Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. Weevaluated whether PSVs inBRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 30 region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.Peer reviewe

Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.Peer reviewe

Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer

Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4

Histopathological Changes of the Heart After Neonatal Dexamethasone Treatment:Studies in 4-, 8-, and 50-Week-Old Rats

Dexamethasone (Dex), for prevention of chronic lung disease in preterm infants, showed potential negative long-term effects. Studies regarding long-term cardiovascular effects are lacking. We investigated possible histopathological myocardial changes after neonatal Dex in the young and adult rat heart. Rats were treated with Dex on d 1, 2, and 3 (0.5, 0.3, and 0. 1 mg/ka) of life. Control-pups received saline. At 4, 8, and 50 wk after birth rats were killed and anatomic data collected. Heart tissue was stained with hematoxylin and eosin, Cadherin-periodic acid schiff, and sirius red for cardiomyocyte morphometry and collagen determination. Presence of macrophages and mast cells was analyzed. Cardiomyocyte length of the Dex-treated rats was increased in all three age groups, whereas ventricular weight was reduced. Cardiomyocyte volumes were increased at 50 wk indicating cellular hypertrophy. Collagen content gradually increased with age and was 62% higher in Dex rats at 50 wk. Macrophage focus score and mast cell count were also higher. Neonatal Dex affects normal heart growth resulting in cellular hypertrophy and increased collagen deposition in the adult rat heart. Because previous studies in rats showed premature death, suggesting cardiac failure, cardiovascular follow-Lip of preterm infants treated with glucocorticoids should be considered. (Pediatr Res 66: 74-79, 2009

Peripheral quantitative computed tomography (pQCT) reveals low bone mineral density in adolescents with motor difficulties

© 2015, International Osteoporosis Foundation and National Osteoporosis Foundation. Summary: This is the first reported study to describe local bone mineral density, assess parameters of fracture risk and report history of fractures in adolescents with motor difficulties. Motor difficulties evidenced by poor coordination in adolescence should be considered a new risk factor for below-average bone strength and structure and fracture risk. Introduction: Adolescents with motor difficulties are characterised by poor coordination and low levels of physical activity and fitness. It is possible these deficits translate into below-average bone strength and structure. The objectives of this study were to describe local bone mineral density (BMD), assess parameters of fracture risk (stress–strain index, SSI) and report history of fractures in this group. Methods: Thirty-three adolescents (13 females), mean age of 14.3 (SD = 1.5) years, with motor difficulties underwent peripheral quantitative computed tomography (pQCT) measurements at proximal (66 %) and distal (4 %) sites of the non-dominant radius (R4 and R66) and tibia (T4 and T66). One sample t test was used to compare Z-scores for total BMD, trabecular density, cortical density and stress strain index (SSI) against standardized norms. Results: Significant differences were present at R4 total density mean Z-score = -0.85 (SD = 0.7, p < 0.001), R66 cortical density mean Z-score = -0.74 (SD = 1.97, p = 0.038), R66 SSI mean Z-score = -1.00 (SD = 1.08, p < 0.001) and T66 SSI mean Z-score = -0.70 (SD = 1.15, p < 0.001). There was a higher incidence of fractures (26.9 %) compared to the normal population (3–9 %). Conclusions: Motor difficulties in adolescence should be considered a risk factor for below-average bone strength and structure and fracture risk. Strategies are needed to improve bone health in this high-risk-group