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3. Two active states of the narrow-line gamma-ray-loud AGN GB 1310+487

Author

Sokolovsky, K. V., Schinzel, F. K., Tanaka, Y. T., Abolmasov, P. K., Angelakis, E., Bulgarelli, A., Carrasco, L., Cenko, S. B., Cheung, C. C., Clubb, K. I., D'Ammando, F., Escande, L., Fegan, S. J., Filippenko, A. V., Finke, J. D., Fuhrmann, L., Fukazawa, Y., Hays, E., Healey, S. E., Ikejiri, Y., Itoh, R., Kawabata, K. S., Komatsu, T., Kovalev, Yu. A., Kovalev, Y. Y., Krichbaum, T. P., Larsson, S., Lister, M. L., Lott, B., Max-Moerbeck, W., Nestoras, I., Pittori, C., Pursimo, T., Pushkarev, A. B., Readhead, A. C. S., Recillas, E., Richards, J. L., Riquelme, D., Romani, R. W., Sakimoto, K., Sasada, M., Schmidt, R., Shaw, M. S., Sievers, A., Thompson, D. J., Uemura, M., Ungerechts, H., Vercellone, S., Verrecchia, F., Yamanaka, M., Yoshida, M., and Zensus, J. A.

Subjects
Astrophysics - High Energy Astrophysical Phenomena, Astrophysics - Cosmology and Nongalactic Astrophysics
Abstract

Previously unremarkable, the extragalactic radio source GB 1310+487 showed a gamma-ray flare on 2009 November 18, reaching a daily flux of ~10^-6 photons/cm^2/s at energies E>100 MeV and becoming one of the brightest GeV sources for about two weeks. Its optical spectrum is not typical for a blazar, instead, it resembles those of narrow emission-line galaxies. We investigate changes of the object's radio-to-GeV spectral energy distribution (SED) during and after the prominent GeV flare with the aim to determine the nature of the object and constrain the origin of the variable high-energy emission. The data collected by the Fermi and AGILE satellites at gamma-ray energies, Swift at X-ray and ultraviolet, Kanata, NOT, and Keck telescopes at optical, OAGH and WISE at infrared, and IRAM 30m, OVRO 40m, Effelsberg 100m, RATAN-600, and VLBA at radio, are analysed together to trace the SED evolution on timescales of months. The gamma-ray/radio-loud narrow-line active galactic nucleus (AGN) is located at redshift z=0.638. It is shining through an unrelated foreground galaxy at z=0.500. The AGN light is likely amplified by a factor of a few because of gravitational lensing. The AGN SED shows a two-humped structure typical of blazars and gamma-ray-loud NLSy1 galaxies, with the high-energy (inverse-Compton) emission dominating by more than an order of magnitude over the low-energy (synchrotron) emission during gamma-ray flares. The difference between the two SED humps is smaller during the low-activity state. Fermi observations reveal a strong correlation between the gamma-ray flux and spectral index, with the hardest spectrum observed during the brightest gamma-ray state. If the gamma-ray flux is a mixture of synchrotron self-Compton (SSC) and external Compton (EC) emission, the observed GeV spectral variability may result from varying relative contributions of these two emission components., Comment: 18 pages, 10 figures, 6 tables; accepted to A&A

Published
2014
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4. 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

5. The Cosmic Evolution of Fermi BL Lacertae Objects

Author

Ajello, M., Romani, R. W., Gasparrini, D., Shaw, M. S., Bolmer, J., Cotter, G., Finke, J., Greiner, J., Healey, S. E., King, O., Max-Moerbeck, W., Michelson, P. F., Potter, W. J., Rau, A., Readhead, A. C. S., Richards, J. L., and Schady, P.

Subjects
Astrophysics - Cosmology and Nongalactic Astrophysics, Astrophysics - High Energy Astrophysical Phenomena
Abstract

Fermi has provided the largest sample of gamma-ray selected blazars to date. In this work we use a uniformly selected set of 211 BL Lacertae (BL Lac) objects detected by it Fermi during its first year of operation. We have obtained redshift constraints for 206 out of the 211 BL Lacs in our sample making it the largest and most complete sample of BL Lacs available in the literature. We use this sample to determine the luminosity function of BL Lacs and its evolution with cosmic time. We find that for most BL Lac classes, the evolution is positive with a space density peaking at modest redshift (z~1.2). The low-luminosity, high-synchrotron peaked (HSP) BL Lacs are an exception, showing strong negative evolution, with number density increasing for z$\lesssim$0.5. Since this rise corresponds to a drop-off in the density of flat-spectrum radio quasars (FSRQs), a possible interpretation is that these HSPs represent an accretion-starved end-state of an earlier merger-driven gas-rich phase. We additionally find that the known BL Lac correlation between luminosity and photon spectral index persists after correction for the substantial observational selection effects with implications for the so called `blazar sequence'. Finally, estimating the beaming corrections to the luminosity function, we find that BL Lacs have an average Lorentz factor of $\gamma=6.1^{+1.1}_{-0.8}$, and that most are seen within 10$^{\circ}$ of the jet axis., Comment: accepted by ApJ

Published
2013
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6. Assessing the Significance of Apparent Correlations Between Radio and Gamma-ray Blazar Fluxes

Author

Pavlidou, V., Richards, J. L., Max-Moerbeck, W., King, O. G., Pearson, T. J., Readhead, A. C. S., Reeves, R., Stevenson, M. A., Angelakis, E., Fuhrmann, L., Zensus, J. A., Giroletti, M., Reimer, A., Healey, S. E., Romani, R. W., and Shaw, M. S.

Subjects
Astrophysics - High Energy Astrophysical Phenomena
Abstract

Whether a correlation exists between the radio and gamma-ray flux densities of blazars is a long-standing question, and one that is difficult to answer confidently because of various observational biases which may either dilute or apparently enhance any intrinsic correlation between radio and gamma-ray luminosities. We introduce a novel method of data randomization to evaluate quantitatively the effect of these biases and to assess the intrinsic significance of an apparent correlation between radio and gamma-ray flux densities of blazars. The novelty of the method lies in a combination of data randomization in luminosity space (to ensure that the randomized data are intrinsically, and not just apparently, uncorrelated) and significance assessment in flux space (to explicitly avoid Malmquist bias and automatically account for the limited dynamical range in both frequencies). The method is applicable even to small samples that are not selected with strict statistical criteria. For larger samples we describe a variation of the method in which the sample is split in redshift bins, and the randomization is applied in each bin individually; this variation is designed to yield the equivalent to luminosity-function sampling of the underlying population in the limit of very large, statistically complete samples. We show that for a smaller number of redshift bins, the method yields a worse significance, and in this way it is conservative in that it does not assign a stronger, artificially enhanced significance. We demonstrate how our test performs as a function of number of sources, strength of correlation, and number of redshift bins used, and we show that while our test is robust against common-distance biases and associated false positives for uncorrelated data, it retains the power of other methods in rejecting the null hypothesis of no correlation for correlated data., Comment: (corrected affiliations) 14 pages, 11 figures, accepted for publication in ApJ

Published
2012
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7. The radio/gamma-ray connection in Active Galactic Nuclei in the era of the Fermi Large Area Telescope

Author

Ackermann, M., Ajello, M., Allafort, A., Angelakis, E., Axelsson, M., Baldini, L., Ballet, J., Barbiellini, G., Bastieri, D., Bellazzini, R., Berenji, B., Blandford, R. D., Bloom, E. D., Bonamente, E., Borgland, A. W., Bouvier, A., Bregeon, J., Brez, A., Brigida, M., Bruel, P., Buehler, R., Buson, S., Caliandro, G. A., Cameron, R. A., Cannon, A., Caraveo, P. A., Casandjian, J. M., Cavazzuti, E., Cecchi, C., Charles, E., Chekhtman, A., Cheung, C. C., Ciprini, S., Claus, R., Cohen-Tanugi, J., Cutini, S., de Palma, F., Dermer, C. D., Silva, E. do Couto e, Drell, P. S., Dubois, R., Dumora, D., Escande, L., Favuzzi, C., Fegan, S. J., Focke, W. B., Fortin, P., Frailis, M., Fuhrmann, L., Fukazawa, Y., Fusco, P., Gargano, F., Gasparrini, D., Gehrels, N., Giglietto, N., Giommi, P., Giordano, F., Giroletti, M., Glanzman, T., Godfrey, G., Grandi, P., Grenier, I. A., Guiriec, S., Hadasch, D., Hayashida, M., Hays, E., Healey, S. E., J, G., Johnson, A. S., Kamae, T., Katagiri, H., Kataoka, J., Kn, J., Kuss, M., Lande, J., Lee, S. -H., Longo, F., Loparco, F., Lott, B., Lovellette, M. N., Lubrano, P., Makeev, A., Max-Moerbeck, W., Mazziotta, M. N., McEnery, J. E., Mehault, J., Michelson, P. F., Mizuno, T., Monte, C., Monzani, M. E., Morselli, A., Moskalenko, I. V., Murgia, S., Naumann-Godo, M., Nishino, S., Nolan, P. L., Norris, J. P., Nuss, E., Ohsugi, T., Okumura, A., Omodei, N., Orlando, E., Ormes, J. F., Ozaki, M., Paneque, D., Pavlidou, V., Pelassa, V., Pepe, M., Pesce-Rollins, M., Pierbattista, M., Piron, F., Porter, T. A., Rain, S., Razzano, M., Readhead, A., Reimer, A., Reimer, O., Richards, J. L., Romani, R. W., Sadrozinski, H. F. -W., Scargle, J. D., Sgr, C., Siskind, E. J., Smith, P. D., Spandre, G., Spinelli, P., Strickman, M. S., Suson, D. J., Takahashi, H., Tanaka, T., Taylor, G. B., Thayer, J. G., Thayer, J. B., Thompson, D. J., Torres, D. F., Tosti, G., Tramacere, A., Troja, E., Vandenbroucke, J., Vianello, G., Vitale, V., Waite, A. P., Wang, P., Winer, B. L., Wood, K. S., Yang, Z., and Ziegler, M.

Subjects
Astrophysics - Cosmology and Nongalactic Astrophysics, Astrophysics - High Energy Astrophysical Phenomena
Abstract

We present a detailed statistical analysis of the correlation between radio and gamma-ray emission of the Active Galactic Nuclei (AGN) detected by Fermi during its first year of operation, with the largest datasets ever used for this purpose. We use both archival interferometric 8.4 GHz data (from the VLA and ATCA, for the full sample of 599 sources) and concurrent single-dish 15 GHz measurements from the Owens Valley Radio Observatory (OVRO, for a sub sample of 199 objects). Our unprecedentedly large sample permits us to assess with high accuracy the statistical significance of the correlation, using a surrogate-data method designed to simultaneously account for common-distance bias and the effect of a limited dynamical range in the observed quantities. We find that the statistical significance of a positive correlation between the cm radio and the broad band (E>100 MeV) gamma-ray energy flux is very high for the whole AGN sample, with a probability <1e-7 for the correlation appearing by chance. Using the OVRO data, we find that concurrent data improve the significance of the correlation from 1.6e-6 to 9.0e-8. Our large sample size allows us to study the dependence of correlation strength and significance on specific source types and gamma-ray energy band. We find that the correlation is very significant (chance probability <1e-7) for both FSRQs and BL Lacs separately; a dependence of the correlation strength on the considered gamma-ray energy band is also present, but additional data will be necessary to constrain its significance., Comment: Accepted for publications by ApJ. Contact authors: M. Giroletti, V. Pavlidou, A. Reimer

Published
2011
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8. Characteristics of Gamma-Ray Loud Blazars in the VLBA Imaging and Polarimetry Survey

Author

Linford, J. D., Taylor, G. B., Romani, R., Healey, S. E., Helmboldt, J. F., Readhead, A. C. S., Reeves, R., Richards, J., and Cotter, G.

Subjects
Astrophysics - Cosmology and Nongalactic Astrophysics
Abstract

The radio properties of blazars detected by the Large Area Telescope (LAT) on board the Fermi Gamma-ray Space Telescope have been observed as part of the VLBA Imaging and Polarimetry Survey (VIPS). This large, flux-limited sample of active galactic nuclei (AGN) provides insights into the mechanism that produces strong gamma-ray emission. At lower flux levels, radio flux density does not directly correlate with gamma-ray flux. We find that the LAT-detected BL Lacs tend to be similar to the non-LAT BL Lacs, but that the LAT-detected FSRQs are often significantly different from the non-LAT FSRQs. The differences between the gamma-ray loud and quiet FSRQs can be explained by Doppler boosting; these objects appear to require larger Doppler factors than those of the BL Lacs. It is possible that the gamma-ray loud FSRQs are fundamentally different from the gamma-ray quiet FSRQs. Strong polarization at the base of the jet appears to be a signature for gamma-ray loud AGN., Comment: 32 pages, 9 figures, accepted by ApJ

Published
2010
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9. Discovery of a GeV blazar shining through the Galactic plane

Author

Vandenbroucke, J., Buehler, R., Ajello, M., Bechtol, K., Bellini, A., Bolte, M., Cheung, C. C., Civano, F., Donato, D., Fuhrmann, L., Funk, S., Healey, S. E., Hill, A. B., Knigge, C., Madejski, G. M., Romani, R. W., Santander-García, M., Shaw, M. S., Steeghs, D., Torres, M. A. P., Van Etten, A., and Williams, K. A.

Subjects
Astrophysics - High Energy Astrophysical Phenomena, Astrophysics - Cosmology and Extragalactic Astrophysics
Abstract

The \emph{Fermi} Large Area Telescope (LAT) discovered a new gamma-ray source near the Galactic plane, \object{Fermi J0109+6134}, when it flared brightly in 2010 February. The low Galactic latitude (b =-1.2\degr) indicated that the source could be located within the Galaxy, which motivated rapid multi-wavelength follow-up including radio, optical, and X-ray observations. We report the results of analyzing all 19 months of LAT data for the source, and of X-ray observations with both \emph{Swift} and the \emph{Chandra X-ray Observatory}. We determined the source redshift, z =0.783, using a Keck LRIS observation. Finally, we compiled a broadband spectral energy distribution (SED) from both historical and new observations contemporaneous with the 2010 February flare. The redshift, SED, optical line width, X-ray absorption, and multi-band variability indicate that this new GeV source is a blazar seen through the Galactic plane. Because several of the optical emission lines have equivalent width >5\AA, this blazar belongs in the flat-spectrum radio quasar category., Comment: 9 pages, 4 figures

Published
2010
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10. J16021+3326: New Multi-Frequency Observations of a Complex Source

Author

Tremblay, S. E., Taylor, G. B., Richards, J. L., Readhead, A. C. S., Helmboldt, J. F., Romani, R. W., and Healey, S. E.

Subjects
Astrophysics - Cosmology and Nongalactic Astrophysics
Abstract

We present multifrequency Very Long Baseline Array (VLBA) observations of J16021+3326. These observations, along with variability data obtained from the Owens Valley Radio Observatory (OVRO) candidate gamma-ray blazar monitoring program, clearly indicate this source is a blazar. The peculiar characteristic of this blazar, which daunted previous classification attempts, is that we appear to be observing down a precessing jet, the mean orientation of which is aligned with us almost exactly., Comment: 16 pages, 7 Figures, 2 Tables, accepted to ApJ

Published
2010
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11. 15 GHz Monitoring of Gamma-ray Blazars with the OVRO 40 Meter Telescope in Support of Fermi

Author

Richards, J. L., Max-Moerbeck, W., Pavlidou, V., Pearson, T. J., Readhead, A. C. S., Stevenson, M. A., Healey, S. E., Romani, R. W., Shaw, M. S., Fuhrmann, L., Angelakis, E., Zensus, J. A., Grainge, K., and Taylor, G. B.

Subjects
Astrophysics - Cosmology and Nongalactic Astrophysics
Abstract

We present results from the first two years of our fast-cadence 15 GHz gamma-ray blazar monitoring program, part of the F-GAMMA radio monitoring project. Our sample includes the 1158 blazars north of -20 degrees declination from the Candidate Gamma-Ray Blazar Survey (CGRaBS), which encompasses a significant fraction of the extragalactic sources detected by the Fermi Gamma-ray Space Telescope. We introduce a novel likelihood analysis for computing a time series variability amplitude statistic that separates intrinsic variability from measurement noise and produces a quantitative error estimate. We use this method to characterize our radio light curves. We also present results indicating a statistically significant correlation between simultaneous average 15 GHz radio flux density and gamma-ray photon flux., Comment: 5 pages, 7 figures; 2009 Fermi Symposium; eConf Proceedings C091122

Published
2009
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12. The Spectral Energy Distribution of Fermi bright blazars

Author

Abdo, A. A., Ackermann, M., Ajello, M., Axelsson, M., Baldini, L., Ballet, J., Barbiellini, G., Bastieri, D., Baughman, B. M., Bechtol, K., Bellazzini, R., Berenji, B., Blandford, R. D., Bloom, E. D., Bonamente, E., Borgland, A., Bregeon, J., Brez, A., Brigida, M., Bruel, P., Burnett, T. H., Buson, S., Caliandro, G. A., Cameron, R. A., Caraveo, P. A., Casandjian, J. M., Cavazzuti, E., Cecchi, C., Celik, O., Charles, E., Chaty, S., Chekhtman, A., Chiang, J., Ciprini, S., Claus, R., Cohen-Tanugi, J., Colafrancesco, S., Cominsky, L. R., Conrad, J., Costamante, L., Cutini, S., Dermer, C. D., de Angelis, A., de Palma, F., Digel, S. W., Silva, E. do Couto e, Drell, P. S., Dubois, R., Dumora, D., Farnier, C., Favuzzi, C., Fegan, S. J., Focke, W. B., Fortin, P., Frailis, M., Fuhrmann, L., Fukazawa, Y., Funk, S., Fusco, P., Gargano, F., Gasparrini, D., Gehrels, N., Germani, S., Giebels, B., Giglietto, N., Giommi, P., Giordano, F., Glanzman, T., Godfrey, G., Grenier, I. A., Grove, J. E., Guillemot, L., Guiriec, S., Hadasch, D., Hanabata, Y., Harding, A. K., Hayashida, M., Hays, E., Healey, S. E., Horan, D., Hughes, R. E., Itoh, R., Jackson, M. S., Johannesson, G., Johnson, A. S., Johnson, W. N., Kadler, M., Kamae, T., Katagiri, H., Kataoka, J., Kawai, N., Kerr, M., Knodlseder, J., Kocian, M. L., Kuss, M., Lande, J., Latronico, L., Longo, F., Loparco, F., Lott, B., Lovellette, M. N., Lubrano, P., Madejski, G. M., Makeev, A., Max-Moerbeck, W., Mazziotta, M. N., McConville, W., McEnery, J. E., Meurer, C., and Michelson, P. F.

Subjects
Astrophysics - Cosmology and Nongalactic Astrophysics
Abstract

(Abridged) We have conducted a detailed investigation of the broad-band spectral properties of the \gamma-ray selected blazars of the Fermi LAT Bright AGN Sample (LBAS). By combining our accurately estimated Fermi gamma-ray spectra with Swift, radio, infra-red, optical and other hard X-ray/gamma-ray data, collected within three months of the LBAS data taking period, we were able to assemble high-quality and quasi-simultaneous Spectral Energy Distributions (SED) for 48 LBAS blazars.The SED of these gamma-ray sources is similar to that of blazars discovered at other wavelengths, clearly showing, in the usual Log $\nu $ - Log $\nu$ F$_\nu$ representation, the typical broad-band spectral signatures normally attributed to a combination of low-energy synchrotron radiation followed by inverse Compton emission of one or more components. We have used these SEDs to characterize the peak intensity of both the low and the high-energy components. The results have been used to derive empirical relationships that estimate the position of the two peaks from the broad-band colors (i.e. the radio to optical and optical to X-ray spectral slopes) and from the gamma-ray spectral index. Our data show that the synchrotron peak frequency $\nu_p^S$ is positioned between 10$^{12.5}$ and 10$^{14.5}$ Hz in broad-lined FSRQs and between $10^{13}$ and $10^{17}$ Hz in featureless BL Lacertae objects.We find that the gamma-ray spectral slope is strongly correlated with the synchrotron peak energy and with the X-ray spectral index, as expected at first order in synchrotron - inverse Compton scenarios. However, simple homogeneous, one-zone, Synchrotron Self Compton (SSC) models cannot explain most of our SEDs, especially in the case of FSRQs and low energy peaked (LBL) BL Lacs. (...), Comment: 85 pages, 38 figures, submitted to ApJ

Published
2009
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13. Characteristics of EGRET Blazars in the VLBA Imaging and Polarimetry Survey (VIPS)

Author

Taylor, G. B., Healey, S. E., Helmboldt, J. F., Tremblay, S., Fassnacht, C. D., Walker, R. C., Sjouwerman, L. O., Pearson, T. J., Readhead, A. C. S., Weintraub, L., Gehrels, N., Romani, R. W., Michelson, P. F., Blandford, R. D., and Cotter, G.

Subjects
Astrophysics
Abstract

We examine the radio properties of EGRET-detected blazars observed as part of the VLBA Imaging and Polarimetry Survey (VIPS). VIPS has a flux limit roughly an order of magnitude below the MOJAVE survey and most other samples that have been used to study the properties of EGRET blazars. At lower flux levels, radio flux density does not directly correlate with gamma-ray flux density. We do find that the EGRET-detected blazars tend to have higher brightness temperatures, greater core fractions, and possibly larger than average jet opening angles. A weak correlation is also found with jet length and with polarization. All of the well-established trends can be explained by systematically larger Doppler factors in the gamma-ray loud blazars, consistent with the measurements of higher apparent velocities found in monitoring programs carried out at radio frequencies above 10 GHz., Comment: 20 pages, 7 figures, accepted to ApJ

Published
2007
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14. The VLBA Imaging and Polarimetry Survey at 5 GHz

Author

Helmboldt, J. F., Taylor, G. B., Tremblay, S., Fassnacht, C. D., Walker, R. C., Myers, S. T., Sjouwerman, L. O., Pearson, T. J., Readhead, A. C. S., Weintraub, L., Gehrels, N., Romani, R. W., Healey, S., Michelson, P. F., Blandford, R. G., and Cotter, G.

Subjects
Astrophysics
Abstract

We present the first results of the VLBA Imaging and Polarimetry Survey (VIPS), a 5 GHz VLBI survey of 1,127 sources with flat radio spectra. Through automated data reduction and imaging routines, we have produced publicly available I, Q, and U images and have detected polarized flux density from 37% of the sources. We have also developed an algorithm to use each source's I image to automatically classify it as a point-like source, a core-jet, a compact symmetric object (CSO) candidate, or a complex source. The mean ratio of the polarized to total 5 GHz flux density for VIPS sources with detected polarized flux density ranges from 1% to 20% with a median value of about 5%. We have also found significant evidence that the directions of the jets in core-jet systems tend to be perpendicular to the electric vector position angles (EVPAs). The data is consistent with a scenario in which ~24% of the polarized core-jets have EVPAs that are anti-aligned with the directions of their jet components and which have a substantial amount of Faraday rotation. In addition to these initial results, plans for future follow-up observations are discussed., Comment: 36 pages, 3 tables, 13 figures; accepted for publication in ApJ

Published
2006
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15. 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

16. 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

17. Initial rhythm control with cryoballoon ablation vs drug therapy: Impact on quality of life and symptoms.

Author

Pavlovic N., Chierchia G.-B., Velagic V., Hermida J.S., Healey S., Arena G., Badenco N., Meyer C., Chen J., Iacopino S., Anselme F., Dekker L., Scazzuso F., Packer D.L., de Asmundis C., Pitschner H.-F., Piazza F.D., Kaplon R.E., Kuniss M., Pavlovic N., Chierchia G.-B., Velagic V., Hermida J.S., Healey S., Arena G., Badenco N., Meyer C., Chen J., Iacopino S., Anselme F., Dekker L., Scazzuso F., Packer D.L., de Asmundis C., Pitschner H.-F., Piazza F.D., Kaplon R.E., and Kuniss M.

Abstract

BACKGROUND: Cryoballoon ablation (CBA) as a first-line rhythm control strategy is superior to antiarrhythmic drugs (AADs) for preventing atrial fibrillation (AF) recurrence; the impact of first-line CBA on quality of life (QoL) and symptoms has not been well characterized. METHOD(S): Patients aged 18 to 75 with symptomatic paroxysmal AF naive to rhythm control therapy were randomized (1:1) to CBA (Arctic Front Advance, Medtronic) or AAD (Class I or III). Symptoms and QoL were assessed at baseline, 1, 3, 6, 9, and 12 months using the EHRA classification and Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) and SF-36v2 questionnaires. Symptomatic palpitations were evaluated via patient diary. RESULT(S): Overall, 107 patients were randomized to CBA and 111 to AAD; crossovers occurred in 9%. Larger improvements in the AFEQT summary, subscale and treatment satisfaction scores were observed at 12 months with CBA vs AAD (all P <0.05). At 12 months, the mean adjusted difference in the AFEQT summary score was 9.9 points higher in the CBA group (95% CI: 5.5 -14.2, P <0.001). Clinically important improvements in the SF-36 physical and mental component scores were observed at 12 months in both groups, with no significant between group differences at this timepoint. In the CBA vs AAD group, larger improvements in EHRA class were observed at 6, 9 and 12 months (P <0.05) and the incidence rate of symptomatic palpitations was lower (4.6 vs 15.2 days/year post-blanking; IRR: 0.30, P <0.001). CONCLUSION(S): In patients with symptomatic AF, first-line CBA was superior to AAD for improving AF-specific QoL and symptoms. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01803438.Copyright © 2021. Published by Elsevier Inc.

Published
2022

18. Cryoballoon ablation vs. antiarrhythmic drugs: First-line therapy for patients with paroxysmal atrial fibrillation.

Author

Kuniss M., Pavlovic N., Velagic V., Hermida J.S., Healey S., Arena G., Badenco N., Meyer C., Chen J., Iacopino S., Anselme F., Packer D.L., Pitschner H.-F., Asmundis C.D., Willems S., Di Piazza F., Becker D., Chierchia G.-B., Kuniss M., Pavlovic N., Velagic V., Hermida J.S., Healey S., Arena G., Badenco N., Meyer C., Chen J., Iacopino S., Anselme F., Packer D.L., Pitschner H.-F., Asmundis C.D., Willems S., Di Piazza F., Becker D., and Chierchia G.-B.

Abstract

Aims: Treatment guidelines for patients with atrial fibrillation (AF) suggest that patients should be managed with an antiarrhythmic drug (AAD) before undergoing catheter ablation (CA). This study evaluated whether pulmonary vein isolation employing cryoballoon CA is superior to AAD therapy for the prevention of atrial arrhythmia (AA) recurrence in rhythm control naive patients with paroxysmal AF (PAF). Methods and Results: A total of 218 treatment naive patients with symptomatic PAF were randomized (1: 1) to cryoballoon CA (Arctic Front Advance, Medtronic) or AAD (Class I or III) and followed for 12 months. The primary endpoint was >=1 episode of recurrent AA (AF, atrial flutter, or atrial tachycardia) >30 s after a prespecified 90-day blanking period. Secondary endpoints included the rate of serious adverse events (SAEs) and recurrence of symptomatic palpitations (evaluated via patient diaries). Freedom from AA was achieved in 82.2% of subjects in the cryoballoon arm and 67.6% of subjects in the AAD arm (HR = 0.48, P = 0.01). There were no group differences in the time-to-first (HR = 0.76, P = 0.28) or overall incidence [incidence rate ratio (IRR)=0.79, P = 0.28] of SAEs. The incidence rate of symptomatic palpitations was lower in the cryoballoon (7.61 days/year) compared with the AAD arm (18.96 days/year; IRR = 0.40, P < 0.001). Conclusion(s): Cryoballoon CA was superior to AAD therapy, significantly reducing AA recurrence in treatment naive patients with PAF. Additionally, cryoballoon CA was associated with lower symptom recurrence and a similar rate of SAEs compared with AAD therapy.Copyright © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Published
2022

22. Bless You

Author

Healey, S. P.

Published
1999

25. Cryoballoon ablation vs. antiarrhythmic drugs: First-line therapy for patients with paroxysmal atrial fibrillation.

Author

Kuniss M., Pavlovic N., Velagic V., Hermida J.S., Healey S., Arena G., Badenco N., Meyer C., Chen J., Iacopino S., Anselme F., Packer D.L., Pitschner H.-F., Asmundis C.D., Willems S., Di Piazza F., Becker D., Chierchia G.-B., Kuniss M., Pavlovic N., Velagic V., Hermida J.S., Healey S., Arena G., Badenco N., Meyer C., Chen J., Iacopino S., Anselme F., Packer D.L., Pitschner H.-F., Asmundis C.D., Willems S., Di Piazza F., Becker D., and Chierchia G.-B.

Abstract

Aims: Treatment guidelines for patients with atrial fibrillation (AF) suggest that patients should be managed with an antiarrhythmic drug (AAD) before undergoing catheter ablation (CA). This study evaluated whether pulmonary vein isolation employing cryoballoon CA is superior to AAD therapy for the prevention of atrial arrhythmia (AA) recurrence in rhythm control naive patients with paroxysmal AF (PAF). Methods and Results: A total of 218 treatment naive patients with symptomatic PAF were randomized (1: 1) to cryoballoon CA (Arctic Front Advance, Medtronic) or AAD (Class I or III) and followed for 12 months. The primary endpoint was >=1 episode of recurrent AA (AF, atrial flutter, or atrial tachycardia) >30 s after a prespecified 90-day blanking period. Secondary endpoints included the rate of serious adverse events (SAEs) and recurrence of symptomatic palpitations (evaluated via patient diaries). Freedom from AA was achieved in 82.2% of subjects in the cryoballoon arm and 67.6% of subjects in the AAD arm (HR = 0.48, P = 0.01). There were no group differences in the time-to-first (HR = 0.76, P = 0.28) or overall incidence [incidence rate ratio (IRR)=0.79, P = 0.28] of SAEs. The incidence rate of symptomatic palpitations was lower in the cryoballoon (7.61 days/year) compared with the AAD arm (18.96 days/year; IRR = 0.40, P < 0.001). Conclusion(s): Cryoballoon CA was superior to AAD therapy, significantly reducing AA recurrence in treatment naive patients with PAF. Additionally, cryoballoon CA was associated with lower symptom recurrence and a similar rate of SAEs compared with AAD therapy.Copyright © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Published
2021

26. Initial Rhythm Control with Cryoballoon Ablation versus Drug Therapy: Impact on Quality of Life and Symptoms: Initial Rhythm Control with Cryoablation.

Author

Pavlovic N., Chierchia G.-B., Velagic V., Hermida J.S., Healey S., Arena G., Badenco N., Meyer C., Chen J., Iacopino S., Anselme F., Dekker L., Scazzuso F., Packer D.L., de Asmundis C., Pitschner H.-F., Piazza F.D., Kaplon R.E., Kuniss M., Cryo-First Investigators, Pavlovic N., Chierchia G.-B., Velagic V., Hermida J.S., Healey S., Arena G., Badenco N., Meyer C., Chen J., Iacopino S., Anselme F., Dekker L., Scazzuso F., Packer D.L., de Asmundis C., Pitschner H.-F., Piazza F.D., Kaplon R.E., Kuniss M., and Cryo-First Investigators

Abstract

BACKGROUND: Cryoballoon ablation (CBA) as a first-line rhythm control strategy is superior to antiarrhythmic drugs (AADs) for preventing atrial fibrillation (AF) recurrence; the impact of first-line CBA on quality of life (QoL) and symptoms has not been well characterized. METHOD(S): Patients aged 18 to 75 with symptomatic paroxysmal AF naive to rhythm control therapy were randomized (1:1) to CBA (Arctic Front Advance, Medtronic) or AAD (Class I or III). Symptoms and QoL were assessed at baseline, 1, 3, 6, 9, and 12 months using the EHRA classification and Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) and SF-36v2 questionnaires. Symptomatic palpitations were evaluated via patient diary. RESULT(S): Overall, 107 patients were randomized to CBA and 111 to AAD; crossovers occurred in 9%. Larger improvements in the AFEQT summary, subscale and treatment satisfaction scores were observed at 12 months with CBA vs. AAD (all P<0.05). At 12 months, the mean adjusted difference in the AFEQT summary score was 9.9 points higher in the CBA group (95% CI: 5.5-14.2, P<0.001). Clinically important improvements in the SF-36 physical and mental component scores were observed at 12 months in both groups, with no significant between group differences at this timepoint. In the CBA vs. AAD group, larger improvements in EHRA class were observed at 6, 9 and 12 months (P<0.05) and the incidence rate of symptomatic palpitations was lower (4.6 vs. 15.2 days/year post-blanking; IRR: 0.30, P<0.001). CONCLUSION(S): In patients with symptomatic AF, first-line CBA was superior to AAD for improving AF-specific QoL and symptoms. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01803438.Copyright © 2021. Published by Elsevier Inc.

Published
2021

27. Impact of initial rhythm control with cryoballoon ablation versus drug therapy on atrial fibrillation recurrence and quality of life: results from the Cryo-FIRST study

Author

Pavlovic, N, primary, Kuniss, M, additional, Velagic, V, additional, Hermida, JS, additional, Healey, S, additional, Arena, G, additional, Badenco, N, additional, Meyer, C, additional, Chen, J, additional, Iacopino, S, additional, Anselme, F, additional, Kaplon, RE, additional, and Chierchia, GB, additional

Published
2021
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28. Two Active States of the Narrow-Line Gamma-Ray-Loud AGN GB 1310 + 487

Author

Sokolovsky, K. V, Schinzel, F. K, Tanaka, Y. T, Abolmasov, P. K, Angelakis, E, Bulgarelli, A, Carrasco, L, Cenko, S. B, Cheung, C. C, Clubb, K. I, D'Ammando, F, Escande, L, Fegan, S. J, Filippenko, A. V, Finke, J. D, Fuhrmann, L, Fukazawa, Y, Hays, E, Healey, S. E, Ikejiri, Y, Itoh, R, Kawabata, K. S, Komatsu, T, Kovalev, Yu. A, Kovalev, Y. Y, and Krichbaum, T. P

Subjects
Astrophysics
Abstract

Context. Previously unremarkable, the extragalactic radio source GB1310 487 showed gamma-ray flare on 2009 November 18, reaching a daily flux of approximately 10(exp -6) photons cm(exp -2) s(exp -1) at energies E greater than 100MeV and became one of the brightest GeV sources for about two weeks. Its optical spectrum shows strong forbidden-line emission while lacking broad permitted lines, which is not typical for a blazar. Instead, the spectrum resembles those of narrow emission-line galaxies. Aims. We investigate changes in the object's radio-to-GeV spectral energy distribution (SED) during and after the prominent gamma-ray flare with the aim of determining the nature of the object and of constraining the origin of the variable high-energy emission. Methods. The data collected by the Fermi and AGILE satellites at gamma-ray energies; Swift at X-ray and ultraviolet (UV); the Kanata, NOT, and Keck telescopes at optical; OAGH and WISE at infrared (IR); and IRAM30m, OVRO 40m, Effelsberg 100m, RATAN-600, and VLBA at radio are analyzed together to trace the SED evolution on timescales of months. Results. The gamma-ray radio-loud narrow-line active galactic nucleus (AGN) is located at redshift z = 0.638. It shines through an unrelated foreground galaxy at z = 0.500. The AGN light is probably amplified by gravitational lensing. The AGN SED shows a two-humped structure typical of blazars and gamma-ray-loud narrow-line Seyfert 1 galaxies, with the high-energy (inverse-Compton) emission dominating by more than an order of magnitude over the low-energy (synchrotron) emission during gamma-ray flares. The difference between the two SED humps is smaller during the low-activity state. Fermi observations reveal a strong correlation between the gamma-ray flux and spectral index, with the hardest spectrum observed during the brightest gamma-ray state. The gamma-ray flares occurred before and during a slow rising trend in the radio, but no direct association between gamma-ray and radio flares could be established. Conclusions. If the gamma-ray flux is a mixture of synchrotron self-Compton (SSC) and external Compton (EC) emission, the observed GeV spectral variability may result from varying relative contributions of these two emission components. This explanation fits the observed changes in the overall IR to gamma-ray SED.

Published
2014

29. Position Statement on the Management of Cardiac Electrophysiology and Cardiac Implantable Electronic Devices in Australia During the COVID-19 Pandemic: A Living Document.

Author

Kistler P., Morton J.B., Skinner J.R., Pflaumer A., McGuire M., Kalman J.M., Kumar S., Haqqani H., Wynn G., Pathak R.K., Lipton J., Mahajan R., Sanders P., Healey S., Wilsmore B., Mariani J.A., Thomas S.P., Weerasooriya R., McGavigan A., Gould P.A., Weatherley P., Saad N., Cowan M., Turnbull S., Trivic I., Wong M., Tonchev I., Kistler P., Morton J.B., Skinner J.R., Pflaumer A., McGuire M., Kalman J.M., Kumar S., Haqqani H., Wynn G., Pathak R.K., Lipton J., Mahajan R., Sanders P., Healey S., Wilsmore B., Mariani J.A., Thomas S.P., Weerasooriya R., McGavigan A., Gould P.A., Weatherley P., Saad N., Cowan M., Turnbull S., Trivic I., Wong M., and Tonchev I.

Abstract

The COVID-19 pandemic poses a significant stress on health resources in Australia. The Heart Rhythm Council of the Cardiac Society of Australia and New Zealand aims to provide a framework for efficient resource utilisation balanced with competing risks when appropriately treating patients with cardiac arrhythmias. This document provides practical recommendations for the electrophysiology (EP) and cardiac implantable electronic devices (CIED) services in Australia. The document will be updated regularly as new evidence and knowledge is gained with time.Copyright © 2020

Published
2020

30. Cryoballoon catheter ablation versus antiarrhythmic drugs as a first-line therapy for patients with paroxysmal atrial fibrillation: Rationale and design of the international Cryo-FIRST study.

Author

de Asmundis C., Packer D.L., Pitschner H.-F., Kuniss M., Chierchia G.B., Hermida J.S., Chen J., Meyer C., Iacopino S., Arena G., Pavlovic N., Velagic V., Healey S., de Asmundis C., Packer D.L., Pitschner H.-F., Kuniss M., Chierchia G.B., Hermida J.S., Chen J., Meyer C., Iacopino S., Arena G., Pavlovic N., Velagic V., and Healey S.

Abstract

BACKGROUND: Radiofrequency current (RFC) catheter ablation for patients with paroxysmal atrial fibrillation (AF) has been shown to be safe and effective in first-line therapy. Recent data demonstrates that RFC ablation provides better clinical outcomes compared to antiarrhythmic drug (AAD) in the treatment of early AF disease. Furthermore, studies comparing RFC and cryoballoon have established comparable efficacy and safety of pulmonary vein isolation (PVI) for patients with symptomatic paroxysmal AF. OBJECTIVE(S): The Cryo-FIRST trial was designed to compare AAD treatment against cryoballoon PVI as a first-line therapy in treatment naive patients with AF. Efficacy and safety will be compared between the two cohorts and amongst subgroups. METHOD(S): The primary hypothesis is that cryoablation is superior to AAD therapy. To test this hypothesis, patients will be randomized in a 1:1 design. Using a 90-day blanking period, primary efficacy endpoint failure is defined as (at least) one episode of atrial arrhythmia with a duration >30 sec (documented by 7-day Holter or 12-lead ECG). Secondary endpoints (Quality-of-Life, rehospitalization, arrhythmia recurrence rate, healthcare utilization, and left atrial function) and adverse events will also be evaluated. Study enrollment will include 218 patients in up to 16 centers. CONCLUSION(S): This study will be a multi-national randomized controlled trial comparing cryoablation against AAD as a first-line treatment in patients with paroxysmal AF. The results may help guide the selection of patients for early AF disease therapy via cryoballoon ablation.Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Published
2020

31. Position Statement on the Management of Cardiac Electrophysiology and Cardiac Implantable Electronic Devices in Australia During the COVID-19 Pandemic: A Living Document

Author

Kumar, S, Haqqani, H, Wynn, G, Pathak, RK, Lipton, J, Mahajan, R, Sanders, P, Healey, S, Wilsmore, B, Mariani, JA, Thomas, SP, Weerasooriya, R, McGavigan, A, Gould, PA, Weatherley, P, Saad, N, Cowan, M, Turnbull, S, Trivic, I, Wong, M, Tonchev, I, Morton, JB, Skinner, JR, Pflaumer, A, McGuire, M, Kistler, P, Kalman, JM, Kumar, S, Haqqani, H, Wynn, G, Pathak, RK, Lipton, J, Mahajan, R, Sanders, P, Healey, S, Wilsmore, B, Mariani, JA, Thomas, SP, Weerasooriya, R, McGavigan, A, Gould, PA, Weatherley, P, Saad, N, Cowan, M, Turnbull, S, Trivic, I, Wong, M, Tonchev, I, Morton, JB, Skinner, JR, Pflaumer, A, McGuire, M, Kistler, P, and Kalman, JM

Abstract

The COVID-19 pandemic poses a significant stress on health resources in Australia. The Heart Rhythm Council of the Cardiac Society of Australia and New Zealand aims to provide a framework for efficient resource utilisation balanced with competing risks when appropriately treating patients with cardiac arrhythmias. This document provides practical recommendations for the electrophysiology (EP) and cardiac implantable electronic devices (CIED) services in Australia. The document will be updated regularly as new evidence and knowledge is gained with time.

Published
2020

32. Granular technologies to accelerate decarbonization

Author

Wilson, C., Grubler, A., Bento, N., Healey, S., De Stercke, S., Zimm, C., Wilson, C., Grubler, A., Bento, N., Healey, S., De Stercke, S., and Zimm, C.

Abstract

Of the 45 energy technologies deemed critical by the International Energy Agency for meeting global climate targets, 38 need to improve substan- tially in cost and performance while accelerating deployment over the next decades.Low-carbon technological solutions vary in scale from solar panels, e-bikes, and smart thermostats to carbon capture and storage, light rail transit, and whole-building retrofits. We make three contributions to long-standing debates on the appropriate scale of technological responses in the energy system. First, we focus on the specific needs of accelerated low-carbon transformation: rapid technology deployment, escaping lock-in, and social legitimacy. Second, we synthesize evidence on energy end-use technologies in homes, transport, and industry, as well as electricity generation and energy supply. Third, we go beyond technical and economic considerations to include innovation, investment, deployment, social, and equity criteria for assessing the relative advantage of alternative technologies as a function of their scale. We suggest numerous potential advantages of more-granular energy technologies for accelerating progress toward climate targets, as well as the conditions on which such progress depends.

Published
2020

36. Gamma-Ray Emission Concurrent with the Nova in the Symbiotic Binary V407 Cygni

Author

Abdo, A. A., Ackermann, M., Ajello, M., Atwood, W. B., Baldini, L., Ballet, J., Barbiellini, G., Bastieri, D., Bechtol, K., Bellazzini, R., Berenji, B., Blandford, R. D., Bloom, E. D., Bonamente, E., Borgland, A. W., Bouvier, A., Brandt, T. J., Bregeon, J., Brez, A., Brigida, M., Bruel, P., Buehler, R., Burnett, T. H., Buson, S., Caliandro, G. A., Cameron, R. A., Caraveo, P. A., Carrigan, S., Casandjian, J. M., Cecchi, C., Celik, O., Charles, E., Chaty, S., Chekhtman, A., Cheung, C. C., Chiang, J., Ciprini, S., Claus, R., Cohen-Tanugi, J., Conrad, J., Corbel, S., Corbet, R., DeCesar, M. E., den Hartog, P. R., Dermer, C. D., de Palma, F., Digel, S. W., Donato, D., do Couto e Silva, E., Drell, P. S., Dubois, R., Dubus, G., Dumora, D., Favuzzi, C., Fegan, S. J., Ferrara, E. C, Fortin, P., Frailis, M., Fuhrmann, L., Fukazawa, Y., Funk, S., Fusco, P., Gargano, F., Gaspamini, D., Gehrels, N., Germani, S., Giglietto, N., Giordano, F., Giroletti, M., Glanzman, T., Godfrey, G., Grenier, I. A., Grondin, M.-H., Grove, J. E., Guiriec, S., Hadasch, D., Harding, A. K., Hayashida, M., Hays, E., Healey, S. E., Hill, A. B., Horan, D., Hughes, R. E., Itoh, R., Jean, P., Jóhannesson, G., Johnson, A. S., Johnson, R. P., Johnson, T. J., Johnson, W. N., Kamae, T., Katagiri, H., Kataoka, J., Kerr, M., Knödlseder, J., Koerding, E., Kuss, M., Lande, J., Latronico, L., Lee, S.-H., Lemoine-Goumard, M., Garde, Llena M., Longo, F., Loparco, F., Lott, B., Lovellette, M. N., Lubrano, P., Makeev, A., Mazziotta, M. N., McConville, W., McEnery, J. E., Mehault, J., Michelson, P. F., Mizuno, T., Moiseev, A. A., Monte, C., Monzani, M. E., Morselli, A., Moskalenko, I. V., Murgia, S., Nakamori, T., Naumann-Godo, M., Nestoras, I., Nolan, P. L., Norris, J. P., Nuss, E., Ohno, M., Ohsugi, T., Okumura, A., Omodei, N., Orlando, E., Ormes, J. F., Ozaki, M., Paneque, D., Panetta, J. H., Parent, D., Pelassa, V., Pepe, M., Pesce-Rollins, M., Piron, F., Porter, T. A, Raino, S., Rando, R., Ray, P. S., Razzano, M., Razzaque, S., Rea, N., Reimer, A., Reimer, O., Reposeur, T., Ripken, J., Ritz, S., Romani, R. W., Roth, M., Sadrozinski, H. F.-W., Sander, A., Saz Parkinson, P. M., Scargle, J. D., Schinzel, F. K., Sgrò, C., Shaw, M. S., Siskind, E. J., Smith, D. A., Smith, P. D., Sokolovsky, K. V., Spandre, G., Spinelli, P., Stawarz, L., Strickman, M. S., Suson, D. J., Takahashi, H., Takahashi, T., Tanaka, T., Tanaka, Y., Thayer, J. B., Thayer, J. G., Thompson, D. J., Tibaldo, L., Torres, D. F., Tosti, G., Tramacere, A., Uchiyama, Y., Usher, T. L, Vandenbroucke, J., Vasileiou, V., Vilchez, N., Vitale, V., Waite, A. P., Wallace, E., Wang, P., Winer, B. L, Wolff, M. T., Wood, K. S., Yang, Z., Ylinen, T., Ziegler, M., Maehara, H., Nishiyama, K., Kabashima, F., Bach, U., Bower, G. C., Falcone, A., Forster, J. R., Henden, A., Kawabata, K. S., Koubsky, P., Mukai, K., Nelson, T., Oates, S. R., Sakimoto, K., Sasada, M., Shenavrin, V. I., Shore, S. N., Skinner, G. K., Sokoloski, J., Stroh, M., Tatarnikov, A. M., Uemura, M., Wahlgren, G. M., and Yamanaka, M.

Published
2010
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39. Self reported symptoms in the neck and upper limbs in nurses

Author

Lusted, M.J., Carrasco, C.L., Mandryk, J.A., and Healey, S.

Subjects
Nurses -- Health aspects, Neck -- Diseases, Extremities, Upper -- Diseases, Workers' compensation -- Research, Engineering and manufacturing industries, Health, Human resources and labor relations
Abstract

This paper describes a cross-sectional study which examines musculoskeletal symptoms in nurses working in two similar units in a residential care centre for the developmentally disabled. Amongst the 30 nurses who were administered the Nordic Questionnaire, neck and upper limb symptoms had resulted in considerable inability to perform work. In contrast, a similar incidence of reported back symptoms in these nurses had not prevented them from doing their work. An examination of the worker's compensation claims made by nurses from the whole facility showed low back claims to be more common than neck and upper limb claims. It appears that nurses are more likely to make a worker's compensation claim for low back symptoms than neck and upper limb symptoms. In other words, worker's compensation claims do not accurately reflect the types of musculoskeletal symptoms actually experienced by nurses and affecting their ability to do their work. Five nurses from each unit were also observed during the entire morning and afternoon shifts to examine the work load and the effects of fatigue on the musculoskeletal system. Heart rate measurements and ratings of perceived exertion were taken. Activities performed and types of transfers carried out were also recorded. Nurses in one of the units had significantly more reported neck and shoulder symptoms than their counterparts. Observations of a sample of five nurses from each unit also showed higher ratings of perceived exertion in this unit. These differences were possibly confounded by the fact that nurses in the unit which experienced these problems were about 8 cm shorter and about 5 kg lighter than their counterparts. Differences in the work practices in the two units, especially methods of manual handling and use of ergonomic interventions were identified as important contributing factors. Keywords: musculoskeletal symptoms, patient transfers, perceived exertion, work organisation

Published
1996

40. Packing products for customers: an ergonomics evaluation of three supermarket checkouts

Author

Carrasco, C., Coleman, N., Healey, S., and Lusted, M.

Subjects
Supermarkets -- Equipment and supplies, Ergonomics -- Research, Workers -- Effect of technological innovations on, Engineering and manufacturing industries, Health, Human resources and labor relations
Abstract

There have been many studies on the laser scanning process in supermarkets and the cumulative trauma disorders in the hands and arms brought on by the process. However, few studies have analyzed the heavy musculoskeletal load and exertion that is exerted when employees manning checkout counters pack bags for customers. Three designs of checkout workstations are evaluated for their effects on checkout staff.

Published
1995

42. Evaluation of the seating of Qantas flight deck crew

Author

Lusted, M., Healey, S., and Mandryk, J.A.

Subjects
Flight crews -- Health aspects, Airplanes -- Seats, Aircraft cabins -- Human factors, Engineering and manufacturing industries, Health, Human resources and labor relations
Abstract

In 1985 Qantas Airways (Australia) requested an ergonomics assessment of three pilots' seats so that one could be selected for fitting in all new aircraft as well as replacement in existing aircraft. The Ipeco seat was chosen. In 1991, after all aircraft were fitted with the Ipeco seats, the company then requested a further evaluation of the seat to see if it was acceptable to the pilots and if there were any outstanding problems. A seat feature checklist plus a body chart discomfort rating scale was given to the total crew of 1030 pilots. The results from the 202 respondents indicated that although the pilots found the Ipeco seat an improvement on the Weber seat there were some modifications required. The main problems included insufficient adjustment range of the lumbar support area and the thigh supports, and infrequent replacement of the seat cushion. The body charts supported the checklist results in that the main areas of discomfort indicated were the buttocks and low back. Recommendations for improvements in design of the Ipeco seat, training in use and maintenance are presented. The method used in this study has application for field assessment of seating in a wide range of occupations, particularly bus drivers, truck drivers and train drivers, who spend long hours seated without being able to take breaks. Keywords: seating, back pain, pilots, long-distance drivers, anthropometry, body charts, evaluation, questionnaire results

Published
1994

46. Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Author

Kuchenbaecker, K.B., McGuffog, L., Barrowdale, D., Lee, Andrew, Soucy, P., Dennis, J., Domchek, S.M., Robson, M., Spurdle, A.B., Ramus, S.J., Mavaddat, N., Terry, M.B., Neuhausen, S.L., Schmutzler, R.K., Simard, J., Pharoah, P.D.P., Offit, K., Couch, F.J., Chenevix-Trench, G., Easton, D.F., Antoniou, A.C., Healey, S., Lush, M., Hamann, U., Southey, M., John, E.M., Chung, W.K., Daly, M. B., Buys, S.S., Goldgar, D.E., Dorfling, C.M., van Rensburg, E.J., Ding, Y.C., Ejlertsen, B., Gerdes, A.-M., Hansen, T.V.O., Slager, S., Hallberg, E., Benitez, J., Osorio, A., Cohen, N., Lawler, W., Weitzel, J.N., Peterlongo, P., Pensotti, V., Dolcetti, R., Barile, M., Aittomäki, K., Nevanlinna, H., Rantala, J., Department of Medical and Clinical Genetics, Kristiina Aittomäki / Principal Investigator, HUS Gynecology and Obstetrics, and Department of Obstetrics and Gynecology

Subjects
Adult, Heterozygote, cancer patient, Multifactorial Inheritance, endocrine system diseases, proportional hazards model, 3122 Cancers, Genes, BRCA2, Genes, BRCA1, Breast Neoplasms, cancer risk, Polymorphism, Single Nucleotide, Article, young adult, Adolescent, Young Adult, breast cancer, single nucleotide polymorphism, Risk Factors, middle aged, statistics and numerical data, Humans, Genetic Predisposition to Disease, genetics, human, procedures, gene mutation, tumor suppressor gene, Proportional Hazards Models, Ovarian Neoplasms, genome-wide association study, ovary cancer, risk assessment, cancer susceptibility, Prognosis, major clinical study, estrogen receptor, adult, female, age, priority journal, risk factor, Receptors, Estrogen, adolescent, Mutation, BRCA2 protein, BRCA1 protein, population research, genetic predisposition, metabolism, estrogen receptor
Abstract

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 × 10-53). InBRCA2 carriers, the strongest association with BC risk was seen for the overall BCPRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 × 10-20). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management. © The Author 2017.

Published
2017

48. RAD51B in familial breast cancer.

Author

Antill Y., Garcia-Closas M., Michailidou K., Links M., Grygiel J., Hill J., Brand A., Byth K., Jaworski R., Harnett P., Wain G., Purdie D., Whiteman D., Ward B., Papadimos D., Crandon A., Horwood K., Obermair A., Perrin L., Wyld D., Nicklin J., Davy S.A.-M., Oehler M.K., Hall C., Dodd T., Healy T., Pittman K., Henderson D., Miller J., Pierdes J., Achan A., Blomfield P., Challis D., McIntosh R., Parker A., Brown B., Rome R., Allen D., Grant P., Hyde S., Laurie R., Robbie M., Healy D., Manolitsas T., McNealage J., Rogers P., Susil B., Sumithran E., Simpson I., Haviv I., Rischin D., Johnson D., Lade S., Loughrey M., O'Callaghan N., Murray B., Mileshkin L., Allan P., Billson V., Pyman J., Neesham D., Quinn M., Hamilton A., McNally O., Underhill C., Ng L.F., Blum R., Ganju V., Hammond I., Leung Y., McCartney A., Stewart C., Zeps N., Bell R., Harris M., Healey S., Jobling T., Jones A., Wilson J., Pelttari L.M., Khan S., Vuorela M., Kiiski J.I., Vilske S., Nevanlinna V., Ranta S., Schleutker J., Winqvist R., Kallioniemi A., Dork T., Bogdanova N.V., Figueroa J., Pharoah P.D.P., Schmidt M.K., Dunning A.M., Bolla M.K., Dennis J., Wang Q., Hopper J.L., Southey M.C., Rosenberg E.H., Fasching P.A., Beckmann M.W., Peto J., Dos-Santos-silva I., Sawyer E.J., Tomlinson I., Burwinkel B., Surowy H., Guenel P., Truong T., Bojesen S.E., Nordestgaard B.G., Benitez J., Gonzalez-Neira A., Neuhausen S.L., Anton-Culver H., Brenner H., Arndt V., Meindl A., Schmutzler R.K., Brauch H., Bruning T., Lindblom A., Margolin S., Mannermaa A., Hartikainen J.M., Chenevix-Trench G., Van Dyck L., Janssen H., Chang-Claude J., Rudolph A., Radice P., Peterlongo P., Hallberg E., Olson J.E., Giles G.G., Milne R.L., Haiman C.A., Schumacher F., Simard J., Dumont M., Kristensen V., Borresen-Dale A.-L., Zheng W., Beeghly-Fadiel A., Grip M., Andrulis I.L., Glendon G., Devilee P., Seynaeve C., Hooning M.J., Collee M., Cox A., Cross S.S., Shah M., Luben R.N., Hamann U., Torres D., Jakubowska A., Lubinski J., Couch F.J., Yannoukakos D., Orr N., Swerdlow A., Darabi H., Li J., Czene K., Hall P., Easton D.F., Mattson J., Blomqvist C., Aittomaki K., Nevanlinna H., Aghmesheh M., Amor D., Andrews L., Armitage S., Arnold L., Balleine R., Bankier A., Bastick P., Beesley J., Beilby J., Bennett B., Bennett I., Berry G., Blackburn A., Bogwitz M., Brennan M., Brown M., Buckley M., Burgess M., Burke J., Butow P., Byron K., Callen D., Campbell I., Chauhan D., Christian A., Clarke C., Colley A., Cotton D., Crook A., Cui J., Culling B., Cummings M., Dawson S.-J., DeFazio A., Delatycki M., Dickson R., Dixon J., Dobrovic A., Dudding T., Edkins T., Edwards S., Eisenbruch M., Farshid G., Fawcett S., Fellows A., Fenton G., Field M., Firgaira F., Flanagan J., Fleming J., Fong P., Forbes J., Fox S., French J., Friedlander M., Gaff C., Gardner M., Gattas M., George P., Gill G., Goldblatt J., Greening S., Grist S., Haan E., Hardie K., Hart S., Hayward N., Heiniger L., Humphrey E., Hunt C., James P., Jenkins M., Kefford R., Kidd A., Kiely B., Kirk J., Koehler J., Kollias J., Kovalenko S., Lakhani S., Leaming A., Leary J., Lim J., Lindeman G., Lipton L., Lobb L., Mann G., Marsh D., McLachlan S.A., Meiser B., Meldrum C., Mitchell G., Newman B., Nightingale S., O'Connell S., O'Loughlin I., Osborne R., Pachter N., Patterson B., Peters L., Phillips K., Price M., Purser L., Reeve T., Reeve J., Richards R., Rickard E., Robinson B., Rudzki B., Saleh M., Salisbury E., Sambrook J., Saunders C., Saunus J., Sayer R., Scott E., Scott R., Scott C., Seshadri R., Sexton A., Sharma R., Shelling A., Simpson P., Spurdle A., Suthers G., Sykes P., Taylor D., Taylor J., Thierry B., Thompson E., Thorne H., Townshend S., Trainer A., Tran L., Tucker K., Tyler J., Visvader J., Walker L., Walpole I., Ward R., Waring P., Warner B., Warren G., Williams R., Winship I., Wu K., Young M.A., Stuart-Harris R., Kirsten F., Rutovitz J., Clingan P., Glasgow A., Proietto A., Braye S., Otton G., Shannon J., Bonaventura T., Stewart J., Begbie S., Bell D., Baron-Hay S., Ferrier A., Gard G., Nevell D., Pavlakis N., Valmadre S., Young B., Camaris C., Crouch R., Edwards L., Hacker N., Marsden D., Robertson G., Beale P., Beith J., Carter J., Dalrymple C., Houghton R., Russell P., Anderson L., Antill Y., Garcia-Closas M., Michailidou K., Links M., Grygiel J., Hill J., Brand A., Byth K., Jaworski R., Harnett P., Wain G., Purdie D., Whiteman D., Ward B., Papadimos D., Crandon A., Horwood K., Obermair A., Perrin L., Wyld D., Nicklin J., Davy S.A.-M., Oehler M.K., Hall C., Dodd T., Healy T., Pittman K., Henderson D., Miller J., Pierdes J., Achan A., Blomfield P., Challis D., McIntosh R., Parker A., Brown B., Rome R., Allen D., Grant P., Hyde S., Laurie R., Robbie M., Healy D., Manolitsas T., McNealage J., Rogers P., Susil B., Sumithran E., Simpson I., Haviv I., Rischin D., Johnson D., Lade S., Loughrey M., O'Callaghan N., Murray B., Mileshkin L., Allan P., Billson V., Pyman J., Neesham D., Quinn M., Hamilton A., McNally O., Underhill C., Ng L.F., Blum R., Ganju V., Hammond I., Leung Y., McCartney A., Stewart C., Zeps N., Bell R., Harris M., Healey S., Jobling T., Jones A., Wilson J., Pelttari L.M., Khan S., Vuorela M., Kiiski J.I., Vilske S., Nevanlinna V., Ranta S., Schleutker J., Winqvist R., Kallioniemi A., Dork T., Bogdanova N.V., Figueroa J., Pharoah P.D.P., Schmidt M.K., Dunning A.M., Bolla M.K., Dennis J., Wang Q., Hopper J.L., Southey M.C., Rosenberg E.H., Fasching P.A., Beckmann M.W., Peto J., Dos-Santos-silva I., Sawyer E.J., Tomlinson I., Burwinkel B., Surowy H., Guenel P., Truong T., Bojesen S.E., Nordestgaard B.G., Benitez J., Gonzalez-Neira A., Neuhausen S.L., Anton-Culver H., Brenner H., Arndt V., Meindl A., Schmutzler R.K., Brauch H., Bruning T., Lindblom A., Margolin S., Mannermaa A., Hartikainen J.M., Chenevix-Trench G., Van Dyck L., Janssen H., Chang-Claude J., Rudolph A., Radice P., Peterlongo P., Hallberg E., Olson J.E., Giles G.G., Milne R.L., Haiman C.A., Schumacher F., Simard J., Dumont M., Kristensen V., Borresen-Dale A.-L., Zheng W., Beeghly-Fadiel A., Grip M., Andrulis I.L., Glendon G., Devilee P., Seynaeve C., Hooning M.J., Collee M., Cox A., Cross S.S., Shah M., Luben R.N., Hamann U., Torres D., Jakubowska A., Lubinski J., Couch F.J., Yannoukakos D., Orr N., Swerdlow A., Darabi H., Li J., Czene K., Hall P., Easton D.F., Mattson J., Blomqvist C., Aittomaki K., Nevanlinna H., Aghmesheh M., Amor D., Andrews L., Armitage S., Arnold L., Balleine R., Bankier A., Bastick P., Beesley J., Beilby J., Bennett B., Bennett I., Berry G., Blackburn A., Bogwitz M., Brennan M., Brown M., Buckley M., Burgess M., Burke J., Butow P., Byron K., Callen D., Campbell I., Chauhan D., Christian A., Clarke C., Colley A., Cotton D., Crook A., Cui J., Culling B., Cummings M., Dawson S.-J., DeFazio A., Delatycki M., Dickson R., Dixon J., Dobrovic A., Dudding T., Edkins T., Edwards S., Eisenbruch M., Farshid G., Fawcett S., Fellows A., Fenton G., Field M., Firgaira F., Flanagan J., Fleming J., Fong P., Forbes J., Fox S., French J., Friedlander M., Gaff C., Gardner M., Gattas M., George P., Gill G., Goldblatt J., Greening S., Grist S., Haan E., Hardie K., Hart S., Hayward N., Heiniger L., Humphrey E., Hunt C., James P., Jenkins M., Kefford R., Kidd A., Kiely B., Kirk J., Koehler J., Kollias J., Kovalenko S., Lakhani S., Leaming A., Leary J., Lim J., Lindeman G., Lipton L., Lobb L., Mann G., Marsh D., McLachlan S.A., Meiser B., Meldrum C., Mitchell G., Newman B., Nightingale S., O'Connell S., O'Loughlin I., Osborne R., Pachter N., Patterson B., Peters L., Phillips K., Price M., Purser L., Reeve T., Reeve J., Richards R., Rickard E., Robinson B., Rudzki B., Saleh M., Salisbury E., Sambrook J., Saunders C., Saunus J., Sayer R., Scott E., Scott R., Scott C., Seshadri R., Sexton A., Sharma R., Shelling A., Simpson P., Spurdle A., Suthers G., Sykes P., Taylor D., Taylor J., Thierry B., Thompson E., Thorne H., Townshend S., Trainer A., Tran L., Tucker K., Tyler J., Visvader J., Walker L., Walpole I., Ward R., Waring P., Warner B., Warren G., Williams R., Winship I., Wu K., Young M.A., Stuart-Harris R., Kirsten F., Rutovitz J., Clingan P., Glasgow A., Proietto A., Braye S., Otton G., Shannon J., Bonaventura T., Stewart J., Begbie S., Bell D., Baron-Hay S., Ferrier A., Gard G., Nevell D., Pavlakis N., Valmadre S., Young B., Camaris C., Crouch R., Edwards L., Hacker N., Marsden D., Robertson G., Beale P., Beith J., Carter J., Dalrymple C., Houghton R., Russell P., and Anderson L.

Abstract

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

Published
2017

49. BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Author

Meeks, H.D., Song, H.L., Michailidou, K., Bolla, M.K., Dennis, J., Wang, Q., Barrowdale, D., Frost, D., McGuffog, L., Ellis, S., Feng, B.J., Buys, S.S., Hopper, J.L., Southey, M.C., Tesoriero, A., James, P.A., Bruinsma, F., Campbell, I.G., Broeks, A., Schmidt, M.K., Hogervorst, F.B.L., Beckman, M.W., Fasching, P.A., Fletcher, O., Johnson, N., Sawyer, E.J., Riboli, E., Banerjee, S., Menon, U., Tomlinson, I., Burwinkel, B., Hamann, U., Marme, F., Rudolph, A., Janavicius, R., Tihomirova, L., Tung, N., Garber, J., Cramer, D., Terry, K.L., Poole, E.M., Tworoger, S.S., Dorfling, C.M., Rensburg, E.J. van, Godwin, A.K., Guenel, P., Truong, T., Stoppa-Lyonnet, D., Damiola, F., Mazoyer, S., Sinilnikova, O.M., Isaacs, C., Maugard, C., Bojesen, S.E., Flyger, H., Gerdes, A.M., Hansen, T.V.O., Jensen, A., Kjaer, S.K., Hogdall, C., Hogdall, E., Pedersen, I.S., Thomassen, M., Benitez, J., Gonzalez-Neira, A., Osorio, A., Hoya, M. de la, Segura, P.P., Diez, O., Lazaro, C., Brunet, J., Anton-Culver, H., Eunjung, L., John, E.M., Neuhausen, S.L., Ding, Y.C., Castillo, D., Weitzel, J.N., Ganz, P.A., Nussbaum, R.L., Chan, S.B., Karlan, B.Y., Lester, J., Wu, A., Gayther, S., Ramus, S.J., Sieh, W., Whittermore, A.S., Monteiro, A.N.A., Phelan, C.M., Terry, M.B., Piedmonte, M., Offit, K., Robson, M., Levine, D., Moysich, K.B., Cannioto, R., Olson, S.H., Daly, M.B., Nathanson, K.L., Domchek, S.M., Lu, K.H., Liang, D., Hildebrant, M.A.T., Ness, R., Modugno, F., Pearce, L., Goodman, M.T., Thompson, P.J., Brenner, H., Butterbach, K., Meindl, A., Hahnen, E., Wappenschmidt, B., Brauch, H., Bruning, T., Blomqvist, C., Khan, S., Nevanlinna, H., Pelttari, L.M., Aittomaki, K., Butzow, R., Bogdanova, N.V., Dork, T., Lindblom, A., Margolin, S., Rantala, J., Kosma, V.M., Mannermaa, A., Lambrechts, D., Neven, P., Claes, K.B.M., Maerken, T. van, Chang-Claude, J., Flesch-Janys, D., Heitz, F., Varon-Mateeva, R., Peterlongo, P., Radice, P., Viel, A., Barile, M., Peissel, B., Manoukian, S., Montagna, M., Oliani, C., Peixoto, A., Teixeira, M.R., Collavoli, A., Hallberg, E., Olson, J.E., Goode, E.L., Hart, S.N., Shimelis, H., Cunningham, J.M., Giles, G.G., Milne, R.L., Healey, S., Tucker, K., Haiman, C.A., Henderson, B.E., Goldberg, M.S., Tischkowitz, M., Simard, J., Soucy, P., Eccles, D.M., N. le, Borresen-Dale, A.L., Kristensen, V., Salvesen, H.B., Bjorge, L., Bandera, E.V., Risch, H., Zheng, W., Beeghly-Fadiel, A., Cai, H., Pylkas, K., Tollenaar, R.A.E.M., Ouweland, A.M.W. van der, Andrulis, I.L., Knight, J.A., Narod, S., Devilee, P., Winqvist, R., Figueroa, J., Greene, M.H., Mai, P.L., Loud, J.T., Garcia-Closas, M., Schoemaker, M.J., Czene, K., Darabi, H., McNeish, I., Siddiquil, N., Glasspool, R., Kwong, A., Park, S.K., Teo, S.H., Yoon, S.Y., Matsuo, K., Hosono, S., Woo, Y.L., Gao, Y.T., Foretova, L., Singer, C.F., Rappaport-Feurhauser, C., Friedman, E., Laitman, Y., Rennert, G., Imyanitov, E.N., Hulick, P.J., Olopade, O.I., Senter, L., Olah, E., Doherty, J.A., Schildkraut, J., Koppert, L.B., Kiemeney, L.A., Massuger, L.F.A.G., Cook, L.S., Pejovic, T., Li, J.M., Borg, A., Ofverholm, A., Rossing, M.A., Wentzensen, N., Henriksson, K., Cox, A., Cross, S.S., Pasini, B.J., Shah, M., Kabisch, M., Torres, D., Jakubowska, A., Lubinski, J., Gronwald, J., Agnarsson, B.A., Kupryjanczyk, J., Moes-Sosnowska, J., Fostira, F., Konstantopoulou, I., Slager, S., Jones, M., Antoniou, A.C., Berchuck, A., Swerdlow, A., Chenevix-Trench, G., Dunning, A.M., Pharoah, P.D.P., Hall, P., Easton, D.F., Couch, F.J., Spurdle, A.B., Goldgar, D.E., EMBRACE, kConFab Investigators, Australia Ovarian Canc Study Grp, HEBON, GEMO Study Collaborators, OCGN, PRostate Canc Assoc Grp, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Clinical Genetics, Obstetrics & Gynecology, Surgery, and [ 1 ] Univ Utah, Huntsman Canc Inst, Canc Control & Populat Sci, Salt Lake City, UT USA [ 2 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England [ 3 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England [ 4 ] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Dermatol, 2000 Circle Hope Dr, Salt Lake City, UT 84112 USA [ 5 ] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT USA [ 6 ] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia [ 7 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 8 ] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic 3052, Australia [ 9 ] KConFab Kathleen Cuningham Consortium Res Familia, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia [ 10 ] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic, Australia [ 11 ] Univ Melbourne, Dept Oncol, Melbourne, Vic, Australia [ 12 ] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia [ 13 ] Univ Melbourne, Peter MacCallum Canc Ctr, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3052, Australia [ 14 ] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia [ 15 ] Peter MacCallum Canc Inst, East Melbourne, Vic, Australia [ 16 ] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands [ 17 ] Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands [ 18 ] Netherlands Canc Inst, Hereditary Breast & Ovarian Canc Res Grp Netherla, Coordinating Ctr, Amsterdam, Netherlands [ 19 ] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Gynaecol & Ostetr, D-91054 Erlangen, Germany [ 20 ] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA [ 21 ] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England [ 22 ] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England [ 23 ] Guys Hosp, Kings Coll London, Div Canc Studies, Res Oncol, London SE1 9RT, England [ 24 ] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England [ 25 ] Royal Marsden NHS Fdn Trust, London, England [ 26 ] Univ Coll London Elizabeth Garrett Anderson EGA, Inst Womens Hlth, Womens Canc, London, England [ 27 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 28 ] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England [ 29 ] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany [ 30 ] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany [ 31 ] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany [ 32 ] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany [ 33 ] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany [ 34 ] State Res Inst Ctr Innovat Med, Vilnius, Lithuania [ 35 ] Latvian Biomed Res & Study Ctr, Riga, Latvia [ 36 ] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA [ 37 ] Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02115 USA [ 38 ] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA [ 39 ] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA [ 40 ] Harvard Univ, Sch Med, Boston, MA 02115 USA [ 41 ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 665 Huntington Ave, Boston, MA 02115 USA [ 42 ] Univ Pretoria, Dept Genet, ZA-0002 Pretoria, South Africa [ 43 ] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA [ 44 ] Natl Inst Hlth & Med Res, Ctr Res Epidemiol & Populat Hlth CESP, Environm Epidemiol Canc, INSERM,U1018, Villejuif, France [ 45 ] Univ Paris Sud, Villejuif, France [ 46 ] UNICANCER Genet Grp, GEMO Study Natl Canc Genet Network, Paris, France [ 47 ] Inst Curie, Dept Tumour Biol, Paris, France [ 48 ] INSERM, U830, Inst Curie, Paris, France [ 49 ] Univ Paris 05, Sorbonne Paris Cite, Paris, France [ 50 ] Univ Lyon, Ctr Rech Cancerol Lyon, INSERM,U1052, CNRS UMR 5286, Lyon, France [ 51 ] Hosp Civils Pyon, Ctr Leon Berard, Unite Mixte Genet Constitutionelle Canc Frequents, Lyon, France [ 52 ] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA [ 53 ] Hop Univ Strasbourg, CHRU Nouvel, Lab Diagnost Genet, Hop Civil, Strasbourg, France [ 54 ] Hop Univ Strasbourg, CHRU Nouvel, Serv Oncohematol, Hop Civil, Strasbourg, France [ 55 ] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark [ 56 ] Copenhagen Univ Hosp, Dept Clin Biochem, Herlev Hosp, Herlev, Denmark [ 57 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark [ 58 ] Copenhagen Univ Hosp, Rigshosp, Dept Clin Genet, Copenhagen, Denmark [ 59 ] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, Copenhagen, Denmark [ 60 ] Danish Canc Soc, Dept Virus Lifestyle & Genes, Res Ctr, Copenhagen, Denmark [ 61 ] Univ Copenhagen, Rigshosp, Dept Gynecol, DK-2100 Copenhagen, Denmark [ 62 ] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark [ 63 ] Aalborg Univ Hosp, Dept Biochem, Sect Mol Diagnost, Aalborg, Denmark [ 64 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark [ 65 ] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Human Genet Grp, Madrid, Spain [ 66 ] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Human Genotyping Unit CEGEN, Madrid, Spain [ 67 ] Biomed Network Rare Dis CIBERER, Madrid, Spain [ 68 ] IdISSC Inst Invest Sanitaria Hosp Clin San Carlos, Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain [ 69 ] IdISSC, Hosp Clin San Carlos, Dept Oncol, Madrid, Spain [ 70 ] Univ Hosp Vall dHebron, VHIO, Oncogenet Grp, Barcelona, Spain [ 71 ] Univ Autonoma Barcelona, E-08193 Barcelona, Spain [ 72 ] Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Hereditary Canc Program, Mol Diagnost Unit, Barcelona, Spain [ 73 ] Catalan Inst Oncol, IDIBGI Inst Invest Biomed Girona, Hereditary Canc Program, Genet Counseling Unit, Girona, Spain [ 74 ] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA [ 75 ] Univ So Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA [ 76 ] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA [ 77 ] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA [ 78 ] City Hope Clin Canc Genet Community Res Network, Clin Canc Genet, Duarte, CA USA [ 79 ] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Sch Med, Div Canc Prevent & Control Res, Los Angeles, CA 90024 USA [ 80 ] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Sch Publ Hlth, Div Canc Prevent & Control Res, Los Angeles, CA 90024 USA [ 81 ] Univ Calif San Francisco, Dept Med & Genet, San Francisco, CA 94143 USA [ 82 ] Univ Calif San Francisco, Helen Diller Family Canc Ctr, Canc Risk Program, San Francisco, CA 94143 USA [ 83 ] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA [ 84 ] Stanford Univ, Dept Hlth Res & Policy Epidemiol, Stanford, CA USA [ 85 ] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA [ 86 ] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA [ 87 ] Roswell Pk Ctr Inst, NRG Oncol Stat & Data Management Ctr, Buffalo, NY USA [ 88 ] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA [ 89 ] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, 1275 York Ave, New York, NY 10021 USA [ 90 ] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA [ 91 ] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 1275 York Ave, New York, NY 10021 USA [ 92 ] Fox Chase Canc Ctr, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA [ 93 ] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Basser Ctr, Philadelphia, PA 19104 USA [ 94 ] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA [ 95 ] Texas So Univ, Coll Pharm & Hlth Sci, Houston, TX 77004 USA [ 96 ] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA [ 97 ] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA [ 98 ] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA [ 99 ] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA [ 100 ] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA USA [ 101 ] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA [ 102 ] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA [ 103 ] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Prevent & Control, Los Angeles, CA 90048 USA [ 104 ] Cedars Sinai Med Ctr, Dept Biomed Sci, Community & Populat Hlth Res Inst, Los Angeles, CA 90048 USA [ 105 ] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany [ 106 ] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany [ 107 ] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England [ 108 ] Tech Univ Munich, Klinikum Rechts Isar, Dept Obstet & Gynaecol, Div Tumor Genet, D-80290 Munich, Germany [ 109 ] Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany [ 110 ] Univ Hosp Cologne, Ctr Mol Med, Cologne, Germany [ 111 ] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 112 ] Univ Hosp Cologne, Dept Obstet & Gynaecol, Cologne, Germany [ 113 ] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, Stuttgart, Germany [ 114 ] Univ Tubingen, Tubingen, Germany [ 115 ] Ruhr Univ Bochum IPA, German Social Accid Insurance & Inst, Inst Prevent & Occupat Med, Bochum, Germany [ 116 ] Univ Helsinki, Dept Oncol, Helsinki, Finland [ 117 ] Helsinki Univ Hosp, Helsinki, Finland [ 118 ] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland [ 119 ] Univ Helsinki, Dept Clin Genet, Helsinki, Finland [ 120 ] Univ Helsinki, Dept Pathol, Helsinki, Finland [ 121 ] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany [ 122 ] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden [ 123 ] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden [ 124 ] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden [ 125 ] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio, Finland [ 126 ] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland [ 127 ] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland [ 128 ] VIB, VRC, Leuven, Belgium [ 129 ] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium [ 130 ] Univ Hosp Leuven, Dept Oncol, Multidisciplinary Breast Ctr, Leuven, Belgium [ 131 ] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium [ 132 ] Univ Med Ctr Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany [ 133 ] Univ Med Ctr Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, Hamburg, Germany [ 134 ] Kliniken Essen Mitte Evang Huyssens Stiftung Knap, Dept Gynecol & Gynecol Oncol, Essen, Germany [ 135 ] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany [ 136 ] Charite, Campus Virchov Klinikum, Inst Human Genet, Berlin, Germany [ 137 ] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy [ 138 ] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy [ 139 ] Aviano Natl Canc Inst, CRO, Div Expt Oncol, Aviano, Italy [ 140 ] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy [ 141 ] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy [ 142 ] Veneto Inst Oncol IOV IRCCS, Immunol & Mol Oncol Unit, Padua, Italy [ 143 ] ULSS5 Ovest Vicentino, UOC Oncol, Veneto, Italy [ 144 ] Portugese Oncol Inst, Dept Genet, Oporto, Portugal [ 145 ] Univ Porto, Biomed Sci Inst ICBAS, Rua Campo Alegre 823, P-4100 Oporto, Portugal [ 146 ] Univ Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy [ 147 ] Univ Hosp Pisa, Pisa, Italy [ 148 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA [ 149 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA [ 150 ] Prince Wales Hosp, Sydney, NSW, Australia [ 151 ] McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H3A 1A1, Canada [ 152 ] McGill Univ, Dept Med, Montreal, PQ, Canada [ 153 ] McGill Univ, Dept Human Genet, Program Canc Genet, Montreal, PQ, Canada [ 154 ] McGill Univ, Dept Oncol, Program Canc Genet, Montreal, PQ, Canada [ 155 ] Univ Cambridge, Sch Med, Cambridge, England [ 156 ] Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ, Canada [ 157 ] Univ Laval, Quebec City, PQ, Canada [ 158 ] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England [ 159 ] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada [ 160 ] Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Genet, Oslo, Norway [ 161 ] Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway [ 162 ] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway [ 163 ] Haukeland Hosp, Dept Gynecol & Obstet, N-5021 Bergen, Norway [ 164 ] Univ Bergen, Dept Clin Sci, Ctr Canc Biomarkers, Bergen, Norway [ 165 ] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA [ 166 ] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA [ 167 ] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr,Vanderbilt Ingram Canc C, Div Epidemiol,Dept Med, 221 Kirkland Hall, Nashville, TN 37235 USA [ 168 ] Univ Oulu, Dept Clin Chem, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 169 ] Univ Oulu, Bioctr Oulu, Oulu, Finland [ 170 ] Northern Finland Lab Ctr Nordlab, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 171 ] Erasmus Univ, Med Ctr, Dept Surg Oncol, Rotterdam, Netherlands [ 172 ] Erasmus Univ, Med Ctr, Dept Clin Genet, Family Canc Clin, Rotterdam, Netherlands [ 173 ] Mt Sinai Hosp, Lunenfeld Res Inst, Ontario Canc Genet Network, Fred A Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada [ 174 ] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada [ 175 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada [ 176 ] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada [ 177 ] Univ Toronto, Womens Coll, Res Inst, Toronto, ON, Canada [ 178 ] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands [ 179 ] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands [ 180 ] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA [ 181 ] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA [ 182 ] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England [ 183 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 184 ] Univ Glasgow, Beatson Inst Canc Res, Wolfson Wohl Canc Res Ctr, Inst Canc Sci, Glasgow, Lanark, Scotland [ 185 ] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow G4 0SF, Lanark, Scotland [ 186 ] Beatson West Scotland Canc Ctr, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland [ 187 ] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China [ 188 ] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China [ 189 ] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea [ 190 ] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea [ 191 ] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea [ 192 ] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Selangor, Malaysia [ 193 ] Univ Malaya, Med Ctr, Fac Med, Canc Res Inst, Kuala Lumpur, Malaysia [ 194 ] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan [ 195 ] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan [ 196 ] Univ Malaya, Med Ctr, Dept Obstet & Gynecol, Kuala Lumpur, Malaysia [ 197 ] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China [ 198 ] Masaryk Mem Canc Inst & Med Fac, Brno, Czech Republic [ 199 ] Med Univ Vienna, Dept Obstet & Gynecol, Vienna, Austria [ 200 ] Med Univ Vienna, Ctr Comprehens Canc, Vienna, Austria [ 201 ] Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel [ 202 ] Carmel Hosp, Clalit Natl Israeli Canc Control Ctr, Haifa, Israel [ 203 ] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel [ 204 ] B Rappaport Fac Med, Haifa, Israel [ 205 ] NN Petrov Inst Oncol, St Petersburg, Russia [ 206 ] NorthShore Univ Hlth Syst, Ctr Med Genet, Evanston, IL USA [ 207 ] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 208 ] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA [ 209 ] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary [ 210 ] Dartmouth Coll, Geisel Sch Med, Sect Biostat & Epidemiol, Dept Community & Family Med, Hanover, NH 03755 USA [ 211 ] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA [ 212 ] Duke Canc Inst, Canc Control & Populat Sci, Durham, NC USA [ 213 ] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6525 ED Nijmegen, Netherlands [ 214 ] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Dept Gynaecol, NL-6525 ED Nijmegen, Netherlands [ 215 ] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA [ 216 ] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA [ 217 ] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA [ 218 ] Lund Univ, Dept Oncol, Lund, Sweden [ 219 ] Sahlgrens Univ Hosp, Dept Clin Genet, Gothenburg, Sweden [ 220 ] Fred Hutchinson Canc Res Ctr, Program Epidemiol, 1124 Columbia St, Seattle, WA 98104 USA [ 221 ] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA [ 222 ] Univ Lund Hosp, Ctr Oncol, Reg Tumour Registry, S-22185 Lund, Sweden [ 223 ] Univ Sheffield, Sheffield Canc Res Dept Oncol, Sheffield, S Yorkshire, England [ 224 ] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England [ 225 ] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia [ 226 ] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland [ 227 ] Landspitali Univ Hosp, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 228 ] Univ Iceland, Sch Med, Reykjavik, Iceland [ 229 ] Maria Sklodowska Curie Mem Canc Ctr, Dept Pathol & Lab Diagnost, Warsaw, Poland [ 230 ] Inst Oncol, Warsaw, Poland [ 231 ] Natl Ctr Sci Res Demokritos, Mol Diagnost Lab, Inst Nucl & Radiol Sci & Technol, Energy & Safety, Athens, Greece [ 232 ] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, endocrine system diseases, LOCI, Estrogen receptor, FAMILY-HISTORY, Prostate cancer, 0302 clinical medicine, Ovarian Neoplasms/pathology, Prostate, Risk Factors, Brjóstakrabbamein, Odds Ratio, skin and connective tissue diseases, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Prostatic Neoplasms/genetics, Research Support, Non-U.S. Gov't, SINGLE-NUCLEOTIDE POLYMORPHISMS, Middle Aged, BRCA2 Protein/genetics, PANCREATIC-CANCER, 3. Good health, SUSCEPTIBILITY GENE, medicine.anatomical_structure, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Codon, Terminator, Female, Risk Factors Substances, Adult, medicine.medical_specialty, Heterozygote, Breast Neoplasms, Blöðruhálskirtilskrabbamein, Breast Neoplasms/genetics, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, Ovarian Neoplasms/genetics, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Research Support, N.I.H., Extramural, Internal medicine, Pancreatic cancer, Krabbameinsrannsóknir, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Neoplasm Invasiveness, Lysine/genetics, Krabbamein, Aged, Gynecology, BRCA2 Protein, Proportional hazards model, Lysine, DNA RECOMBINATION, CONSORTIUM, GERM-LINE MUTATION, Prostatic Neoplasms, Odds ratio, Arfgengi, medicine.disease, ESTROGEN-RECEPTOR, 030104 developmental biology, Logistic Models, PTT12, Eggjastokkar, FANCONI-ANEMIA, Ovarian cancer
Abstract

Contains fulltext : 172007.pdf (Publisher’s version ) (Closed access) BACKGROUND: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. METHODS: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. RESULTS: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. CONCLUSIONS: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.

Published
2016
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50. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author

Vigorito, E., Kuchenbaecker, K.B., Beesley, J., Adlard, J., Agnarsson, B.A., Andrulis, I.L., Arun, B.K., Barjhoux, L., Belotti, M., Benitez, J., Berger, A., Bojesen, A., Bonanni, B., Brewer, C., Caldes, T., Caligo, M.A., Campbell, I., Chan, S.B., Claes, K.B., Cohn, D.E., Cook, J., Daly, M.B., Damiola, F., Davidson, R., Pauw, A. de, Delnatte, C., Diez, O., Domchek, S.M., Dumont, M., Durda, K., Dworniczak, B., Easton, D.F., Eccles, D., Edwinsdotter Ardnor, C., Eeles, R., Ejlertsen, B., Ellis, S., Evans, D.G., Feliubadalo, L., Fostira, F., Foulkes, W.D., Friedman, E., Frost, D., Gaddam, P., Ganz, P.A., Garber, J., Garcia-Barberan, V., Gauthier-Villars, M., Gehrig, A., Gerdes, A.M., Giraud, S., Godwin, A.K., Goldgar, D.E., Hake, C.R., Hansen, T.V., Healey, S., Hodgson, S., Hogervorst, F.B., Houdayer, C., Hulick, P.J., Imyanitov, E.N., Isaacs, C., Izatt, L., Izquierdo, A., Jacobs, L, Jakubowska, A., Janavicius, R., Jaworska-Bieniek, K., Jensen, U.B., John, E.M., Vijai, J., Karlan, B.Y., Kast, K., Khan, S., Kwong, A., Laitman, Y., Lester, J., Lesueur, F., Liljegren, A., Lubinski, J., Mai, P.L., Manoukian, S., Mazoyer, S., Meindl, A., Mensenkamp, A.R., Montagna, M., Nathanson, K.L., Neuhausen, S.L., Nevanlinna, H., Niederacher, D., Olah, E., Olopade, O.I., Ong, K.R., Osorio, A., Park, S.K., Paulsson-Karlsson, Y., Pedersen, I.S., Peissel, B., Peterlongo, P., and Prokunina-Olsson, Ludmila

Subjects
endocrine system diseases, General Science & Technology, Chromosomes, Rare Diseases, Clinical Research, Breast Cancer, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Aetiology, Polymorphism, skin and connective tissue diseases, Cancer, Ovarian Neoplasms, Prevention, Genetic Carrier Screening, Human Genome, Chromosome Mapping, Single Nucleotide, BRCA1, BRCA2, Ovarian Cancer, Genes, Female, KConFab Investigators, Human, Pair 9
Abstract

Contains fulltext : 172560.PDF (Publisher’s version ) (Open Access) Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2x 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 x 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

Published
2016
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