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Mlh1 heterozygosity and promoter methylation associates with microsatellite instability in mouse sperm.

ABSTRACT: DNA mismatch repair (MMR) proteins play an important role in maintaining genome stability, both in somatic and in germline cells. Loss of MLH1, a central MMR protein, leads to infertility and to microsatellite instability (MSI) in spermatocytes, however, the effect of Mlh1 heterozygosity on germline genome stability remains unexplored. To test the effect of Mlh1 heterozygosity on MSI in mature sperm, we combined mouse genetics with single-molecule PCR that detects allelic changes at unstable microsatellites. We discovered 4.5% and 5.9% MSI in sperm of 4- and 12-month-old Mlh1+/- mice, respectively, and that Mlh1 promoter methylation in Mlh1+/- sperm correlated with higher MSI. No such elevated MSI was seen in non-proliferating somatic cells. Additionally, we show contrasting dynamics of deletions versus insertions at unstable microsatellites (mononucleotide repeats) in sperm.

SUBMITTER: Shrestha KS

PROVIDER: S-EPMC8262379 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Incorrect DNA methylation of the DAZL promoter CpG island associates with defective human sperm.

Project description:BackgroundSuccessful gametogenesis requires the establishment of an appropriate epigenetic state in developing germ cells. Nevertheless, an association between abnormal spermatogenesis and epigenetic disturbances in germline-specific genes remains to be demonstrated.MethodsIn this study, the DNA methylation pattern of the promoter CpG island (CGI) of two germline regulator genes--DAZL and DAZ, was characterized by bisulphite genomic sequencing in quality-fractioned ejaculated sperm populations from normozoospermic (NZ) and oligoasthenoteratozoospermic (OAT) men.ResultsOAT patients display increased methylation defects in the DAZL promoter CGI when compared with NZ controls. Such differences are recorded when analyzing sperm fractions enriched either in normal or defective germ cells (P< 0.001 in both cases). Significant differences in DNA methylation profiles are also observable when comparing the qualitatively distinct germ cell fractions inside the NZ and OAT groups (P= 0.003 and P= 0.007, respectively). Contrastingly, the unmethylation pattern of the DAZ promoter CGI remains correctly established in all experimental groups.ConclusionsAn association between disrupted DNA methylation of a key spermatogenesis gene and abnormal human sperm is described here for the first time. These results suggest that incorrect epigenetic marks in germline genes may be correlated with male gametogenic defects.

| S-EPMC2939755 | biostudies-literature

The MLH1 polymorphism rs1800734 and risk of endometrial cancer with microsatellite instability.

Project description:Both colorectal (CRC, 15%) and endometrial cancers (EC, 30%) exhibit microsatellite instability (MSI) due to MLH1 hypermethylation and silencing. The MLH1 promoter polymorphism, rs1800734 is associated with MSI CRC risk, increased methylation and reduced MLH1 expression. In EC samples, we investigated rs1800734 risk using MSI and MSS cases and controls. We found no evidence that rs1800734 or other MLH1 SNPs were associated with the risk of MSI EC. We found the rs1800734 risk allele had no effect on MLH1 methylation or expression in ECs. We propose that MLH1 hypermethylation occurs by different mechanisms in CRC and EC.

| S-EPMC7346630 | biostudies-literature

IGFBP3 promoter methylation in colorectal cancer: relationship with microsatellite instability, CpG island methylator phenotype, and p53.

Project description:Insulin-like growth factor binding protein 3 (IGFBP3), which is induced by wild-type p53, regulates IGF and interacts with the TGF-beta pathway. IGFBP3 promoter methylation may occur in colorectal cancer with or without the CpG island methylator phenotype (CIMP), which is associated with microsatellite instability (MSI) and TGFBR2 mutation. We examined the relationship between IGFBP3 methylation, p53 expression, CIMP and MSI in 902 population-based colorectal cancers. Utilizing real-time PCR (MethyLight), we quantified promoter methylation in IGFBP3 and eight other CIMP-high-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1). IGFBP3 methylation was far more frequent in non-MSI-high CIMP-high tumors (85% = 35/41) than in MSI-high CIMP-high (49% = 44/90, P < .0001), MSI-high non-CIMP-high (17% = 6/36, P < .0001), and non-MSI-high non-CIMP-high tumors (22% = 152/680, P < .0001). Among CIMP-high tumors, the inverse relationship between MSI and IGFBP3 methylation persisted in p53-negative tumors (P < .0001), but not in p53-positive tumors. IGFBP3 methylation was associated inversely with TGFBR2 mutation in MSI-high non-CIMP-high tumors (P = .02). In conclusion, IGFBP3 methylation is inversely associated with MSI in CIMP-high colorectal cancers, and this relationship is limited to p53-negative tumors. Our data suggest complex relationship between global genomic/epigenomic phenomena (such as MSI/CIMP), single molecular events (e.g., IGFBP3 methylation, TP53 mutation, and TGFBR2 mutation), and the related pathways.

| S-EPMC2134905 | biostudies-literature

Correction to: The MLH1 polymorphism rs1800734 and risk of endometrial cancer with microsatellite instability.

Project description: Not available

| S-EPMC8015168 | biostudies-literature

Genetic instability in lung cancer: concurrent analysis of chromosomal, mini- and microsatellite instability and loss of heterozygosity.

Project description:To investigate what kind of genetic instability plays important roles in lung carcinogenesis, we analyzed micro- and minisatellite instability, loss of heterozygosity (LOH) and chromosome instability in 55 cases of lung cancer, including, 10 squamous cell, 5 large cell, and 3 small cell carcinomas, and 37 adenocarcinomas. Analysis of minisatellite instability, the mechanism of which is different from microsatellite instability, has not been reported previously. Minisatellite instability was detected in only one case (1/55, 1.8%), and the frequency of microsatellite instability was low, being found only in three cases (3/55, 5.5%). In contrast, LOH, for at least in one locus, was observed in 27 cases (49.1%). In adenocarcinomas, the frequency of LOH was higher in poorly differentiated compared to more differentiated carcinomas. For chromosome instability, a similar correlation between differentiation grade and instability was observed in adenocarcinomas. And instability was more common in large cell and small cell carcinomas than in adenocarcinomas. Our analysis showed that chromosome instability and LOH, rather than mini- and microsatellite instability, play significant roles in the development of lung cancer.

| S-EPMC2361274 | biostudies-other

Haploinsufficiency by minute MutL homolog 1 promoter DNA methylation may represent unique phenotypes of microsatellite instability-gastric carcinogenesis.

Project description:Promoter DNA methylation of MutL homolog 1 (MLH1) is considered to play a causative role in microsatellite instability (MSI) carcinogenesis in primary gastric cancer, and a high MSI status is associated with treatment sensitivity to human cancers. Nevertheless, clinicopathological analysis is defective for MLH1 methylation status in a quantitative manner. We newly developed quantitative methylation specific PCR using a TaqMan probe and applied it to 138 patients with primary gastric cancer who underwent gastrectomy in addition to basic molecular features such as MSI, Epstein Barr virus, and other DNA methylation status. (1) In primary gastric cancer, median methylation value was 0.055, ranging from 0 to 124.3. First, MLH1 hypermethylation was strongly correlated with MSI-High/MSI-Low status and suppressed immunostaining (P < 0.0001). (2) The MLH1 hypermethylation was associated with advanced age (P = 0.0048), antral location (P = 0.0486), synchronous multiple gastric cancer (P = 0.0001), and differentiated histology (P = 0.028). (3) Log-rank plot analysis identified the most relevant cut-off value (0.23) to reflect gentle phenotypes in MLH1 hypermethylation cases (P = 0.0019), especially in advanced gastric cancer (P = 0.0132), which are designated as haploinsufficiency of MSI (MSI-haplo) phenotype in this study. (4) In synchronous multiple gastric cancer, MLH1 hypermethylation was not necessarily confirmed as field cancerization. (5) MSI-haplo defined by MLH1 methylation status represented distinct prognostic phenotype even after molecular classifications. MLH1 hypermethylation designated as MSI-haplo may represent unique prognostic phenotype during gastric carcinogenesis.

| S-EPMC8694418 | biostudies-literature

Clinicopathological significance of loss of heterozygosity and microsatellite instability in hepatocellular carcinoma in China.

Project description:AIM:To determine the features of microsatellite alterations and their association with clinicopathological characteristics of hepatocellular carcinoma (HCC). METHODS:Loss of heterozygosity (LOH) and microsatellite instability (MSI) of 55 microsatellite loci were detected with PCR-based microsatellite polymorphism analyses in tumors and corresponding noncancerous liver tissues of 56 surgically resected HCCs using the MegaBACE 500 automatic DNA analysis system. RESULTS:LOH was found in 44 of 56 HCCs (78.6%) at one or several loci. Frequencies of LOH on 1p, 4q, 8p, 16q, and 17p were 69.6% (39/56), 71.4% (40/56), 66.1% (37/56), 66.1% (37/56), and 64.3% (36/56), respectively. MSI was found in 18 of 56 HCCs (32.1%) at one or several loci. Ten of fifty-six (17.9%) HCCs had MSI-H. Serum HBV infection, alpha-fetoprotein concentration, tumor size, cirrhosis, histological grade, tumor capsule, as well as tumor intrahepatic metastasis, might be correlated with LOH on certain chromosome regions. CONCLUSION:Frequent microsatellite alterations exist in HCC. LOH, which represents a tumor suppressor gene pathway, plays a more important role in hepatocarcinogenesis. MSI, which represents a mismatch repair gene pathway, is a rare event during liver carcinogenesis. Furthermore, LOH on certain chromosome regions may be correlated with clinicopathological characteristics in HCC.

| S-EPMC4305835 | biostudies-literature

Loss of heterozygosity and microsatellite instability as predictive markers among Iranian esophageal cancer patients.

Project description:ObjectivesVariation in microsatellite sequences that are dispersed in the genome has been linked to a deficiency in cellular mismatch repair system and defects in several genes of this system are involved in carcinogenesis. Our aim in this study was to illustrate microsatellite DNA alteration in esophageal cancer.Materials and methodsDNA was extracted from formalin fixed paraffin embedded (FFPE) tissues from surgical and matched margin-normal samples. Microsatellite instability (MSI) and loss of heterozygosity (LOH) were studied in 50 cases of esophageal squamous cell carcinoma (ESCC) by amplifying six microsatellite markers: D13S260 (13q12.3), D13S267 (13q12.3), D9S171 (9p21), D2S123 (2p), D5S2501 (5q21) and TP53 (17p13.1) analyzed on 6% denaturing polyacrylamide gel electrophoresis.ResultsStatistical analysis indicated a near significant reverse correlation between grade and LOH (P= 0.068, correlation coefficient= -0.272). Specifically, increased LOH in tumor DNA has a significant correlation with increased differentiation from poorly differentiated to well differentiated tumors (P= 0.002 and P= 0.016 respectively). In addition, higher number of chromosomal loci with LOH showed a reverse correlation with lymph node metastasis (P= 0.026, correlation coefficient= -0.485). Furthermore, there was a positive correlation between addiction and MSI (P= 0.026, correlation coefficient= 0.465).ConclusionMicrosatellite DNA alterations may be a prognostic tool for detection and the evolution of prognosis in patients with SCC of esophagus. It can be concluded that regional lymph node metastasis would be less likely with increased heterozygote loci and addiction with any of opium, cigarette, water pipe or alcohol can be a susceptibility factor(s) for MSI.

| S-EPMC5010844 | biostudies-literature

Correlation between gastric carcinoma and ZAC gene-associated microsatellite instability and loss of heterozygosity.

Project description:The present study explored the association between loss of heterozygosity (LOH) or microsatellite instability (MSI) of the zinc finger regulator of apoptosis and cell-cycle arrest (ZAC) gene and the clinicopathological factors of gastric cancer. Samples of cancer and cancer-adjacent normal tissue from 30 patients with gastric cancer were collected. The genomic DNA was extracted from each and amplified with primers specific to ZAC microsatellite mutations, then run on a polyacrylamide gel for analysis. The CA197 microsatellite locus exhibited LOH in cancer sample 4. There was LOH in the 15AAAG locus in cancer sample 27 and cancer-adjacent tissue 23, and MSI at 15AAAG in cancer-adjacent tissue 27. There was MSI at the D6S1703 microsatellite locus in cancer-adjacent tissue 28. There was no LOH or MSI in the CA340 microsatellite locus in the gastric cancer or adjacent tissues analyzed. Thus, the frequency of LOH or MSI at ZAC gene-associated microsatellite loci for all patients was 13.3% (4/30). The present study has demonstrated that LOH and MSI events may contribute to the downregulation of ZAC; however, it is unlikely to be the primary cause, as it was only identified in 13.3% of cases.

| S-EPMC5530142 | biostudies-other

Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study.

Project description:PurposeThe best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS.Patients and methodsECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women.ResultsAnalysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years.ConclusionCombined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease.

| S-EPMC4678181 | biostudies-literature

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