Estrogen receptor-positive breast cancer is subdivided into subtypes LuminalA and LuminalB, based on different expression patterns. MicroRNA-190b has been reported to be up-regulated in estrogen receptor-positive breast cancers. In this study we aimed to investigate the role of CpG promoter methylation in regulating miR-190b expression and its impact on clinical presentation and prognosis. DNA methylation analysis for the promotor of microRNA-190b was performed by pyrosequencing 549 primary breast tumors, of which 62 were carriers of the BRCA2 999del5 founder mutation, 71 proximal normal breast samples and 16 breast derived cell lines. MicroRNA-190b expression was analysed in 67 primary breast tumors, 14 paired normal breast samples and 16 breast derived cell lines. Tissue microarrays (TMAs) were available for ER ( n = 436), PR ( n = 436), HER-2 ( N = 258) and Ki67 ( n = 248). MiR-190b had reduced promoter methylation in estrogen receptor-positive breast cancers ( P = 1.02e–12, Median values: ER+ 24.3, ER– 38.26) and miR-190b’s expression was up-regulated in a correlative manner ( P = 1.83e–06, Spearman’s rho –0.62). Through breast cancer specific survival analysis, we demonstrated that LuminalA patients exhibiting miR-190b hypo-methylation had better survival than other patients ( P = 0.034, HR = 0.29, 95% CI 0.09-0.91). We, furthermore, demonstrated that miR-190b hypo-methylation occurs less frequently in ER+ tumors from BRCA2 999del5 mutation carriers than in non-mutated individuals ( P = 0.038, Χ 2 = 4.32, n = 335). Our results suggest that upregulation of miR-190b may occur through loss of promoter DNA methylation during the development of estrogen-receptor (ER) positive breast cancers, and that miR-190b hypo-methylation leads to increased breast cancer specific survival within the LuminalA- subtype but not LuminalB.
A decline in forced expiratory volume (FEV1) is a hallmark of obstructive respiratory diseases, an important cause of morbidity among the elderly. While some data exist on biomarkers that are related to FEV1, we sought to do a systematic analysis of causal relations of biomarkers with FEV1. Data from the general population-based AGES-Reykjavik study were used. Proteomic measurements were done using 4,782 DNA aptamers (SOMAmers). Data from 1,648 participants with spirometric data were used to assess the association of SOMAmer measurements with FEV1 using linear regression. Bi-directional Mendelian randomisation (MR) analyses were done to assess causal relations of observationally associated SOMAmers with FEV1, using genotype and SOMAmer data from 5,368 AGES-Reykjavik participants and genetic associations with FEV1 from a publicly available GWAS (n = 400,102). In observational analyses, 473 SOMAmers were associated with FEV1 after multiple testing adjustment. The most significant were R-Spondin 4, Alkaline Phosphatase, Placental Like 2 and Retinoic Acid Receptor Responder 2. Of the 235 SOMAmers with genetic data, eight were associated with FEV1 in MR analyses. Three were directionally consistent with the observational estimate, Thrombospondin 2 (THBS2), Endoplasmic Reticulum Oxidoreductase 1 Beta and Apolipoprotein M. THBS2 was further supported by a colocalization analysis. Analyses in the reverse direction, testing whether changes in SOMAmer levels were caused by changes in FEV1, were performed but no significant associations were found after multiple testing adjustments. In summary, this large scale proteogenomic analyses of FEV1 reveals protein markers of FEV1, as well as several proteins with potential causality to lung function.
Aim: To investigate the utility of serum proteins to predict new-onset heart failure (HF), including those with reduced or preserved ejection fraction (HFrEF or HFpEF), with or without the consideration of known HF-associated clinical variables. Methods and results: The study included 612 participants with HF events from the prospective population-based AGES-Reykjavik cohort of the elderly (N = 5457), 440 of whom were incident cases, with a median follow-up time of 5.45 years. The incident HF population with echocardiographic data included patients with HFrEF (n = 167) and HFpEF (n = 188). The least absolute shrinkage and selection operator (LASSO) model in conjunction with bootstrap resampling validation (500 replications) were used to select predictor variables based on the analysis of 4782 serum proteins and numerous clinical variables related to HF. In at least 80% of bootstrap replications, a subset of 8 to 13 serum proteins had non-zero coefficients for predicting all incident HF, HFpEF, or HFrEF separately. We used C-statistics to assess the goodness of fit when modeling a prognostic risk score for incident HF. In the null model, which did not take age, sex or clinical variables into account, 13 proteins combined had a C-index of 0.80 for all incident HF, whereas for incident HFpEF and HFrEF, the C-index for a subset of 8 or 10 protein predictors combined was 0.78 and 0.80, respectively. The concordance gain for each set of protein predictors was also investigated in the context of the approved biomarker NPPB as well as a number of clinical variables such as Framingham risk score components and calcium in the coronary artery and thoracic aorta. We show that these proteins improve prediction of future HF events even when a large number of HF-associated clinical variables are not included in the model. Conclusion: A small number of circulating proteins were found to accurately predict new-onset HF when no demographic or other information was included, and they also improved the prediction when the main known biomarker NPPB and many HF-associated clinical risk factors of the condition were taken into account.
Background: In the year 2020 breast cancer was the most common form of cancer. Roughly 70% of breast cancers are estrogen receptor positive. MicroRNA-190b has previously been reported to be up-regulated in estrogen receptor positive breast cancers. Our group has previously demonstrated that microRNA-190b is hypomethylated in ER+ breast cancers, potentially leading to its upregulation. Results: In this study, using data from the Cancer Genome Atlas, we confirm that microRNA-190b is overexpressed in breast cancer via differential expression analysis and show that high expression of microRNA-190b results in more favorable outcomes in Luminal A patients (HR=0.29, 95% CI 0.12-0.71, P value=0.0063). MicroRNA190b target analysis, using immunoprecipitation of biotin labelled microRNA-190b, followed by RNA sequencing, identified RFWD3 as one of microRNA-190b’s regulatory targets in estrogen receptor positive breast cancer. Survival analysis of RFWD3 showed that elevated levels result in poorer overall survival in Luminal A breast cancer patients (HR = 2.22, 95% CI 1.33-3.71, P = 0.002). Gene ontology analysis of our sequencing results indicate that miR-190b may have a role in breast cancer development and/or tumorigenesis and that it may be a suitable tool in characterization between the estrogen receptor positive subtypes, Luminal A and Luminal B.Conclusions: We show that miR-190b targets RFWD3 in ER+ breast cancers leading to lower RFWD3 protein expression. Low levels of RFWD3 are associated with better outcomes in Luminal A breast cancer patients but not in Luminal B patients.
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