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2. Metal-silicate partitioning of W and Mo and the role of carbon in controlling their abundances in the Bulk Silicate Earth

Author

Jennings, E. S., Jacobson, S. A., Rubie, D. C., Nakajima, Y., Vogel, A. K., Rose-Weston, L. A., and Frost, D. J.

Subjects
Astrophysics - Earth and Planetary Astrophysics, Physics - Geophysics
Abstract

The liquid metal-liquid silicate partitioning of molybdenum and tungsten during core formation must be well-constrained in order to understand the evolution of Earth and other planetary bodies, in particular because the Hf-W isotopic system is used to date early planetary evolution. We combine 48 new high pressure and temperature experimental results with a comprehensive database of previous experiments to re-examine the systematics of Mo and W partitioning. W partitioning is particularly sensitive to silicate and metallic melt compositions and becomes more siderophile with increasing temperature. We show that W has a 6+ oxidation state in silicate melts over the full experimental fO2 range of $\Delta$IW -1.5 to -3.5. Mo has a 4+ oxidation state and its partitioning is less sensitive to silicate melt composition, but also depends on metallic melt composition. DMo stays approximately constant with increasing depth in Earth. Both W and Mo become more siderophile with increasing C content of the metal, so we fit epsilon interaction parameters. W and Mo along with C are incorporated into a combined N-body accretion and core-mantle differentiation model. We show that W and Mo require the early accreting Earth to be sulfur-depleted and carbon-enriched so that W and Mo are efficiently partitioned into Earth's core and do not accumulate in the mantle. If this is the case, the produced Earth-like planets possess mantle compositions matching the BSE for all simulated elements. However, there are two distinct groups of estimates of the bulk mantle's C abundance in the literature: low (100 ppm), and high (800 ppm), and all models are consistent with the higher estimated carbon abundance. The low BSE C abundance would be achievable when the effects of the segregation of dispersed metal droplets produced in deep magma oceans by the disproportionation of Fe2+ to Fe3+ plus metallic Fe is considered., Comment: 61 pages including supplemental material

Published
2022
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3. State Strategies to Develop Teacher Capacity for Personalized, Competency-Based Learning. Issue Brief

Author

iNACOL, Patrick, S., Worthen, M., and Frost, D.

Abstract

This issue brief shares state policy recommendations and action steps for policymakers who are supporting the redesign of educator workforce systems to enable educators to build the skills, competencies and knowledge needed to thrive in modern, student-centered learning environments. By modernizing educator preparation and development systems, policymakers will support transformation at scale toward education systems that prepare every student for success in higher education, the modern workforce and as citizens. Transforming K-12 education systems to student-centered learning requires building teacher capacity for personalized, competency-based education. This issue brief highlights four strategies for states and school districts to transform educator workforce systems to prepare teachers with the skills they need for student-centered learning: (1) identifying clear, specific educator competencies for personalized, competency-based learning environments; (2) creating multiple, high-quality pathways to educator credentials and development; (3) developing educator professional judgment for student-centered learning; and (4) building assessment literacy.

Published
2018

4. Innovation Zones: Creating Policy Flexibility for Competency-Based Personalized Learning. Issue Brief

Author

iNACOL, Patrick, S., Worthen, M., Frost, D., and Truong, N.

Abstract

Innovation zones help state policy leaders create space in state policy for local educators to design innovative education models. They allow local districts or schools to request a waiver from outdated state policies and regulations that communities have identified as a barrier to high-quality, student-centered learning. These models are also known as "districts of innovation" or "schools of innovation;" the concept name varies from state to state. This issue brief describes innovation zones, explains why they are important, and provides examples of legislation, statutes or regulations creating innovation zones. It concludes with a recommendation for state policymakers.

Published
2018

5. Redesigning Systems of Assessments for Student-Centered Learning. Issue Brief

Author

iNACOL, Patrick, S., Worthen, M., and Frost, D.

Abstract

This issue brief discusses opportunities for states under the Every Student Succeeds Act (ESSA) to redesign systems of assessments to support student-centered learning. In addition, this brief introduces "balanced systems of assessments" and "assessment literacy" as two key concepts required for long-term sustainable systems transformation to student-centered learning.

Published
2017

8. High pressure and high temperature Brillouin scattering measurements of pyrope single crystals using flexible CO2 laser heating systems.

Author

Kurnosov, A., Criniti, G., Boffa Ballaran, T., Marquardt, H., and Frost, D. J.

Abstract

Single-crystal Brillouin scattering measurements are important for interpreting seismic velocities within the Earth and other planetary interiors. These measurements are rare, however, at temperatures above 1000 K, due to the fact that the transparent samples cannot be heated by common laser heating systems operating at a wavelength on the order of 1 μm. Here we present Brillouin scattering data on pyrope collected at pressures up to 23.8 GPa and temperatures between 850 and 1900 K using a novel CO2 laser heating system confined in either a flexible hollow silica waveguide or an articulated arm with mirrors mounted in each junction to direct the laser to the exit point. Pyrope has been chosen because it has been extensively studied at high pressures and moderate temperatures and therefore it is an excellent sample for bench-marking the CO2 laser heating system. The new high-temperature velocity data collected in this study allow the room pressure thermal parameters of pyrope to be constrained more tightly, resulting in values that reproduce the temperature dependence of the unit-cell volume of pyrope measured in recent studies at ambient pressure. Aggregate wave velocities of pyrope calculated along an adiabat using the thermoelastic parameters determined in this study are larger than those obtained using published values, implying that velocities for many mantle components may be underestimated at mantle temperatures because high temperature experimental data are lacking. [ABSTRACT FROM AUTHOR]

Published
2024
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13. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Author

Blein, S, Bardel, C, Danjean, V, McGuffog, L, Healey, S, Barrowdale, D, Lee, A, Dennis, J, Kuchenbaecker, KB, Soucy, P, Terry, MB, Chung, WK, Goldgar, DE, Buys, SS, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Gerdes, AM, Ejlertsen, B, Nielsen, FC, Hansen, TVO, Osorio, A, Benitez, J, Conejero, RA, Segota, E, Weitzel, JN, Thelander, M, Peterlongo, P, Radice, P, Pensotti, V, Dolcetti, R, Bonanni, B, Peissel, B, Zaffaroni, D, Scuvera, G, Manoukian, S, Varesco, L, Capone, GL, Papi, L, Ottini, L, Yannoukakos, D, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brady, A, Brewer, C, Foo, C, Evans, DG, Frost, D, Eccles, D, Douglas, F, Cook, J, Adlard, J, Barwell, J, Walker, L, Izatt, L, Side, LE, Kennedy, MJ, Tischkowitz, M, Rogers, MT, Porteous, ME, Morrison, PJ, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Cole, T, Godwin, AK, Isaacs, C, Claes, K, De Leeneer, K, Meindl, A, Gehrig, A, Wappenschmidt, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Plendl, H, Kast, K, Rhiem, K, Ditsch, N, Arnold, N, Varon-Mateeva, R, Schmutzler, RK, Preisler-Adams, S, Markov, NB, Wang-Gohrke, S, de Pauw, A, Lefol, C, Lasset, C, Leroux, D, Rouleau, E, Damiola, F, and Dreyfus, H

Subjects
Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

Published
2015

15. Examining aspects of psychological flexibility within the integrated motivational‐volitional model of suicidal behavior: A prospective investigation.

Author

Moscardini, Emma H., Breaux, Eathan A., Oakey‐Frost, D. Nicolas, and Tucker, Raymond P.

Subjects
ADAPTABILITY (Personality), SUICIDAL ideation, YOUNG adults, SUICIDAL behavior, EXPERIENTIAL learning
Abstract

Background: According to the integrated motivational‐volitional model of suicide, feelings of entrapment are related to the emergence of suicidal ideation (SI). However, this relation can be moderated by certain protective factors. Methods: This study examined whether aspects of psychological flexibility (i.e., experiential avoidance, experiential acceptance, harnessing) moderated the relation between aspects of entrapment and SI severity in college students experiencing SI (N = 553) both cross‐sectionally and when SI severity was measured 1 week later (N = 247). Results: At baseline, experiential acceptance, but not experiential avoidance or harnessing, significantly moderated the relation between external entrapment and SI severity and internal entrapment and SI severity. No aspects of psychological flexibility prospectively moderated relations between entrapment and SI severity. Conclusions: Aspects of psychological flexibility may influence immediate vulnerability to SI severity among young adults experiencing feelings of entrapment. Implications for clinical interventions influencing changes in psychological flexibility are discussed. [ABSTRACT FROM AUTHOR]

Published
2024
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16. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

Author

Antoniou, AC, Kuchenbaecker, KB, Soucy, P, Beesley, J, Chen, X, McGuffog, L, Lee, A, Barrowdale, D, Healey, S, Sinilnikova, OM, Caligo, MA, Loman, N, Harbst, K, Lindblom, A, Arver, B, Rosenquist, R, Karlsson, P, Nathanson, K, Domchek, S, Rebbeck, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Zlowowcka-Perlowska, E, Osorio, A, Duran, M, Andres, R, Benitez, J, Hamann, U, Hogervorst, FB, van Os, TA, Verhoef, S, Meijers-Heijboer, HEJ, Wijnen, J, Garcia, EBG, Ligtenberg, MJ, Kriege, M, Collee, M, Ausems, MGEM, Oosterwijk, JC, Peock, S, Frost, D, Ellis, SD, Platte, R, Fineberg, E, Evans, DG, Lalloo, F, Jacobs, C, Eeles, R, Adlard, J, Davidson, R, Cole, T, Cook, J, Paterson, J, Douglas, F, Brewer, C, Hodgson, S, Morrison, PJ, Walker, L, Rogers, MT, Donaldson, A, Dorkins, H, Godwin, AK, Bove, B, Stoppa-Lyonnet, D, Houdayer, C, Buecher, B, de Pauw, A, Mazoyer, S, Calender, A, Leone, M, Bressac-de Paillerets, B, Caron, O, Sobol, H, Frenay, M, Prieur, F, Ferrer, SF, Mortemousque, I, Buys, S, Daly, M, Miron, A, Terry, MB, Hopper, JL, John, EM, Southey, M, Goldgar, D, Singer, CF, Fink-Retter, A, Tea, M-K, Kaulich, DG, Hansen, TVO, Nielsen, FC, Barkardottir, RB, Gaudet, M, Kirchhoff, T, Joseph, V, Dutra-Clarke, A, Offit, K, and Piedmonte, M

Published
2012

17. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Mulligan, AM, Couch, FJ, Barrowdale, D, Domchek, SM, Eccles, D, Nevanlinna, H, Ramus, SJ, Robson, M, Sherman, M, Spurdle, AB, Wappenschmidt, B, Lee, A, McGuffog, L, Healey, S, Sinilnikova, OM, Janavicius, R, Hansen, TV, Nielsen, FC, Ejlertsen, B, Osorio, A, Muñoz-Repeto, I, Durán, M, Godino, J, Pertesi, M, Benítez, J, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Cattaneo, E, Bonanni, B, Viel, A, Pasini, B, Papi, L, Ottini, L, Savarese, A, Bernard, L, Radice, P, Hamann, U, Verheus, M, Meijers-Heijboer, HEJ, Wijnen, J, Gómez García, EB, Nelen, MR, Kets, CM, Seynaeve, C, Tilanus-Linthorst, MMA, van der Luijt, RB, Os, TV, Rookus, M, Frost, D, Jones, JL, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Adlard, J, Davidson, R, Cook, J, Donaldson, A, Dorkins, H, Gregory, H, Eason, J, Houghton, C, Barwell, J, Side, LE, McCann, E, Murray, A, Peock, S, Godwin, AK, Schmutzler, RK, Rhiem, K, Engel, C, Meindl, A, Ruehl, I, Arnold, N, Niederacher, D, Sutter, C, Deissler, H, Gadzicki, D, Kast, K, Preisler-Adams, S, Varon-Mateeva, R, Schoenbuchner, I, Fiebig, B, Heinritz, W, Schäfer, D, Gevensleben, H, and Caux-Moncoutier, V

Abstract

Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour.Methods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach.Results: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status.Conclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers. © 2011 Mulligan et al.; licensee BioMed Central Ltd.

Published
2011

25. Contralateral breast cancer risk in patients with breast cancer and a germline-BRCA1/2 pathogenic variant undergoing radiation.

Author

Barele, M. van, Akdeniz, D., Heemskerk-Gerritsen, B.A., Andrieu, N., Noguès, C., Asperen, C.J. van, Wevers, M.R., Ausems, M.G., Bock, G.H. de, Dommering, C.J., Gómez-García, E.B., Leeuwen, F.E. van, Mooij, T.M., Easton, D.F., Antoniou, A.C., Evans, D.G., Izatt, L., Tischkowitz, M., Frost, D., Brewer, C., Olah, E., Simard, J., Singer, C.F., Thomassen, M., Kast, K., Rhiem, K., Engel, C., Hoya, M. de la, Foretová, L., Jakubowska, A., Jager, Agnes, Sattler, M.G., Schmidt, M.K., Hooning, M.J., Barele, M. van, Akdeniz, D., Heemskerk-Gerritsen, B.A., Andrieu, N., Noguès, C., Asperen, C.J. van, Wevers, M.R., Ausems, M.G., Bock, G.H. de, Dommering, C.J., Gómez-García, E.B., Leeuwen, F.E. van, Mooij, T.M., Easton, D.F., Antoniou, A.C., Evans, D.G., Izatt, L., Tischkowitz, M., Frost, D., Brewer, C., Olah, E., Simard, J., Singer, C.F., Thomassen, M., Kast, K., Rhiem, K., Engel, C., Hoya, M. de la, Foretová, L., Jakubowska, A., Jager, Agnes, Sattler, M.G., Schmidt, M.K., and Hooning, M.J.

Abstract

Contains fulltext : 300004.pdf (Publisher’s version ) (Open Access), BACKGROUND: Radiation-induced secondary breast cancer (BC) may be a concern after radiation therapy (RT) for primary breast cancer (PBC), especially in young patients with germline (g)BRCA-associated BC who already have high contralateral BC (CBC) risk and potentially increased genetic susceptibility to radiation. We sought to investigate whether adjuvant RT for PBC increases the risk of CBC in patients with gBRCA1/2-associated BC. METHODS: The gBRCA1/2 pathogenic variant carriers diagnosed with PBC were selected from the prospective International BRCA1/2 Carrier Cohort Study. We used multivariable Cox proportional hazards models to investigate the association between RT (yes vs no) and CBC risk. We further stratified for BRCA status and age at PBC diagnosis (<40 and >40 years). Statistical significance tests were 2-sided. RESULTS: Of 3602 eligible patients, 2297 (64%) received adjuvant RT. Median follow-up was 9.6 years. The RT group had more patients with stage III PBC than the non-RT group (15% vs 3%, P < .001), received chemotherapy more often (81% vs 70%, P < .001), and received endocrine therapy more often (50% vs 35%, P < .001). The RT group had an increased CBC risk compared with the non-RT group (adjusted hazard ratio [HR] = 1.44; 95% confidence interval [CI] = 1.12 to 1.86). Statistical significance was observed in gBRCA2 (HR = 1.77; 95% CI = 1.13 to 2.77) but not in gBRCA1 pathogenic variant carriers (HR = 1.29; 95% CI = 0.93 to 1.77; P = .39 for interaction). In the combined gBRCA1/2 group, patients irradiated when they were younger than or older than 40 years of age at PBC diagnosis showed similar risks (HR = 1.38; 95% CI = 0.93 to 2.04 and HR = 1.56; 95% CI = 1.11 to 2.19, respectively). CONCLUSIONS: RT regimens minimizing contralateral breast dose should be considered in gBRCA1/2 pathogenic variant carriers.

Published
2023

30. A New Method for Determining Fluid Flux at High Pressures Applied to the Dehydration of Serpentinites

Author

Eberhard, L., Thielmann, M., Eichheimer, P., Néri, A., Suzuki, A., Ohl, M., Fujita, W., Uesugi, K., Nakamura, M., Golabek, G. J., Frost, D. J., 1 Bayerisches Geoinstitut University of Bayreuth Bayreuth Germany, 4 Department of Earth Science Tohoku University Sendai Japan, 2 Department of Earth Sciences Utrecht University Utrecht The Netherlands, and 5 Japan Synchrotron Radiation Research Institute (JASRI/Spring‐8) Hyogo Japan

Subjects
Geophysics, ddc:552.4, Geochemistry and Petrology, fluid flux, multi‐anvil, serpentine, excess pressure, dehydration, brucite
Abstract

A new method to determine fluid flux at high pressures and temperatures has been developed and used to study serpentinites at subduction zone conditions. Drill cores of a natural antigorite‐serpentinite with a strong foliation were used in multi‐anvil experiments in the range of 2–5 GPa and 450–800°C. Fluids released upon dehydration are fixed by the formation of brucite in an adjacent fluid sink. The amount and distribution of brucite serves as a proxy for fluid flow. In our specific setup the sample reacted with the surrounding fluid sink to form an additional layer of olivine, which has the potential to limit fluid flux within our experiments. For conditions prior to serpentine dehydration we used Al(OH)3 as fluid source. Fluid in this experiment did not migrate through the serpentinite, indicating that serpentine has a low diffusivity. The experiments also show that small deviatoric stresses have an influence on the fluid flux and can cause an anisotropic fluid flux. Comparison between the time scales of the determined fluid flux with fluid production rates indicates fluid pressure buildup during dehydration reactions. Adjacent less permeable layers can inhibit fluid flux and cause fluid pressure buildup even at conditions when an interconnected pore space formed., Plain Language Summary: Subduction zones are regions where tectonic plates are recycled into the Earth's interior. Prior to subduction, the plates experienced extensive chemical interaction with the ocean water, forming hydrous minerals. Serpentine is an important hydrous mineral that can transport significant amounts of water into the Earth's interior. During subduction both pressure and temperature increase whereby hydrous minerals break down and release their water. The fluid migrates into the overlying mantle wedge, where it accounts for hydration as well as melting processes. The global flux balances would require this process to be very effective. However, it was so far not possible to measure the fluid flux at the subduction zone conditions in laboratories. In this study, we present a new method to determine the fluid flux prior and during dehydration. We found that prior to dehydration, the fluid flux in serpentinites is small. During dehydration the rocks ability to let fluids pass through increases. However, adjacent rocks with a low ability for fluid transport can further inhibit a fluid flux at these conditions. Generally, our experimental setup can be used for any system that immobilizes migrating fluids by hydration reactions., Key Points: A new method to determine fluid flux at high pressure and temperature conditions is developed. Slow fluid migration in serpentinites promotes brittle fracturing in subduction zones. Fast fluid migration upon dehydration of serpentinites promotes large‐scale fluid flux, if not inhibited by adjacent less permeable layers., Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659, JSPS Japanese‐German Graduate Externship, Nederlandse Organisatie voor Wetenschappelijk Onderzoek http://dx.doi.org/10.13039/501100003246, https://doi.org/10.24416/UU01-PB440D

Published
2022

36. Experimental calibration of a garnet-clinopyroxene geobarometer for mantle eclogites

Author

Beyer, C., Frost, D. J., and Miyajima, N.

Subjects
Thermodynamics, Rocks, Igneous -- Inclusions, Earth sciences
Abstract

Thermodynamic parameters have been calibrated for a geobarometer suitable for use on eclogitic mantle xenoliths. The barometer is based on the incorporation of tetrahedrally coordinated aluminum in clinopyroxene coexisting with garnet and has been calibrated using the results of piston cylinder and multi-anvil experiments performed between pressures of 3 and 7 GPa and temperatures from 1,200 to 1,550 °C. Starting materials were hydrous and anhydrous synthetic mixtures of basaltic bulk compositions that yielded homogeneous bimineralic garnet-clinopyroxene phase assemblages. The experimental data set was expanded by employing results from previous experimental studies conducted in eclogitic systems, which widened the range of applicable conditions and compositions. The calibration reproduces experimental pressures of bimineralic eclogite assemblages, in addition to SiO.sub.2-saturated and kyanite-bearing eclogites, to within 0.4 GPa at the 95 % confidence interval. The barometer was then used to examine equilibration pressures recorded by natural mantle eclogites from various xenolith locations covering a wide pressure, temperature, and compositional range. Electronic supplementary material The online version of this article (doi:10.1007/s00410-015-1113-z) contains supplementary material, which is available to authorized users., Author(s): C. Beyer[sup.1] , D. J. Frost[sup.1] , N. Miyajima[sup.1] Author Affiliations: (1) Bayerisches Geoinsitut, University of Bayreuth, 95440, Bayreuth, Germany Introduction Geobarometry measurements are essential for understanding the thickness, [...]

Published
2015
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39. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Author

Barnes, DR, Silvestri, V, Leslie, G, McGuffog, L, Dennis, J, Yang, X, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arason, A, Arnold, N, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Belotti, M, Benitez, J, Berthet, P, Boonen, SE, Borg, A, Bozsik, A, Brady, AF, Brennan, P, Brewer, C, Brunet, J, Bucalo, A, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Cassingham, H, Christensen, LL, Cini, G, Claes, KBM, Cook, J, Coppa, A, Cortesi, L, Damante, G, Darder, E, Davidson, R, de la Hoya, M, De Leeneer, K, de Putter, R, Del Valle, J, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Eeles, R, Engel, C, Evans, DG, Feliubadalo, L, Fostira, F, Frone, M, Frost, D, Gallagher, D, Gehrig, A, Giraud, S, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gregory, H, Gross, E, Hahnen, E, Hamann, U, Hansen, TVO, Hanson, H, Hentschel, J, Horvath, J, Izatt, L, Izquierdo, A, James, PA, Janavicius, R, Jensen, UB, Johannsson, OT, John, EM, Kramer, G, Kroeldrup, L, Kruse, TA, Lautrup, C, Lazaro, C, Lesueur, F, Lopez-Fernandez, A, Mai, PL, Manoukian, S, Matrai, Z, Matricardi, L, Maxwell, KN, Mebirouk, N, Meindl, A, Montagna, M, Monteiro, AN, Morrison, PJ, Muranen, TA, Murray, A, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Tu, N-D, Niederacher, D, Olah, E, Olopade, O, Palli, D, Parsons, MT, Pedersen, IS, Peissel, B, Perez-Segura, P, Peterlongo, P, Petersen, AH, Pinto, P, Porteous, ME, Pottinger, C, Pujana, MA, Radice, P, Ramser, J, Rantala, J, Robson, M, Rogers, MT, Ronlund, K, Rump, A, Sanchez de Abajo, AM, Shah, PD, Sharif, S, Side, LE, Singer, CF, Stadler, Z, Steele, L, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Tommasi, S, Toss, A, Trainer, AH, Tripathi, V, Valentini, V, van Asperen, CJ, Venturelli, M, Viel, A, Vijai, J, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Whaite, A, Zanna, I, Offit, K, Thomassen, M, Couch, FJ, Schmutzler, RK, Simard, J, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Ottini, L, Barnes, DR, Silvestri, V, Leslie, G, McGuffog, L, Dennis, J, Yang, X, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arason, A, Arnold, N, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Belotti, M, Benitez, J, Berthet, P, Boonen, SE, Borg, A, Bozsik, A, Brady, AF, Brennan, P, Brewer, C, Brunet, J, Bucalo, A, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Cassingham, H, Christensen, LL, Cini, G, Claes, KBM, Cook, J, Coppa, A, Cortesi, L, Damante, G, Darder, E, Davidson, R, de la Hoya, M, De Leeneer, K, de Putter, R, Del Valle, J, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Eeles, R, Engel, C, Evans, DG, Feliubadalo, L, Fostira, F, Frone, M, Frost, D, Gallagher, D, Gehrig, A, Giraud, S, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gregory, H, Gross, E, Hahnen, E, Hamann, U, Hansen, TVO, Hanson, H, Hentschel, J, Horvath, J, Izatt, L, Izquierdo, A, James, PA, Janavicius, R, Jensen, UB, Johannsson, OT, John, EM, Kramer, G, Kroeldrup, L, Kruse, TA, Lautrup, C, Lazaro, C, Lesueur, F, Lopez-Fernandez, A, Mai, PL, Manoukian, S, Matrai, Z, Matricardi, L, Maxwell, KN, Mebirouk, N, Meindl, A, Montagna, M, Monteiro, AN, Morrison, PJ, Muranen, TA, Murray, A, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Tu, N-D, Niederacher, D, Olah, E, Olopade, O, Palli, D, Parsons, MT, Pedersen, IS, Peissel, B, Perez-Segura, P, Peterlongo, P, Petersen, AH, Pinto, P, Porteous, ME, Pottinger, C, Pujana, MA, Radice, P, Ramser, J, Rantala, J, Robson, M, Rogers, MT, Ronlund, K, Rump, A, Sanchez de Abajo, AM, Shah, PD, Sharif, S, Side, LE, Singer, CF, Stadler, Z, Steele, L, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Tommasi, S, Toss, A, Trainer, AH, Tripathi, V, Valentini, V, van Asperen, CJ, Venturelli, M, Viel, A, Vijai, J, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Whaite, A, Zanna, I, Offit, K, Thomassen, M, Couch, FJ, Schmutzler, RK, Simard, J, Easton, DF, Chenevix-Trench, G, Antoniou, AC, and Ottini, L

Abstract

BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. METHODS: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. RESULTS: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. CONCLUSIONS: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.

Published
2022

40. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

Author

Hakkaart, C, Pearson, JF, Marquart, L, Dennis, J, Wiggins, GAR, Barnes, DR, Robinson, BA, Mace, PD, Aittomaki, K, Andrulis, IL, Arun, BK, Azzollini, J, Balmana, J, Barkardottir, RB, Belhadj, S, Berger, L, Blok, MJ, Boonen, SE, Borde, J, Bradbury, AR, Brunet, J, Buys, SS, Caligo, MA, Campbell, I, Chung, WK, Claes, KBM, Collonge-Rame, M-A, Cook, J, Cosgrove, C, Couch, FJ, Daly, MB, Dandiker, S, Davidson, R, de la Hoya, M, de Putter, R, Delnatte, C, Dhawan, M, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Easton, DF, Ehrencrona, H, Engel, C, Evans, DG, Faust, U, Feliubadalo, L, Fostira, F, Friedman, E, Frone, M, Frost, D, Garber, J, Gayther, SA, Gehrig, A, Gesta, P, Godwin, AK, Goldgar, DE, Greene, MH, Hahnen, E, Hake, CR, Hamann, U, Hansen, TVO, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, PA, Janavicius, R, John, EM, Joseph, V, Karlan, BY, Kemp, Z, Kirk, J, Konstantopoulou, I, Koudijs, M, Kwong, A, Laitman, Y, Lalloo, F, Lasset, C, Lautrup, C, Lazaro, C, Legrand, C, Leslie, G, Lesueur, F, Mai, PL, Manoukian, S, Mari, V, Martens, JWM, McGuffog, L, Mebirouk, N, Meindl, A, Miller, A, Montagna, M, Moserle, L, Mouret-Fourme, E, Musgrave, H, Nambot, S, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nguyen-Dumont, T, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, OI, Osorio, A, Ott, C-E, Park, SK, Parsons, MT, Pedersen, IS, Peixoto, A, Perez-Segura, P, Peterlongo, P, Pocza, T, Radice, P, Ramser, J, Rantala, J, Rodriguez, GC, Ronlund, K, Rosenberg, EH, Rossing, M, Schmutzler, RK, Shah, PD, Sharif, S, Sharma, P, Side, LE, Simard, J, Singer, CF, Snape, K, Steinemann, D, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Trainer, AH, Tripathi, V, Tung, N, van Engelen, K, van Rensburg, EJ, Vega, A, Viel, A, Walker, L, Weitzel, JN, Wevers, MR, Chenevix-Trench, G, Spurdle, AB, Antoniou, AC, Walker, LC, Hakkaart, C, Pearson, JF, Marquart, L, Dennis, J, Wiggins, GAR, Barnes, DR, Robinson, BA, Mace, PD, Aittomaki, K, Andrulis, IL, Arun, BK, Azzollini, J, Balmana, J, Barkardottir, RB, Belhadj, S, Berger, L, Blok, MJ, Boonen, SE, Borde, J, Bradbury, AR, Brunet, J, Buys, SS, Caligo, MA, Campbell, I, Chung, WK, Claes, KBM, Collonge-Rame, M-A, Cook, J, Cosgrove, C, Couch, FJ, Daly, MB, Dandiker, S, Davidson, R, de la Hoya, M, de Putter, R, Delnatte, C, Dhawan, M, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Easton, DF, Ehrencrona, H, Engel, C, Evans, DG, Faust, U, Feliubadalo, L, Fostira, F, Friedman, E, Frone, M, Frost, D, Garber, J, Gayther, SA, Gehrig, A, Gesta, P, Godwin, AK, Goldgar, DE, Greene, MH, Hahnen, E, Hake, CR, Hamann, U, Hansen, TVO, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, PA, Janavicius, R, John, EM, Joseph, V, Karlan, BY, Kemp, Z, Kirk, J, Konstantopoulou, I, Koudijs, M, Kwong, A, Laitman, Y, Lalloo, F, Lasset, C, Lautrup, C, Lazaro, C, Legrand, C, Leslie, G, Lesueur, F, Mai, PL, Manoukian, S, Mari, V, Martens, JWM, McGuffog, L, Mebirouk, N, Meindl, A, Miller, A, Montagna, M, Moserle, L, Mouret-Fourme, E, Musgrave, H, Nambot, S, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nguyen-Dumont, T, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, OI, Osorio, A, Ott, C-E, Park, SK, Parsons, MT, Pedersen, IS, Peixoto, A, Perez-Segura, P, Peterlongo, P, Pocza, T, Radice, P, Ramser, J, Rantala, J, Rodriguez, GC, Ronlund, K, Rosenberg, EH, Rossing, M, Schmutzler, RK, Shah, PD, Sharif, S, Sharma, P, Side, LE, Simard, J, Singer, CF, Snape, K, Steinemann, D, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Trainer, AH, Tripathi, V, Tung, N, van Engelen, K, van Rensburg, EJ, Vega, A, Viel, A, Walker, L, Weitzel, JN, Wevers, MR, Chenevix-Trench, G, Spurdle, AB, Antoniou, AC, and Walker, LC

Abstract

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

Published
2022

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