Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues

Abstract

Genome-wide DNA hypomethylation is an early event in the carcinogenic process. Percent methylation of long interspersed nucleotide element-1 (LINE-1) is a biomarker of genome-wide methylation and is a potential biomarker for breast cancer. Understanding factors associated with percent LINE-1 DNA methylation in histologically normal tissues could provide insight into early stages of carcinogenesis. In a cross-sectional study of 121 healthy women with no prior history of cancer who underwent reduction mammoplasty, we examined associations between plasma and breast folate, genetic variation in one-carbon metabolism, and percent LINE-1 methylation using multivariable regression models (adjusting for race, oral contraceptive use, and alcohol use). Results are expressed as the ratio of LINE-1 methylation relative to that of the referent group, with the corresponding 95% confidence intervals (CI). We found no significant associations between plasma or breast folate and percent LINE-1 methylation. Variation in MTHFR, MTR, and MTRR were significantly associated with percent LINE-1 methylation. Variant allele carriers of MTHFR A1289C had 4% lower LINE-1 methylation (Ratio 0.96, 95% CI 0.93-0.98), while variant allele carriers of MTR A2756G (Ratio 1.03, 95% CI 1.01-1.06) and MTRR A66G (Ratio 1.03, 95% CI 1.01-1.06) had 3% higher LINE-1 methylation, compared to those carrying the more common genotypes of these SNPs. DNA methylation of LINE-1 elements in histologically normal breast tissues is influenced by polymorphisms in genes in the one-carbon metabolism pathway. Future studies are needed to investigate the sociodemographic, environmental and additional genetic determinants of DNA methylation in breast tissues and the impact on breast cancer susceptibility.

Metabolic adaptations underlie epigenetic vulnerabilities in chemoresistant breast cancer

“…An important consequence of the altered methionine metabolism observed in taxane-resistant TNBC cells is the global decrease in DNA methylation compensated by the acquisition of H3K27me3 LOCKs, specifically occurring over TEs. This parallels previous studies showing that altered one-carbon metabolism resulting from genetic alterations in metabolic enzymes or from methionine-restricted diets associate with global changes in LINE-1 methylation (Friso et al, 2002;Kloypan et al, 2015;Kottakis et al, 2016;Llanos et al, 2015) .…”

Racial differences in genome-wide methylation profiling and gene expression in breast tissues from healthy women

“…1 This disparity in breast cancer is believed to be a complex combination of breast cancer risk factors including environment, socioeconomic status, and genetics. 12 Previous studies have shown biological differences of DNA methylation in breast cancers by races, 3 suggesting the impact of race on molecular pathways in cancers. However, these studies have been limited by a focus on tumor suppressor genes (e.g., CDH13, HIN-1, TWIST1, CCND2, and RASSF1A).…”

“…There are data that suggest that low breast folate and alcohol consumption are associated with p16 gene hypermethylation 11 ; genetic variation in genes for one-carbon metabolism may affect global methylation in normal tissues from healthy individuals. 12 To date, however, few studies have examined differential methylation by race in histologically normal tissues. [13][14][15] Among them, analyses have been limited to global methylation and to blood specimens.…”

Methylation polymorphism influences practice effects in children during attention tasks

“…We have found that the improvement in RT in 7-year-old children is related to a gene that influences executive attention (COMT) in interaction with a gene that affects the efficiency of the process of methylation. We find that the CC genotype of MTHFR, which has been linked to better overall methylation (Llanos et al 2015), shows improvement in RT over the three sessions. This learning effect occurs in interaction with COMT, suggesting that methylation works upon genes associated with cognitive performance.…”

“…One gene that may influence the efficiency of methylation is the methylenetetrahydrofolate reductase (MTHFR) gene, which has been related in human studies to overall levels of genome methylation (Friso et al, 2002; Llanos et al, 2015; Stern, Mason, Selhub, & Choi, 2000). Mice deficient in MTHFR expression show evidence of reduced methylation (Chen et al, 2001).…”