Cardiac hypertrophy has been well-characterized at the level of transcription. During cardiac hypertrophy, genes normally expressed primarily during fetal heart development are reexpressed, and this fetal gene program is believed to be a critical component of the hypertrophic process. Recently, alternative splicing of mRNA transcripts has been shown to be temporally regulated during heart development, leading us to consider whether fetal patterns of splicing also reappear during hypertrophy. We hypothesized that patterns of alternative splicing occurring during heart development are recapitulated during cardiac hypertrophy. Here we present a study of isoform expression during pressure-overload cardiac hypertrophy induced by 10 days of transverse aortic constriction (TAC) in rats and in developing fetal rat hearts compared to sham-operated adult rat hearts, using high-throughput sequencing of poly(A) tail mRNA. We find a striking degree of overlap between the isoforms expressed differentially in fetal and pressure-overloaded hearts compared to control: forty-four percent of the isoforms with significantly altered expression in TAC hearts are also expressed at significantly different levels in fetal hearts compared to control (P < 0.001). The isoforms that are shared between hypertrophy and fetal heart development are significantly enriched for genes involved in cytoskeletal organization, RNA processing, developmental processes, and metabolic enzymes. Our data strongly support the concept that mRNA splicing patterns normally associated with heart development recur as part of the hypertrophic response to pressure overload. These findings suggest that cardiac hypertrophy shares post-transcriptional as well as transcriptional regulatory mechanisms with fetal heart development.
ObjectivesA cross-sectional epidemiological study explored genetic susceptibility to oral precancer and cancer in Puerto Rico (PR).Materials and MethodsThree hundred three individuals with a benign oral condition, oral precancer (oral epithelial hyperplasia/hyperkeratosis, oral epithelial dysplasia), or oral squamous cell carcinoma (SCCA) were identified via PR pathology laboratories. A standardized, structured questionnaire obtained information on epidemiological variables; buccal cells were collected for genetic analysis. Genotyping was performed using Taqman® assays. Allelic frequencies of single nucleotide polymorphisms (SNPs) were evaluated in cytokine genes and genes influencing tumor metastasis. Risk estimates for a diagnosis of oral precancer or SCCA while having a variant allele were generated using logistic regression. Adjusted models controlled for age, gender, ancestry, education, smoking and alcohol consumption.ResultsRelative to persons with a benign oral lesion, individuals with homozygous recessive allelic variants of tumor necrosis factor (TNF-α) −238 A/G SNP had a reduced odds of having an oral precancer (ORadjusted = 0.15; 95% CI 0.03–0.70). The transforming growth factor beta-1 (TGFβ-1 −509 C/T) polymorphism was inversely associated with having an oral SCCA among persons homozygous for the recessive variant (ORcrude = 0.27; 95% CI 0.09–0.79). The matrix metalloproteinase gene (MMP-1) variant, rs5854, was associated with oral SCCA; participants with even one variant allele were more likely to have oral SCCA (ORadjusted = 2.62, 95% CI 1.05–6.53) compared to people with ancestral alleles.ConclusionOur exploratory analyses suggest that genetic alterations in immune system genes and genes with metastatic potential are associated with oral precancer and SCCA risk in PR.
Gene promoter hypermethylation is now regarded as a promising biomarker for the risk and progression of lung cancer. The one-carbon metabolism pathway is postulated to affect deoxyribonucleic acid (DNA) methylation because it is responsible for the generation of S-adenosylmethionine (SAM), the methyl donor for cellular methylation reactions. This study investigated the association of single nucleotide polymorphisms (SNPs) in six one-carbon metabolism-related genes with promoter hypermethylation in sputum DNA from non-Hispanic white smokers in the Lovelace Smokers Cohort (LSC) (n = 907). Logistic regression was used to assess the association of SNPs with hypermethylation using a high/low methylation cutoff. SNPs in the cystathionine beta synthase (CBS) and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) genes were significantly associated with high methylation in males [CBS rs2850146 (-8283G > C), OR = 4.9; 95% CI: 1.98, 12.2, P = 0.0006] and low methylation in females [MTRR rs3776467 (7068A > G), OR = 0.57, 95% CI: 0.42, 0.77, P = 0.0003]. The variant allele of rs2850146 was associated with reduced gene expression and increased plasma homocysteine (Hcy) concentrations. Three plasma metabolites, Hcy, methionine and dimethylglycine, were associated with increased risk for gene methylation. These studies suggest that SNPs in CBS and MTRR have sex-specific associations with aberrant methylation in the lung epithelium of smokers that could be mediated by the affected one-carbon metabolism and transsulfuration in the cells.
BackgroundHispanics are known to be an extremely diverse and genetically admixed ethnic group. The lack of methodologies to control for ethnicity and the unknown admixture in complex study populations of Hispanics has left a gap in understanding certain cancer disparity issues. Incidence rates for oral and pharyngeal cancer (OPC) in Puerto Rico are among the highest in the Western Hemisphere. We conducted an epidemiological study to examine risk and protective factors, in addition to possible genetic susceptibility components, for oral cancer and precancer in Puerto Rico.Methodology/Principal FindingsWe recruited 310 Puerto Rico residents who had been diagnosed with either an incident oral squamous cell carcinoma, oral precancer, or benign oral condition. Participants completed an in-person interview and contributed buccal cells for DNA extraction. ABI Biosystem Taqman™ primer sets were used for genotyping 12 ancestry informative markers (AIMs). Ancestral group estimates were generated using maximum likelihood estimation software (LEADMIX), and additional principal component analysis was carried out to detect population substructures. We used unconditional logistic regression to assess the contribution of ancestry to the risk of being diagnosed with either an oral cancer or precancer while controlling for other potential confounders. The maximum likelihood estimates showed that study participants had a group average ancestry contribution of 69.9% European, 24.5% African, and 5.7% detectable Native American. The African and Indigenous American group estimates were significantly higher than anticipated. Neither self-identified ethnicity nor ancestry markers showed any significant associations with oral cancer/precancer risk in our study.Conclusions/SignificanceThe application of ancestry informative markers (AIMs), specifically designed for Hispanics, suggests no hidden population substructure is present based on our sampling and provides a viable approach for the evaluation and control of ancestry in future studies involving Hispanic populations.
Hypermethylation of promoter regions serve as potential biomarkers for the early detection of lung cancer. Because folate metabolism is necessary for nucleotide synthesis and DNA methylation reactions, that when perturbed, may both contribute to the development of cancer, hypermethylation of promoter regions in folate metabolism genes may be particularly important to explore. Dietary folate was recently found to protect against gene promoter hypermethylation patterns. This study investigated the association of functional and haplotype tagging single nucleotide polymorphisms (SNPs) in folate metabolism genes with promoter hypermethylation in sputum cell DNA from a cohort of current and former smokers (n=937). This cohort was a subset of the Lovelace Smokers’ Cohort of approximately 2000 high risk current and former smokers who were non-Hispanic white and for whom a complete methylation panel was obtained. Methylation panel status from a 12 gene panel was dichotomized into high and low methylation based on a cutoff of the number of genes methylated (> = 3 genes for women and > = 4 genes for men were categorized as high). Lymphocyte DNA was interrogated on a 96 SNP Illumina Goldengate platform. A SNP in the cystathionine-beta synthase gene (CBS), that converts homocysteine to cystathionine, was found to be significantly associated with gene promoter hypermethylation. Analyses used logistic regression and adjusted for multiple comparisons. There was an interaction between gender and CBS (p<0.0001), so we conducted a stratified analysis by gender. Males with the variant allele had an increased risk of methylation (OR = 3.61; 95% CI: 1.71, 7.64); p<0.001) and females with the variant allele had a decreased risk for methylation (OR = 0.64; 95% CI: 0.40, 1.00; p=0.05). A 20% reduction in CBS gene transcription was seen in bronchial epithelial cells heterozygous for the CBS variant allele compared to cells without the variant allele but was not statistically significant. Epidemiological studies have shown that men have higher levels of homocysteine compared to women but the mechanisms regulating this difference are not known. This study shows that a SNP in the CBS gene is associated with methylation patterns in smokers at high risk to develop lung cancer and differs by gender. This work may further help to elucidate the differences in lung cancer risk by gender. Grant Support: This work is supported by K01CA128823 NCI and R01CA097356 NCI Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 891. doi:10.1158/1538-7445.AM2011-891
Lung cancer is the leading cause of cancer related deaths and most lung cancers are detected at a late stage. Gene promoter hypermethylation is now regarded as a promising biomarker to identify early risk and progression of lung cancer. The one carbon metabolism pathway is postulated to affect DNA methylation because it is necessary for the generation of S-adenosyl methionine or (SAM), the methyl donor for cellular DNA methylation reactions, through complex interactions with metabolites including folate, homocysteine, and methionine. This study investigated the association of single nucleotide polymorphisms (SNPs) in one carbon metabolism related genes with DNA promoter hypermethylation in sputum cell DNA from current and former smokers in the Lovelace Smokers Cohort (n=907). The association of SNPs with methylation was analyzed by logistic regression using gender specific high and low methylation cutoffs from a 12 gene methylation panel as the outcome. SNPs in the cystathionine beta-synthase (CBS) and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) genes were found to be statistically associated with methylation in a gender specific fashion (CBS SNP, OR=4.9; CI: 1.98, 12.2, p=.0006 in males) and (MTRR SNP, OR= 0.57, CI: 0.42, 0.77, p=0.0003 in females). Plasma homocysteine levels and the ratio of homocysteine to cystathionine increased in male samples with heterozygous or homozygous minor alleles of the CBS SNP compared to male samples with homozygous common alleles (n=86). This study suggests that SNPs in the CBS and MTRR genes are associated with methylation patterns in smokers by gender. The CBS SNP may be important in regulating plasma homocysteine and cystathionine levels that could theoretically mediate the aberrant DNA methylation in smokers at high risk to develop lung cancer. Grant Support: This work is supported by K01CA128823 NCI (Flores) and R01CA097356 NCI (Belinsky). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2633. doi:1538-7445.AM2012-2633
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