC families and in 288 patients suspected of having HNPCC. We identified ten different germline MLH3
ght:700;'>MLH3 variants, one frameshift and nine missense mutations, in 12 patients suspected of HNPCC. Three of the 12 also carried a mutation in MSH6.
Markandona O, etal., J Assist Reprod Genet. 2015 Dec;32(12):1795-9. doi: 10.1007/s10815-015-0594-z. Epub 2015 Oct 31.
PURPOSE: MLH3, a MutL homolog protein in mammals playing a role in DNA mismatch repair, is associated with spermatogenesis and male infertility. The purpose of the present study was to investigate the association of the single-nucleotide polymorphism (SNP), rs 1
75080 in the MLH3 gene, with sperm parameters in a Greek population. METHODS: The study included 300 men of couples undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) treatments (years 2011-2013). Genomic DNA was extracted from 300 peripheral blood samples, and conventional quantitative real-time PCR was performed for genotyping. Of them, 122 were from men used as "controls" and 178 from men used as "cases." Allocation to the two groups was based on sperm concentrations (>/=15 and <15 million/ml, respectively). Serum FSH, LH, estradiol, testosterone, and prolactin concentrations as well as sperm parameters were compared between three genotypes (GG, GA, and AA). Furthermore, the frequencies of these three genotypes were compared between "cases" and "controls." RESULTS: Anthropometric parameters and hormonal values did not differ significantly between the three genotypes. Significantly lower sperm concentrations were found in men with the AA genotype as compared to men with the GG and GA genotypes (p < 0.001). The AA genotype had the lower progressive motility values as compared to the other two genotypes (p < 0.05). Also, there was a significantly different distribution of the frequencies of the three genotypes between "cases" and "controls" (p < 0.001). CONCLUSIONS: It is suggested that the studied SNP in the MLH3 gene may be linked to oligozoospermia in Caucasian men of a certain area.
Diffuse astrocytomas and oligodendrogliomas (WHO grade II) are the most common histological subtypes of low-grade gliomas (LGGs). Several molecular and epigenetic markers have been identified that predict tumor progression. Our aim was in detail to investigate the genetic and epigenetic background o
f LGGs and to identify new markers that might play a role in tumor behavior. Twenty-three patients with oligodendroglioma or oligoastrocytoma (LGO) and 22 patients with diffuse astrocytoma (LGA) were investigated using several molecular-cytogenetic and molecular methods to assess their copy number variations, mutational status and level of promoter methylation. The most frequent findings were a 1p/19q codeletion in 83% of LGO and copy-neutral loss of heterozygosity (CN-LOH) of 17p in 72% of LGA. Somatic mutations in the isocitrate dehydrogenase 1 or 2 (IDH1/IDH2) genes were detected in 96% of LGO and 91% of LGA. The O-6-methylguanine-DNA-methyltransferase (MGMT) promoter was methylated in 83% of LGO and 59% of LGA. MutL homolog 3 (MLH3) promoter methylation was observed in 61% of LGO and 27% of LGA. Methylation of the MGMT promoter, 1p/19q codeletion, mutated IDH1, and CN-LOH of 17p were the most frequent genetic aberrations in LGGs. The findings were more diverse in LGA than in LGO. To the best of our knowledge, this is the first time description of methylation of the MLH3 gene promoter in LGGs. Further studies are required to determine the role of the methylated MLH3 promoter and the other aberrations detected.
Zhang Q, etal., Cancer Med. 2018 Apr;7(4):1264-1274. doi: 10.1002/cam4.1319. Epub 2018 Mar 8.
Colorectal cancer (CRC), as a malignant tumor of lower digestive tract, has been found to have an increasing morbidity and mortality in China. It was particularly important to find some earlier biomarkers to predict the risk and prognosis. In this study, several polymorphisms on 3'UTR of three DNA r
epair genes including MLH3 rs10862, ERCC1 rs3212986, ERCC1 rs735482, ERCC1 rs2336219, and OGG1 rs1052133 were chosen by bioinformatics exploration, and then, a case-control study of 200 CRC cases and controls was performed. Furthermore, a dual-luciferase assay was also carried out to certify whether the candidate miRNA can regulate its target gene and the selected SNPs have a valid effect on the target miRNA. Finally, both of ERCC1 rs3212986 and MLH3 rs108621 were shown to be associated with the risk of CRC. Comparing with rs3212986 CC genotype, AA was at a higher risk (OR = 3.079, 95% CI: 1.192-7.952). For MLH3 rs108621, comparing with TT genotype, CC and TC were at a higher risk of CRC in male (OR = 5.171, 95% CI: 1.009-26.494; OR = 1.904, 95% CI: 1.049-3.455). Interestingly, an analysis combining both ERCC1 rs3212986 and MLH3 rs108621 also showed an increased risk of CRC. In addition, a dual-luciferase assay showed that miR-193a-3p could regulate MLH3, and the polymorphism rs108621 could alter the miR-193a-3p binding to MLH3. Therefore, MLH3 rs108621 may be associated with the risk of CRC due to the effect of miR-193a-3p on MLH3, which reminded the possibility as potential susceptibility biomarkers to predict the risk of CRC.
