Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1.

Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.

MicroRNA related polymorphisms and breast cancer risk.

Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS).

Temporal stability and determinants of white blood cell DNA methylation in the breakthrough generations study.

Background: Epigenome-wide association studies (EWAS) using measurements of blood DNA methylation are performed to identify associations of methylation changes with environmental and lifestyle exposures and disease risk. However, little is known about the variation of methylation markers in the population and their stability over time, both important factors in the design and interpretation of EWAS. We aimed to identify stable variable methylated probes (VMP), i.

Synthetic lethality and cancer therapy: lessons learned from the development of PARP inhibitors.

The genetic concept of synthetic lethality, in which the combination or synthesis of mutations in multiple genes results in cell death, provides a framework to design novel therapeutic approaches to cancer. Already there are promising indications, from clinical trials exploiting this concept by using poly(ADP-ribose) polymerase (PARP) inhibitors in patients with germline BRCA1 or BRCA2 gene mutations, that this approach could be beneficial. We discuss the biological rationale for BRCA-PARP synthetic lethality, how the synthetic lethal approach is being assessed in the clinic, and how mechanisms of resistance are starting to be dissected.

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data.

Investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors.

A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls.

DAISY: picking synthetic lethals from cancer genomes.

A better understanding of genetic interactions in cancer might help identify new therapeutic approaches that exploit the concept of synthetic lethality. Ruppin and colleagues have developed a new computational method, DAISY, that predicts such interactions and potentially facilitates the delineation and validation of comprehensive genetic interaction networks.

Long-term quality of life after liver donation in the adult to adult living donor liver transplantation cohort study (A2ALL).

Background & Aims: There are few long-term studies of the health-related quality of life (HRQOL) in living liver donors. This study aimed to characterize donor HRQOL in the Adult to Adult Living Donor Liver Transplantation Study (A2ALL) up to 11 years post-donation.

Methods: Between 2004 and 2013, HRQOL was assessed at evaluation, at 3 months, and yearly post-donation in prevalent liver donors using the short-form survey (SF-36), which provides a physical (PCS) and a mental component summary (MCS).

Dsh homolog DVL3 mediates resistance to IGFIR inhibition by regulating IGF-RAS signaling.

Drugs that inhibit insulin-like growth factor 1 (IGFI) receptor IGFIR were encouraging in early trials, but predictive biomarkers were lacking and the drugs provided insufficient benefit in unselected patients. In this study, we used genetic screening and downstream validation to identify the WNT pathway element DVL3 as a mediator of resistance to IGFIR inhibition. Sensitivity to IGFIR inhibition was enhanced specifically in vitro and in vivo by genetic or pharmacologic blockade of DVL3.

Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.

Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS).

The Importance of Sleep: Attentional Problems in School-Aged Children With Down Syndrome and Williams Syndrome.

In typically developing (TD) children, sleep problems have been associated with day-time attentional difficulties. Children with developmental disabilities often suffer with sleep and attention problems, yet their relationship is poorly understood. The present study investigated this association in school-aged children with Down syndrome (DS) and Williams syndrome (WS).

Unbiased analysis of potential targets of breast cancer susceptibility loci by Capture Hi-C.

Genome-wide association studies have identified more than 70 common variants that are associated with breast cancer risk. Most of these variants map to non-protein-coding regions and several map to gene deserts, regions of several hundred kilobases lacking protein-coding genes. We hypothesized that gene deserts harbor long-range regulatory elements that can physically interact with target genes to influence their expression.

Acute acepromazine overdose: clinical effects and toxicokinetic evaluation.

Introduction: Acepromazine is a phenothiazine that is used exclusively in veterinary medicine for multiple purposes. Human overdoses are rarely reported and toxicokinetic data has never been reported. We present a case of intentional acepromazine overdose resulting in central nervous system and cardiovascular toxicity with confirmatory toxicokinetic data.

Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium.

Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression.

Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade.

Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls).

An individual patient data metaanalysis of outcomes and prognostic factors after treatment of oligometastatic non-small-cell lung cancer.

Introduction/background: An individual patient data metaanalysis was performed to determine clinical outcomes, and to propose a risk stratification system, related to the comprehensive treatment of patients with oligometastatic NSCLC.

Materials And Methods: After a systematic review of the literature, data were obtained on 757 NSCLC patients with 1 to 5 synchronous or metachronous metastases treated with surgical metastectomy, stereotactic radiotherapy/radiosurgery, or radical external-beam radiotherapy, and curative treatment of the primary lung cancer, from hospitals worldwide. Factors predictive of overall survival (OS) and progression-free survival were evaluated using Cox regression.

Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study.

Introduction: We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years.

Methods: We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium.

The relationship between obesity and exposure to light at night: cross-sectional analyses of over 100,000 women in the Breakthrough Generations Study.

There has been a worldwide epidemic of obesity in recent decades. In animal studies, there is convincing evidence that light exposure causes weight gain, even when calorie intake and physical activity are held constant. Disruption of sleep and circadian rhythms by exposure to light at night (LAN) might be one mechanism contributing to the rise in obesity, but it has not been well-investigated in humans.

Genome-wide characterization reveals complex interplay between TP53 and TP63 in response to genotoxic stress.

In response to genotoxic stress the TP53 tumour suppressor activates target gene expression to induce cell cycle arrest or apoptosis depending on the extent of DNA damage. These canonical activities can be repressed by TP63 in normal stratifying epithelia to maintain proliferative capacity or drive proliferation of squamous cell carcinomas, where TP63 is frequently overexpressed/amplified. Here we use ChIP-sequencing, integrated with microarray analysis, to define the genome-wide interplay between TP53 and TP63 in response to genotoxic stress in normal cells.

Reproducibility of estradiol and testosterone levels in postmenopausal women over 5 years: results from the breakthrough generations study.

Prospective cohort studies examining sex hormones in relation to cancer risk have generally collected blood samples at 1 time point, with an assumption that hormone levels measured in these samples will be reliable markers of true levels at other times. In postmenopausal women, body fat is a major source of estradiol; therefore, changes in adiposity may affect the correlation of single measurements to more relevant long-term averages. To estimate the intraclass correlation coefficient (ICC) for estradiol and testosterone, we collected repeat blood samples from 119 postmenopausal women (average age = 59.

Type of anesthesia and postoperative delirium after vascular surgery.

Objective: The purpose of this study was to investigate the association between general (GA), regional (RA), and local (LA) anesthetic techniques with respect to the development of delirium after vascular surgery. The authors hypothesized that patients undergoing GA for vascular surgery would have a higher incidence of postoperative delirium. The role of LA with respect to postoperative delirium in vascular surgery patients previously has not been reported.

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

Background: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk.