Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.UK funding includes Cancer Research UK and NIH.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13058-016-0718-

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

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

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Síntese de trans-resveratrol e controle de podridão em maçãs com uso de elicitores em pós-colheita Synthesis of trans-resveratrol and rotting control in apples with use of elicitors in post-harvest

O objetivo deste trabalho foi avaliar o efeito da aplicação de elicitores abióticos na biossíntese de resveratrol e na indução de resistência à podridão póscolheita de maçãs 'Gala' e 'Fuji'. Foram realizados os tratamentos: radiação ultravioleta, fosfito e acibenzolar-Smetil - aplicados antes do armazenamento - e ozônio - aplicado intermitente durante o armazenamento. As condições de armazenamento foram: 'Gala', 1,5 kPa de O2 e 2,5 kPa de CO2, a 0,5±0,1ºC, por oito meses, e 'Fuji', 1,0 kPa de O2 e <0,5 kPa de CO2, a 0,5±0,1ºC, por sete meses. O delineamento experimental foi inteiramente ao acaso, com oito repetições de 25 frutos. Na casca dos frutos, determinou-se: trans-resveratrol, polifenóis totais, antocianinas totais e diâmetro de lesão, após inoculação de Penicillium sp. no ferimento. Analisou-se na polpa: firmeza de polpa, acidez titulável, sólidos solúveis totais, açúcares redutores e nãoredutores. Os elicitores não alteram a concentração de polifenóis totais e antocianinas, com exceção do acibenzolar-Smetil que reduz o conteúdo de antocianinas na maçã 'Gala'. Os elicitores induzem, na 'Fuji', mas não na maçã 'Gala', a síntese de trans-resveratrol na seqüência: acibenzolar-Smetil> fosfito> irradiação UV-C> ozônio. Na maçã 'Gala', o fosfito reduz a ocorrência de podridão, porém, em ambas as cultivares, não há correlação entre síntese de trans-resveratrol e controle de podridão.<br>The objective of this study was evaluate the effect of the application of abiotic elicitors of resveratrol in 'Gala' and 'Fuji' apples, and rotting control. The treatment was with ultraviolet irradiation, phosphite and acibenzolar-Smethyl, applied before controlled atmosphere storage and ozone, applied so intermittently during storage. The storage conditions were: 'Gala' (1.5 kPa O2 and 2.5 kPa CO2, at 0.5±0.1°C by eight months) and 'Fuji' (1.0 kPa O2 and <0.5 kPa CO2, at 0.5±0.1°C for seven months). The experimental design was a completely randomized with eight repetitions of 25 fruits. In the skin of fruit trans-resveratrol were analyzed by high performance liquid chromatography; total polyphenols and anthocyanins by spectrophotometry and diameter of injury after inoculation by Penicillium sp. Firmness, acidity, total soluble solids, and reducing and nonreducing sugars were analyzed in the flesh. The elicitores do not change the concentration of phenols and anthocyanins, with the exception of the loss of total anthocyanins with acibenzolar-Smethyl in 'Gala' apple. The elicitors induce in 'Fuji' apples the synthesis of trans-resveratrol in the sequence: acibenzolar-Smethyl>phosphite>UV-C irradiation>ozone. There isn't correlation between synthesis of trans-resveratrol and rotting control, but the phosphite controlled rot in 'Gala'