Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers

Item does not contain fulltextBACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m(2) increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.

BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175). BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community´s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 16 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defense (W81XWH-10-1- 0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Project established by the National Cancer Institute and National Human Genome Research Institute.This is the author accepted manuscript. The final version is available from BMJ Group at http://dx.doi.org/10.1136/jmedgenet-2015-103529

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

Research Needs Concerning Non-target Impacts of Biological Control Introductions

Two workshops were held in 1999 on research needs concerning non-target impacts of biological control introductions. One took place on the Internet for 9 months, and the other in Montpellier, France, for 1 day. Altogether, over 200 researchers from over 30 countries participated, representing a wide variety of viewpoints on the issues involved. The deliberations of these workshops are summarized here. Both workshops highlighted the need for retrospective studies to: (i) identify cases of significant non-target impacts; (ii) explore mechanisms involved when such impacts are found; (iii) evaluate the reliability of host-range testing protocols; and (iv) determine whether and under what circumstances host ranges of biological control agents have evolved subsequent to introduction. Both workshops also emphasized the need for better understanding of the mechanisms underlying host specificity. Finally, both workshops recognized the desirability of collaboration among ecologists, economists, sociologists and biological control practitioners in research to assess and reduce the potential for non-target impacts of biological control introductions

Does time until mating affect progeny sex ratio ? A manipulative experiment with the parasitoid wasp Aphelinus asychis

International audienc

Isotopic dilution of {sup 233}U with depleted uranium for criticality safety in processing and disposal

The disposal of excess {sup 233}U as waste is being considered. Because {sup 233}U is a fissile material, a key requirement for processing {sup 233}U to a final waste form and disposing of it is the avoidance of nuclear criticality. For many processing and disposal options, isotopic dilution is the most feasible and preferred option to avoid nuclear criticality. Isotopic dilution is dilution of fissile {sup 233}U with nonfissile {sup 238}U. The use of isotopic dilution removes any need to control nuclear criticality in process or disposal facilities through geometry or chemical composition. Isotopic dilution allows the use of existing waste management facilities that are not designed for significant quantities of fissile materials to be used for processing and disposing of {sup 233}U. The amount of isotopic dilution required to reduce criticality concerns to reasonable levels was determined in this study to be approximately 0.53 wt % {sup 233}U. The numerical calculations used to define this limit consisted of a homogeneous system of silicon dioxide (SiO{sub 2}), water (H{sub 2}O), {sup 233}U and depleted uranium (DU) in which the ratio of each component was varied to learn the conditions of maximum nuclear reactivity. About 188 parts of DU (0.2 wt % {sup 235}U) are required to dilute 1 part of {sup 233}U to this limit in a water-moderated system with no SiO{sub 2} present. Thus for the U.S. inventory of {sup 233}U, several hundred metric tons of DU would be required for isotopic dilution

Bounding Values for Low-Level-Waste Transport Exemptions and Disposal

Characterizations and bounding computational results determined by the Oak Ridge National Laboratory have been offered to the U.S. Nuclear Regulatory Commission as supporting technical bases for regulatory considerations in the packaging, transport, retrievable emplacement and disposal of radioactive low-level waste contaminated with fissile materials. The fissile materials included 100 wt % U, 10 wt % U in uranium, 100 wt % U, 100 wt % Pu, or plutonium as less than 235 235 233 239 76 wt % Pu, more than 12 wt % Pu, and less than 12 wt % Pu. The considered waste matrixes 239 240 241 included silicon dioxide, carbon, light water and polyethylene, heavy water, or beryllium with summary examinations of other potential matrixes. The limiting concentrations and geometries for these bounding conjectured low-level-waste matrixes are presented in this paper