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

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

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Improving peptide relative quantification in MALDI-TOF MS for biomarker assessment

Proteomic profiling by MALDI-TOF MS presents various advantages (speed of analysis, ease of use, relatively low cost, sensitivity, tolerance against detergents and contaminants, and possibility of automation) and is being currently used in many applications (e.g. peptide/protein identification and quantification, biomarker discovery, and imaging MS). Earlier studies by many groups indicated that moderate reproducibility in relative peptide quantification is a major limitation of MALDI-TOF MS. In the present work, we examined and demonstrate a clear effect, in cases apparently random, of sample dilution in complex samples (urine) on the relative quantification of peptides by MALDI-TOF MS. Results indicate that in urine relative abundance of peptides cannot be assessed with confidence based on a single MALDI-TOF MS spectrum. To account for this issue, we developed and propose a novel method of determining the relative abundance of peptides, taking into account that peptides have individual linear quantification ranges in relation to sample dilution. We developed an algorithm that calculates the range of dilutions at which each peptide responds in a linear manner and normalizes the received peptide intensity values accordingly. This concept was successfully applied to a set of urine samples from patients diagnosed with diabetes presenting normoalbuminuria (controls) and macroalbuminuria (cases)

A Regenerative Agricultural System at Scale: an Outline of Required Outcomes for the Netherlands

Regenerative agriculture is considered a more sustainable alternative to current farming practices, but it is not yetwell defined. Building on scientific literature we have defined regenerative agriculture as ‘an approach to farming thatuses soil conservation as the entry point to regenerate and contribute to multiple provisioning, regulating and supportingecosystem services, with the aspiration that this will enhance not only the environmental, but also the social andeconomic dimensions of sustainable food production’. In addition to this definition at farm level we propose thefollowing vision for a regenerative agricultural system at landscape or higher system levels: A regenerative agriculturalsystem enables production of food and biomass and enables ecosystems to maintain a healthy state and evolve, whilecontributing to biological diversity, integrity of the biosphere, human and farm animal well-being and economicprosperity of society. Based on this long-term vision we have defined a comprehensive outline of a regenerativeagricultural system that includes, and takes into account, all ecosystem services, soil functions and planetaryboundaries. This outline covers fourteen topics and describes the ‘outcomes’ that are needed to meet the objectives of a regenerative agricultural system, without being prescriptive on ‘how’ these outcomes should be achieved. Therefore, weuse the term ‘required outcomes’ which precisely and quantitatively describe the target performance of the regenerativeagricultural system. These ‘required outcomes’ are related to the inputs and use of resources, the output (i.e. food,biomass) and losses/emissions, and the preferred state of soils, water bodies, animals, biodiversity and society. Theoutcomes encompass environmental, social, and economic aspects, and are defined at five different system levels: 1)field (above and below ground), 2) farm, 3) local landscape (including air and water bodies), 4) the Netherlands and 5)international. All required outcomes are based on and supported by scientific literatur