Expression of human endogenous retrovirus-K is strongly associated with the basal-like breast cancer phenotype

International audienceHuman endogenous retroviruses (HERVs), which make up approximately 8% of the human genome, are overexpressed in some breast cancer cells and tissues but without regard to cancer subtype. We, therefore, analyzed TCGA RNA-Seq data to evaluate differences in expression of the HERV-K family in breast cancers of the various subtypes. Four HERV-K loci on different chromosomes were analyzed in basal, Her2E, LumA, and LumB breast cancer subtypes of 512 breast cancer patients with invasive ductal carcinoma (IDC). The results for all four loci showed higher HERV-K expression in the basal subtype, suggesting similar mechanisms of regulation regardless of locus. Expression of the HERV-K envelope gene (env) was highly significantly increased in basal tumors in comparison with the also-upregulated expression of other HERV-K genes. Analysis of reverse-phase protein array data indicated that increased expression of HERV-K is associated with decreased mutation of H-Ras (wild-type). Our results show elevation of HERV-K expression exclusively in the basal subtype of IDC breast cancer (as opposed to the other subtypes) and suggest HERV-K as a possible target for cancer vaccines or immunotherapy against this highly aggressive form of breast cancer

A lower degree of PBMC L1 methylation in women with lower folate status may explain the MTHFR C677T polymorphism associated higher risk of CIN in the US post folic acid fortification era.

BackgroundStudies in populations unexposed to folic acid (FA) fortification have demonstrated that MTHFR C677T polymorphism is associated with increased risk of higher grades of cervical intraepithelial neoplasia (CIN 2+). However, it is unknown whether exposure to higher folate as a result of the FA fortification program has altered the association between MTHFR C677T and risk of CIN, or the mechanisms involved with such alterations. The current study investigated the following in a FA fortified population: 1) The association between MTHFR C677T polymorphism and risk of CIN 2+; 2) The modifying effects of plasma folate concentrations on this association; and 3) The modifying effects of plasma folate on the association between the polymorphism and degree of methylation of long interspersed nucleotide elements (L1s), in peripheral blood mononuclear cell (PBMC) DNA, a documented biomarker of CIN risk.MethodsThe study included 457 US women diagnosed with either CIN 2+ (cases) or ≤ CIN 1 (non-cases). Unconditional logistic regression models were used to test the associations after adjusting for relevant risk factors for CIN.ResultsThe 677CT/TT MTHFR genotypes were not associated with the risk of CIN 2+. Women with CT/TT genotype with lower folate, however, were more likely to be diagnosed with CIN 2+ compared to women with CT/TT genotype with higher folate (OR = 2.41, P = 0.030). Women with CT/TT genotype with lower folate were less likely to have a higher degree of PBMC L1 methylation compared to women with CT/TT genotype with higher folate (OR = 0.28, P = 0.017).ConclusionsThis study provides the first evidence that the MTHFR 677CT/TT genotype-associated lower degree of PBMC L1 methylation increases the risk of CIN 2+ in women in the US post-FA fortification era. Thus, even in the post-FA fortification era, not all women have adequate folate status to overcome MTHFR 677CT/TT genotype-associated lower degree of L1 methylation

A Lower Degree of PBMC L1 Methylation Is Associated with Excess Body Weight and Higher HOMA-IR in the Presence of Lower Concentrations of Plasma Folate

<div><h3>Background</h3><p>Identification of associations between global DNA methylation and excess body weight (EBW) and related diseases and their modifying factors are an unmet research need that may lead to decreasing DNA methylation-associated disease risks in humans. The purpose of the current study was to evaluate the following; 1) Association between the degree of peripheral blood mononuclear cell (PBMC) L1 methylation and folate, and indicators of EBW, 2) Association between the degree of PBMC L1 methylation and folate, and insulin resistance (IR) as indicated by a higher homeostasis model assessment (HOMA-IR).</p> <h3>Methods</h3><p>The study population consisted of 470 child-bearing age women diagnosed with abnormal pap. The degree of PBMC L1 methylation was assessed by pyrosequencing. Logistic regression models specified indicators of EBW (body mass index–BMI, body fat–BF and waist circumference–WC) or HOMA-IR as dependent variables and the degree of PBMC L1 methylation and circulating concentrations of folate as the independent predictor of primary interest.</p> <h3>Results</h3><p>Women with a lower degree of PBMC L1 methylation and lower plasma folate concentrations were significantly more likely to have higher BMI, % BF or WC (OR = 2.49, 95% CI:1.41–4.47, <em>P</em> = 0.002; OR = 2.49, 95% CI:1.40–4.51, <em>P</em> = 0.002 and OR = 1.98, 95%  = 1.14–3.48 <em>P</em> = 0.0145, respectively) and higher HOMA-IR (OR = 1.78, 95% CI:1.02–3.13, P = 0.041).</p> <h3>Conclusion</h3><p>Our results demonstrated that a lower degree of PBMC L1 methylation is associated with excess body weight and higher HOMA-IR, especially in the presence of lower concentrations of plasma folate.</p> </div

Interaction of plasma folate and the degree of PBMC L1 methylation on indicators of EBW after adjusting for demographic and lifestyle factors.

<p>PBMC L1-peripheral blood mononuclear cell long interspersed nucleotide element-1, EBW- excess body weight BMI-body mass index, BF-body fat, WC-waist circumference</p>*<p>P < 0.05</p

The distribution of women by different combinations of plasma and RBC folate and the degree of PBMC L1 methylation by EBW indicators and HOMA-IR.

<p>PBMC L1-peripheral blood mononuclear cell long interspersed nucleotide element-1, EBW- excess body weight BMI-body mass index, BF-body fat, WC-waist circumference</p>*<p>Pearson's chi-square test</p

The association between the degree of PBMC L1 methylation and indicators of EBW after controlling for demographic and lifestyle factors.

<p>PBMC L1-peripheral blood mononuclear cell long interspersed nucleotide element-1, EBW- excess body weight BMI-body mass index, BF-body fat, WC-waist circumference</p>*<p>P < 0.05</p

Mean ± SD and median degree of PBMC L1 methylation by categories of EBW indicators and circulating concentrations of folate.

<p>PBMC L1-peripheral blood mononuclear cell long interspersed nucleotide element-1, EBW- excess body weight, BMI-body mass index, BF-body fat, WC-waist circumference</p>*<p>Wilcoxon rank sum test</p