Differential Orthopedia Homeobox expression in pulmonary carcinoids is associated with changes in DNA methylation

Limited number of tumor types have been examined for Orthopedia Homeobox (OTP) expression. In pulmonary carcinoids, loss of expression is a strong indicator of poor prognosis. Here, we investigated OTP expression in 37 different tumor types, and the association between OTP expression and DNA methylation levels in lung neuroendocrine neoplasms. We analyzed publicly available multi-omics data (whole-exome-, whole-genome-, RNA sequencing and Epic 850K-methylation array) of 58 typical carcinoids, 27 atypical carcinoids, 69 large cell neuroendocrine carcinoma and 51 small cell lung cancer patients and TCGA (The Cancer Genome Atlas) data of 33 tumor types. 850K-methylation analysis was cross-validated using targeted pyrosequencing on 35 carcinoids. We report bimodality of OTP expression in carcinoids (OTPhigh vs OTPlow group, likelihood-ratio test P = 1.5 × 10−2), with the OTPhigh group specific to pulmonary carcinoids while absent from all other cohorts analyzed. Significantly different DNA methylation levels were observed between OTPhigh and OTPlow carcinoids in 12/34 OTP infinium probes (FDR .2). OTPlow carcinoids harbor high DNA methylation levels as compared to OTPhigh carcinoids. OTPlow carcinoids showed a significantly worse overall survival (log-rank test P =.0052). Gene set enrichment analysis for somatically mutated genes associated with hallmarks of cancer showed robust enrichment of three hallmarks in the OTPlow group, that is, sustaining proliferative signaling, evading growth suppressor and genome instability and mutation. Together our data suggest that high OTP expression is a unique feature of pulmonary carcinoids with a favorable prognosis and that in poor prognostic patients, OTP expression is lost, most likely due to changes in DNA methylation levels

Microvascular endothelial dysfunction is associated with albuminuria: the Maastricht Study

OBJECTIVE: Albuminuria is thought to be a biomarker of microvascular and macrovascular endothelial dysfunction. However, direct evidence for an association of microvascular endothelial dysfunction with albuminuria is limited. In addition, experimental data suggest a stronger association of microvascular endothelial dysfunction with albuminuria in individuals with than in those without diabetes. METHODS: We examined cross-sectional associations of flicker light-induced retinal arteriolar dilation (n = 2095) and heat-induced skin hyperemia (n = 1508) with 24-h albuminuria in the population-based, diabetes-enriched Maastricht Study. We used linear regression analyses to adjust for age, sex, type 2 diabetes, and cardiovascular disease risk factors. In addition, we tested for statistical interaction with type 2 diabetes. RESULTS: Median [interquartile range] albuminuria was 6.5 [3.9-11.6] mg/24 h and 8.2% had albuminuria at least 30 mg/24 h. After adjustment, albuminuria was 1.168 (95% confidence interval, 1.046-1.303) times greater in participants in the quartile with the smallest flicker light-induced retinal arteriolar dilation relative to those with the greatest dilation, and this association was stronger in participants with type 2 diabetes (Pinteraction < 0.10). Further, each 100 percentage points lower heat-induced skin hyperemia was associated with a 1.022 (1.010-1.035) times greater albuminuria in participants with type 2 diabetes, whereas it was not associated with albuminuria in nondiabetic participants (Pinteraction < 0.10). CONCLUSION: This is the first population-based study that provides direct evidence that microvascular endothelial dysfunction is associated with albuminuria, and that this association is stronger in individuals with than in those without type 2 diabetes