Biological basis of extensive pleiotropy between blood traits and cancer risk.

BACKGROUND: The immune system has a central role in preventing carcinogenesis. Alteration of systemic immune cell levels may increase cancer risk. However, the extent to which common genetic variation influences blood traits and cancer risk remains largely undetermined. Here, we identify pleiotropic variants and predict their underlying molecular and cellular alterations. METHODS: Multivariate Cox regression was used to evaluate associations between blood traits and cancer diagnosis in cases in the UK Biobank. Shared genetic variants were identified from the summary statistics of the genome-wide association studies of 27 blood traits and 27 cancer types and subtypes, applying the conditional/conjunctional false-discovery rate approach. Analysis of genomic positions, expression quantitative trait loci, enhancers, regulatory marks, functionally defined gene sets, and bulk- and single-cell expression profiles predicted the biological impact of pleiotropic variants. Plasma small RNAs were sequenced to assess association with cancer diagnosis. RESULTS: The study identified 4093 common genetic variants, involving 1248 gene loci, that contributed to blood-cancer pleiotropism. Genomic hotspots of pleiotropism include chromosomal regions 5p15-TERT and 6p21-HLA. Genes whose products are involved in regulating telomere length are found to be enriched in pleiotropic variants. Pleiotropic gene candidates are frequently linked to transcriptional programs that regulate hematopoiesis and define progenitor cell states of immune system development. Perturbation of the myeloid lineage is indicated by pleiotropic associations with defined master regulators and cell alterations. Eosinophil count is inversely associated with cancer risk. A high frequency of pleiotropic associations is also centered on the regulation of small noncoding Y-RNAs. Predicted pleiotropic Y-RNAs show specific regulatory marks and are overabundant in the normal tissue and blood of cancer patients. Analysis of plasma small RNAs in women who developed breast cancer indicates there is an overabundance of Y-RNA preceding neoplasm diagnosis. CONCLUSIONS: This study reveals extensive pleiotropism between blood traits and cancer risk. Pleiotropism is linked to factors and processes involved in hematopoietic development and immune system function, including components of the major histocompatibility complexes, and regulators of telomere length and myeloid lineage. Deregulation of Y-RNAs is also associated with pleiotropism. Overexpression of these elements might indicate increased cancer risk.

Defining Optimal Conditions for Tumor Extracellular Vesicle DNA Extraction for Mutation Profiling.

(1) Background: Extracellular vesicles (EVs) have emerged as crucial players in the communication between cells in both physiological and pathological scenarios. The functions of EVs are strongly determined by their molecular content, which includes all bioactive molecules, such as proteins, lipids, RNA, and, as more recently described, double-stranded DNA. It has been shown that in oncological settings DNA associated with EVs (EV-DNA) is representative of the genome of parental cells and that it reflects the mutational status of the tumor, gaining much attention as a promising source of biomarker mutant DNA. However, one of the challenges in studies of EV-DNA is the lack of standardization of protocols for the DNA extraction from EVs, as well as ways to assess quality control, which hinders its future implementation in clinics. (2) Methods: We performed a comprehensive comparison of commonly used approaches for EV-DNA extraction by assessing DNA quantity, quality, and suitability for downstream analyses. (3) Results: We here established strategic points to consider for EV-DNA preparation for mutational analyses, including qPCR and NGS. (4) Conclusions: We put in place a workflow that can be applied for the detection of clinically relevant mutations in the EV-DNA of cancer patients.

Prevalence of Migraine in General Spanish Population; Factors Related and Use of Health Resources.

Migraine is a common neurological disorder considered the second most disabling condition worldwide. Its prevalence ranges from 2.6% to 21.7% in population studies. This study aimed to know the prevalence of diagnosed and undiagnosed migraine in the general Spanish adult population, their health care use, and factors related. A descriptive cross-sectional study was undertaken with 23,089 individuals >15 years from the 2017 Spanish National Health Survey. Three groups were defined: people diagnosed with migraine (DM), people reporting undiagnosed migraine (UM) and people without migraine. Sociodemographic, clinical and use of health resources data were collected. The scales Duke Social Support Index (DSSI) and General Health Questionnaire (GHQ-12) were used. Prevalence of DM and UM were determined with 95% confidence intervals. To determine the factors associated with DM and UM, a multinomial logistic regression model was used. The prevalence of DM was 8.6% (95%CI: 8.2-9), and UM, 0.9% (95%CI: 0.8-1). People with DM more frequently visited healthcare professionals (47.8%), required more supplementary tests (86.8), had a higher percentage of hospitalization (11.3%), and used emergency services (45.1%). Women had nearly three times the risk of DM and UM. Worse mental health was a risk factor for UM (OR = 1.20) and DM (OR = 1.18). The greater the work stress, the greater the risk of DM (OR = 1.12). An adequate monitoring and management of migraine in people with these characteristics could contribute to improving their quality of life and reducing costs in the system.