Biology subjects

Blanco, A.

Publications and source records attributed to Blanco, A..

21 records · Page 2Linked to original sources

bioRxiv2019

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study (GWAS) including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status and tumor grade. We identified 32 novel susceptibility loci (P<5.0x10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate <0.05). Five loci showed associations (P<0.05) in opposite directions between luminal- and non-luminal subtypes. In-silico analyses showed these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 37.6% for triple-negative and 54.2% for luminal A-like disease. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

genetics↗

bioRxiv2019

Senolytic activity of small molecular polyphenols from olive restores chondrocyte redifferentiation and cartilage regeneration in osteoarthritis

Osteoarthritis (OA) is the most prevalent disorder of articulating joints and a leading cause of disability in humans, affecting half of the worlds population aged 65 years or older. Articular cartilage and synovial tissue from OA patients show an overactivity of the membrane channel protein connexin43 (Cx43) and accumulation of senescent cells associated with disrupted tissue regeneration. We have recently demonstrated the use of the Cx43 as an appropriate therapeutic target to halt OA progression by decreasing the accumulation of senescent cells and by triggering redifferentiation of osteoarthritic chondrocytes (OACs) into a more differentiated state, restoring the fully mature phenotype and cartilage regeneration. In this study we have found that small molecular polyphenols derived by olive extracts target Cx43 and senescence in OACs, synovial and bone cells from patients and in human mesenchymal stem cells (hMSCs). Our results indicate that these small molecules including oleuropein regulate the promoter activity of Cx43 gene. The downregulation of Cx43 expression by oleuropein reduce gap junction intercellular communication, cellular senescence in chondrocytes and enhance the propensity of hMSCs to differentiate into chondrocytes and bone cells, reducing adipogenesis. In concordance with these results, these small molecules reduce Cx43 and decrease Twist-1 activity leading to redifferentiation of OACs, which restores the synthesis of cartilage ECM components (Col2A1 and proteoglycans) and reduces inflammatory and catabolic factors IL-1{beta}, IL-6, COX-2 and MMP-3 and cellular senescence orchestrated by p53/p21 together with the synthesis of SASP via NF-kB. Altogether, our results demonstrate the use of the olive-derived polyphenols such as oleuropein as potentially effective therapeutic agents to enhance the efficacy of hMSC therapy and to induce a pro-regenerative environment in OA patients by restoring cellular phenotype and clearing out senescent cells in joint tissues in order to stop or prevent the progression of the disease.

cell biology↗

bioRxiv2019

Fine-mapping of 150 breast cancer risk regions identifies 178 high confidence target genes

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants (CCVs) in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium, and enriched genomic features to determine variants with high posterior probabilities (HPPs) of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of potentially causal variants, using gene expression (eQTL), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways, were over-represented among the 178 highest confidence target genes.

genetics↗