Dataset Information

LINE-1 hypomethylation in familial and sporadic cancer.

ABSTRACT: Increased and decreased methylation at specific sequences (hypermethylation and hypomethylation, respectively) is characteristic of tumor DNA compared to normal DNA and promotes carcinogenesis in multiple ways including genomic instability. Long interspersed element (LINE), an abundant class of retrotransposons, provides a surrogate marker for global hypomethylation. We developed methylation-specific multiplex ligation-dependent probe amplification assays to study LINE-1 methylation in cases of colorectal, gastric, and endometrial cancer (N?=?276), stratified by patient category [sporadic; Lynch syndrome (LS); familial colorectal cancer type X (FCCX)] and microsatellite instability status. Within each patient group, LINE-1 showed lower methylation in tumor DNA relative to paired normal DNA and hypomethylation was statistically significant in most cases. Interestingly, normal colorectal mucosa samples from different patient groups displayed differences in LINE-1 methylation that mirrored differences between the respective tumor tissues, with a decreasing trend for LINE-1 methylation from patients with sporadic colorectal cancer to LS to FCCX. Despite the fact that the degree of LINE-1 methylation is generally tissue specific, normal colorectal mucosa, gastric mucosa, and endometrium from LS patients showed similar levels of LINE-1 methylation. Our results suggest that the degree of LINE-1 methylation may constitute a "field defect" that may predispose normal tissues for cancer development.

SUBMITTER: Pavicic W

PROVIDER: S-EPMC3383956 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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LINE-1 hypomethylation in familial and sporadic cancer.

Pavicic Walter W Joensuu Emmi I EI Nieminen Taina T Peltomäki Päivi P

Journal of molecular medicine (Berlin, Germany) 20120108 7

Increased and decreased methylation at specific sequences (hypermethylation and hypomethylation, respectively) is characteristic of tumor DNA compared to normal DNA and promotes carcinogenesis in multiple ways including genomic instability. Long interspersed element (LINE), an abundant class of retrotransposons, provides a surrogate marker for global hypomethylation. We developed methylation-specific multiplex ligation-dependent probe amplification assays to study LINE-1 methylation in cases of ...[more]

PMID: 22228215

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Project description:The RNASEL gene on chromosome 1q25 was recently identified as a candidate gene for hereditary prostate cancer (PC). To confirm these findings, we screened 326 patients from 163 families with familial PC for potential germline mutations, by use of conformation-sensitive gel electrophoresis, followed by direct sequence analysis. A total of six variants were identified, including one intronic and five exonic changes (three missense and two silent alterations). There were no unequivocal pathogenic changes. To further test for potential associations between genes and increased risk for disease, the three missense polymorphisms (Ile97Leu, Arg462Gln, and Glu541Asp) were genotyped in 438 patients with familial PC and in 510 population-based control subjects. Association testing revealed no significant differences between patients and control subjects for either the Leu97 variant (chi(2) trend test = 1.42; P=.23) or the Asp541 variant (chi2=1.52; P=.22). However, significant differences were detected for the Arg462Gln genotypes (chi2=5.20; P=.02; odds ratio [OR] = 0.54; 95% confidence interval [CI] 0.32-0.91) when the genotype Gln/Gln was compared with Arg/Arg. In subset analyses, associations were also observed in the younger group (age at diagnosis </=64 years) (P=.0008; OR=0.29; 95% CI = 0.13-0.66), in node-negative patients (P=.01; OR=0.48; 95% CI 0.27-0.84), patients with stage T(1)/T(2) disease (P=.008; OR=0.39; 95% CI 0.2-0.75), and patients with low-grade disease (P=.01; OR=0.40; 95% CI 0.20-0.78). To evaluate whether this variant was also associated with sporadic PC, we genotyped an additional 499 patients with sporadic PC. Differences in frequency were not detected between patients with sporadic disease and control subjects. However, the same association was observed between patients with familial disease and patients with sporadic disease for the entire group (chi2=4.82; P=.03), as well as in the subset analyses. These results suggest that polymorphic changes within the RNASEL gene may be associated with increased risk of familial but not sporadic PC.

Project description:In human cancers, the methylation of long interspersed nuclear element -1 (LINE-1 or L1) retrotransposons is reduced. This occurs within the context of genome wide hypomethylation, and although it is common, its role is poorly understood. L1s are widely distributed both inside and outside of genes, intragenic and intergenic, respectively. Interestingly, the insertion of active full-length L1 sequences into host gene introns disrupts gene expression. Here, we evaluated if intragenic L1 hypomethylation influences their host gene expression in cancer. First, we extracted data from L1base (http://l1base.molgen.mpg.de), a database containing putatively active L1 insertions, and compared intragenic and intergenic L1 characters. We found that intragenic L1 sequences have been conserved across evolutionary time with respect to transcriptional activity and CpG dinucleotide sites for mammalian DNA methylation. Then, we compared regulated mRNA levels of cells from two different experiments available from Gene Expression Omnibus (GEO), a database repository of high throughput gene expression data, (http://www.ncbi.nlm.nih.gov/geo) by chi-square. The odds ratio of down-regulated genes between demethylated normal bronchial epithelium and lung cancer was high (p<1E(-27); OR = 3.14; 95% CI = 2.54-3.88), suggesting cancer genome wide hypomethylation down-regulating gene expression. Comprehensive analysis between L1 locations and gene expression showed that expression of genes containing L1s had a significantly higher likelihood to be repressed in cancer and hypomethylated normal cells. In contrast, many mRNAs derived from genes containing L1s are elevated in Argonaute 2 (AGO2 or EIF2C2)-depleted cells. Hypomethylated L1s increase L1 mRNA levels. Finally, we found that AGO2 targets intronic L1 pre-mRNA complexes and represses cancer genes. These findings represent one of the mechanisms of cancer genome wide hypomethylation altering gene expression. Hypomethylated intragenic L1s are a nuclear siRNA mediated cis-regulatory element that can repress genes. This epigenetic regulation of retrotransposons likely influences many aspects of genomic biology.

Project description:BACKGROUND:It is unknown whether clinical parameters differ between migraineurs with and without first-degree family members with migraine. OBJECTIVES:The present cross-sectional study describes differences between familial and sporadic migraine with a focus on migraine characteristics, migraine severity, comorbidities, and treatment. METHOD:From the Danish Headache Center we recruited 358 patients with familial migraine and 1727 patients with sporadic migraine. Each participant was assessed using a validated semi-structured interview. RESULTS:No differences in age (Mean = 44 and 44 [SD = 12.28 and 12.58] for familial and sporadic migraineurs, respectively; P = .900) or sex (295/358 (82.4%) and 1413/1727 (81.8%) women in familial and sporadic migraineurs, respectively; P = .853) were found. Familial migraineurs had more aphasic aura than sporadic migraineurs (41% vs 27%, P = .001). Sporadic migraineurs had more lifetime attacks ie, >100 attacks (45% vs 70%, P < .001) and prolonged attacks ie, lasting >72 hours (5% vs 12%, P < .001) than familial migraineurs. Further, sporadic migraineurs had a higher incidence of concussions (37% vs 41%, P = .001) compared to familial migraineurs. In agreement with a previous study, there was no difference between familial and sporadic migraine regarding triptan response (84% vs 81%, P = .440). CONCLUSION:Headache characteristics, triptan response, and comorbidities where similar in individulas with and without inherited migraine, suggesting that migraine are to be considered a hmogenoues disease. The difference in the clinical presentation of migraine with aura symptoms among patients with familial migraine should be considered in future studies. Further, more severe migraine among patients with sporadic migraine with aura could suggest that sporadic migraineurs have been exposed to stronger or multiple environmental factors and indicate that an early intervention in migraine treatment could lessen the severity of migraine.

Dataset Information

LINE-1 hypomethylation in familial and sporadic cancer.

Publications

LINE-1 hypomethylation in familial and sporadic cancer.

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