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. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. Methods:Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. Results:Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95 confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. Conclusion:Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2. © 2014 Cancer Research UK

A century of sea level measurements at Newlyn, SW England

The Newlyn Tidal Observatory is the most important sea level station in the UK. It commenced operations in 1915 as part of the Second Geodetic Levelling of England and Wales, and the mean sea level determined from the tide gauge during the first six years (May 1915-April 1921) defined Ordnance Datum Newlyn (ODN) which became the national height datum for the whole of Great Britain. The 100 years of sea level data now available have contributed significantly to many studies in oceanography, geology and climate change. This paper marks the centenary of this important station by reviewing the sea level (and, more recently, detailed land level) measurements and Newlyn’s contributions to UK cartography, geodesy and sea-level science in general. Recommendations are made on how sea and land level measurements at Newlyn might be enhanced in the future

The blood metabolome of incident kidney cancer: A case-control study nested within the MetKid consortium.

BackgroundExcess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI).Methods and findingsWe assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds.ConclusionsThis study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer

Isospin dependence of electromagnetic transition strengths among an isobaric triplet

Electric quadrupole matrix elements, M, for the J=2→0, ΔT=0, T=1 transitions across the A=46 isobaric multiplet Cr-V-Ti have been measured at GSI with the FRS-LYCCA-AGATA setup. This allows direct insight into the isospin purity of the states of interest by testing the linearity of M with respect to T. Pairs of nuclei in the T=1 triplet were studied using identical reaction mechanisms in order to control systematic errors. The M values were obtained with two different methodologies: (i) a relativistic Coulomb excitation experiment was performed for Cr and Ti; (ii) a “stretched target” technique was adopted here, for the first time, for lifetime measurements in V and Ti. A constant value of M across the triplet has been observed. Shell-model calculations performed within the fp shell fail to reproduce this unexpected trend, pointing towards the need of a wider valence space. This result is confirmed by the good agreement with experimental data achieved with an interaction which allows excitations from the underlying sd shell. A test of the linearity rule for all published data on complete T=1 isospin triplets is presented.Peer Reviewe

High-throughput automated scoring of Ki67 in breast cancer tissue microarrays from the Breast Cancer Association Consortium (BCAC)

Automated methods are needed to facilitate high-throughput and reproducible scoring of Ki67 and other markers in breast cancer tissue microarrays (TMAs) in large-scale studies. To address this need, we developed an automated protocol for Ki67 scoring and evaluated its performanc

Prominence seismology using small amplitude oscillations

Quiescent prominences are thin slabs of cold, dense plasma embedded in the much hotter and rarer solar corona. Although their global shape is rather irregular, they are often characterised by an internal structure consisting of a large number of thin, parallel threads piled together. Prominences often display periodic disturbances mostly observed in the Doppler displacement of spectral lines and with an amplitude typically of the order of or smaller than 2--3 km s$^{-1}$, a value which seems to be much smaller than the characteristic speeds of the prominence plasma (namely the Alfv\'en and sound velocities). Two particular features of these small amplitude prominence oscillations is that they seem to damp in a few periods and that they seem not to affect the whole prominence structure. In addition, in high spatial resolution observations, in which threads can be discerned, small amplitude oscillations appear to be clearly associated to these fine structure constituents. Prominence seismology tries to bring together the results from these observations (e.g. periods, wavelengths, damping times) and their theoretical modeling (by means of the magnetohydrodynamic theory) to gain insight into physical properties of prominences that cannot be derived from direct observation. In this paper we discuss works that have not been described in previous reviews, namely the first seismological application to solar prominences and theoretical advances on the attenuation of prominence oscillations

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

MicroRNA Related Polymorphisms and Breast Cancer Risk

Peer reviewe