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9. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Author

Landi, M.T. Bishop, D.T. MacGregor, S. Machiela, M.J. Stratigos, A.J. Ghiorzo, P. Brossard, M. Calista, D. Choi, J. Fargnoli, M.C. Zhang, T. Rodolfo, M. Trower, A.J. Menin, C. Martinez, J. Hadjisavvas, A. Song, L. Stefanaki, I. Scolyer, R. Yang, R. Goldstein, A.M. Potrony, M. Kypreou, K.P. Pastorino, L. Queirolo, P. Pellegrini, C. Cattaneo, L. Zawistowski, M. Gimenez-Xavier, P. Rodriguez, A. Elefanti, L. Manoukian, S. Rivoltini, L. Smith, B.H. Loizidou, M.A. Del Regno, L. Massi, D. Mandala, M. Khosrotehrani, K. Akslen, L.A. Amos, C.I. Andresen, P.A. Avril, M.-F. Azizi, E. Soyer, H.P. Bataille, V. Dalmasso, B. Bowdler, L.M. Burdon, K.P. Chen, W.V. Codd, V. Craig, J.E. Dębniak, T. Falchi, M. Fang, S. Friedman, E. Simi, S. Galan, P. Garcia-Casado, Z. Gillanders, E.M. Gordon, S. Green, A. Gruis, N.A. Hansson, J. Harland, M. Harris, J. Helsing, P. Henders, A. Hočevar, M. Höiom, V. Hunter, D. Ingvar, C. Kumar, R. Lang, J. Lathrop, G.M. Lee, J.E. Li, X. Lubiński, J. Mackie, R.M. Malt, M. Malvehy, J. McAloney, K. Mohamdi, H. Molven, A. Moses, E.K. Neale, R.E. Novaković, S. Nyholt, D.R. Olsson, H. Orr, N. Fritsche, L.G. Puig-Butille, J.A. Qureshi, A.A. Radford-Smith, G.L. Randerson-Moor, J. Requena, C. Rowe, C. Samani, N.J. Sanna, M. Schadendorf, D. Schulze, H.-J. Simms, L.A. Smithers, M. Song, F. Swerdlow, A.J. van der Stoep, N. Kukutsch, N.A. Visconti, A. Wallace, L. Ward, S.V. Wheeler, L. Sturm, R.A. Hutchinson, A. Jones, K. Malasky, M. Vogt, A. Zhou, W. Pooley, K.A. Elder, D.E. Han, J. Hicks, B. Hayward, N.K. Kanetsky, P.A. Brummett, C. Montgomery, G.W. Olsen, C.M. Hayward, C. Dunning, A.M. Martin, N.G. Evangelou, E. Mann, G.J. Long, G. Pharoah, P.D.P. Easton, D.F. Barrett, J.H. Cust, A.E. Abecasis, G. Duffy, D.L. Whiteman, D.C. Gogas, H. De Nicolo, A. Tucker, M.A. Newton-Bishop, J.A. Peris, K. Chanock, S.J. Demenais, F. Brown, K.M. Puig, S. Nagore, E. Shi, J. Iles, M.M. Law, M.H. GenoMEL Consortium Q-MEGA QTWIN Investigators ATHENS Melanoma Study Group 23andMe The SDH Study Group IBD Investigators Essen-Heidelberg Investigators AMFS Investigators MelaNostrum Consortium

Abstract

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10−8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis. © 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Published
2020

10. Erythrocyte membrane fatty acid composition of smokers and non-smokers: effects of vitamin E supplementation

Author

Brown, K.M., Morrice, P.C., and Duthie, G.G.

Subjects
Vitamin E -- Physiological aspects, Smoking -- Physiological aspects, Dietary supplements -- Health aspects, Erythrocytes -- Research, Unsaturated fatty acids -- Health aspects, Lipid peroxidation -- Health aspects
Abstract

The effect of vitamin E supplementation on vitamin E and polyunsaturated fatty acid (PUFA) concentrations in red blood cells (RBC) among smokers was investigated. Thirty male smokers and 30 male nonsmokers were recruited in a study to analyze the effects of vitamin E, RBC PUFA composition and smoking on the susceptibility of the cells to lipid peroxidation. Results showed that the levels of essential fatty acids (EFA) in RBC were higher in nonsmokers than in smokers. Vitamin E supplementation increased the RBC EFA concentrations in smokers.

Published
1998

11. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Author

Landi, M.T. Bishop, D.T. MacGregor, S. Machiela, M.J. Stratigos, A.J. Ghiorzo, P. Brossard, M. Calista, D. Choi, J. Fargnoli, M.C. Zhang, T. Rodolfo, M. Trower, A.J. Menin, C. Martinez, J. Hadjisavvas, A. Song, L. Stefanaki, I. Scolyer, R. Yang, R. Goldstein, A.M. Potrony, M. Kypreou, K.P. Pastorino, L. Queirolo, P. Pellegrini, C. Cattaneo, L. Zawistowski, M. Gimenez-Xavier, P. Rodriguez, A. Elefanti, L. Manoukian, S. Rivoltini, L. Smith, B.H. Loizidou, M.A. Del Regno, L. Massi, D. Mandala, M. Khosrotehrani, K. Akslen, L.A. Amos, C.I. Andresen, P.A. Avril, M.-F. Azizi, E. Soyer, H.P. Bataille, V. Dalmasso, B. Bowdler, L.M. Burdon, K.P. Chen, W.V. Codd, V. Craig, J.E. Dębniak, T. Falchi, M. Fang, S. Friedman, E. Simi, S. Galan, P. Garcia-Casado, Z. Gillanders, E.M. Gordon, S. Green, A. Gruis, N.A. Hansson, J. Harland, M. Harris, J. Helsing, P. Henders, A. Hočevar, M. Höiom, V. Hunter, D. Ingvar, C. Kumar, R. Lang, J. Lathrop, G.M. Lee, J.E. Li, X. Lubiński, J. Mackie, R.M. Malt, M. Malvehy, J. McAloney, K. Mohamdi, H. Molven, A. Moses, E.K. Neale, R.E. Novaković, S. Nyholt, D.R. Olsson, H. Orr, N. Fritsche, L.G. Puig-Butille, J.A. Qureshi, A.A. Radford-Smith, G.L. Randerson-Moor, J. Requena, C. Rowe, C. Samani, N.J. Sanna, M. Schadendorf, D. Schulze, H.-J. Simms, L.A. Smithers, M. Song, F. Swerdlow, A.J. van der Stoep, N. Kukutsch, N.A. Visconti, A. Wallace, L. Ward, S.V. Wheeler, L. Sturm, R.A. Hutchinson, A. Jones, K. Malasky, M. Vogt, A. Zhou, W. Pooley, K.A. Elder, D.E. Han, J. Hicks, B. Hayward, N.K. Kanetsky, P.A. Brummett, C. Montgomery, G.W. Olsen, C.M. Hayward, C. Dunning, A.M. Martin, N.G. Evangelou, E. Mann, G.J. Long, G. Pharoah, P.D.P. Easton, D.F. Barrett, J.H. Cust, A.E. Abecasis, G. Duffy, D.L. Whiteman, D.C. Gogas, H. De Nicolo, A. Tucker, M.A. Newton-Bishop, J.A. Peris, K. Chanock, S.J. Demenais, F. Brown, K.M. Puig, S. Nagore, E. Shi, J. Iles, M.M. Law, M.H. GenoMEL Consortium Q-MEGA QTWIN Investigators ATHENS Melanoma Study Group 23andMe The SDH S and Landi, M.T. Bishop, D.T. MacGregor, S. Machiela, M.J. Stratigos, A.J. Ghiorzo, P. Brossard, M. Calista, D. Choi, J. Fargnoli, M.C. Zhang, T. Rodolfo, M. Trower, A.J. Menin, C. Martinez, J. Hadjisavvas, A. Song, L. Stefanaki, I. Scolyer, R. Yang, R. Goldstein, A.M. Potrony, M. Kypreou, K.P. Pastorino, L. Queirolo, P. Pellegrini, C. Cattaneo, L. Zawistowski, M. Gimenez-Xavier, P. Rodriguez, A. Elefanti, L. Manoukian, S. Rivoltini, L. Smith, B.H. Loizidou, M.A. Del Regno, L. Massi, D. Mandala, M. Khosrotehrani, K. Akslen, L.A. Amos, C.I. Andresen, P.A. Avril, M.-F. Azizi, E. Soyer, H.P. Bataille, V. Dalmasso, B. Bowdler, L.M. Burdon, K.P. Chen, W.V. Codd, V. Craig, J.E. Dębniak, T. Falchi, M. Fang, S. Friedman, E. Simi, S. Galan, P. Garcia-Casado, Z. Gillanders, E.M. Gordon, S. Green, A. Gruis, N.A. Hansson, J. Harland, M. Harris, J. Helsing, P. Henders, A. Hočevar, M. Höiom, V. Hunter, D. Ingvar, C. Kumar, R. Lang, J. Lathrop, G.M. Lee, J.E. Li, X. Lubiński, J. Mackie, R.M. Malt, M. Malvehy, J. McAloney, K. Mohamdi, H. Molven, A. Moses, E.K. Neale, R.E. Novaković, S. Nyholt, D.R. Olsson, H. Orr, N. Fritsche, L.G. Puig-Butille, J.A. Qureshi, A.A. Radford-Smith, G.L. Randerson-Moor, J. Requena, C. Rowe, C. Samani, N.J. Sanna, M. Schadendorf, D. Schulze, H.-J. Simms, L.A. Smithers, M. Song, F. Swerdlow, A.J. van der Stoep, N. Kukutsch, N.A. Visconti, A. Wallace, L. Ward, S.V. Wheeler, L. Sturm, R.A. Hutchinson, A. Jones, K. Malasky, M. Vogt, A. Zhou, W. Pooley, K.A. Elder, D.E. Han, J. Hicks, B. Hayward, N.K. Kanetsky, P.A. Brummett, C. Montgomery, G.W. Olsen, C.M. Hayward, C. Dunning, A.M. Martin, N.G. Evangelou, E. Mann, G.J. Long, G. Pharoah, P.D.P. Easton, D.F. Barrett, J.H. Cust, A.E. Abecasis, G. Duffy, D.L. Whiteman, D.C. Gogas, H. De Nicolo, A. Tucker, M.A. Newton-Bishop, J.A. Peris, K. Chanock, S.J. Demenais, F. Brown, K.M. Puig, S. Nagore, E. Shi, J. Iles, M.M. Law, M.H. GenoMEL Consortium Q-MEGA QTWIN Investigators ATHENS Melanoma Study Group 23andMe The SDH S

Abstract

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10−8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis. © 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Published
2020

12. Massively parallel reporter assays of melanoma risk variants identify MX2 as a gene promoting melanoma

Author

Choi, Jiyeon, Zhang, Tongwu, Vu, Andrew, Ablain, Julien, Makowski, M.M., Colli, Leandro M., Grawe, Cathrin, Vermeulen, Michiel, Zon, Leonard, I, Brown, K.M., Choi, Jiyeon, Zhang, Tongwu, Vu, Andrew, Ablain, Julien, Makowski, M.M., Colli, Leandro M., Grawe, Cathrin, Vermeulen, Michiel, Zon, Leonard, I, and Brown, K.M.

Abstract

Contains fulltext : 224935.pdf (publisher's version ) (Open Access)

Published
2020

13. 2DEG base hot electron transistors fabricated using MBE and in situ ion beam lithography

Author

Ingram, S.G., Linfield, E.H., Brown, K.M., Jones, G.A.C., Ritchie, D.A., and Kelly, M.J.

Subjects
Molecular beams -- Methods, Microelectronics -- Research, Transistors -- Design and construction, Business, Electronics, Electronics and electrical industries
Abstract

Creation of a vertical hot electron transistor having a two-dimensional electron gas base is done with molecular beam epitaxy (MBE) and in situ focused ion beam (FIB) lithography. A combination of FIB isolation and MBE regrowth is employed to solve problems of forming selective ohmic contacts. This research will contribute towards super fast unipolar transistors which might run at room temperature.

Published
1995

16. Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways (vol 9, 4774, 2018)

Author

Duffy, D.L., Zhu, G., Li, X., Sanna, M., Iles, M.M., Jacobs, L.C., Evans, D.M., Yazar, S., Beesley, J., Law, M.H., Kraft, P., Visconti, A., Taylor, J.C., Liu, F., Wright, M.J., Henders, A.K., Bowdler, L., Glass, D., Ikram, M.A., Uitterlinden, A.G., Madden, P.A., Heath, A.C., Nelson, E.C., Green, A.C., Chanock, S., Barrett, J.H., Brown, M.A., Hayward, N.K., MacGregor, S., Sturm, R.A., Hewitt, A.W., Kayser, M., Hunter, D.J., Bishop, J.A.N., Spector, T.D., Montgomery, G.W., Mackey, D.A., Smith, G.D., Nijsten, T.E., Bishop, D.T., Bataille, V., Falchi, M., Han, J., Martin, N.G., Lee, J.E., Brossard, M., Moses, E.K., Song, F., Kumar, R., Easton, D.F., Pharoah, P.D.P., Swerdlow, A.J., Kypreou, K.P., Harland, M., Randerson-Moor, J., Akslen, L.A., Andresen, P.A., Avril, M.F., Azizi, E., Scarra, G.B., Brown, K.M., Debniak, T., Elder, D.E., Fang, S.Y., Friedman, E., Galan, P., Ghiorzo, P., Gillanders, E.M., Goldstein, A.M., Gruis, N.A., Hansson, J., Helsing, P., Hocevar, M., Hoiom, V., Ingvar, C., Kanetsky, P.A., Chen, W.V., Landi, M.T., Lang, J., Lathrop, G.M., Lubinski, J., Mackie, R.M., Mann, G.J., Molven, A., Novakovic, S., Olsson, H., Puig, S., Puig-Butille, J.A., Radford-Smith, G.L., Stoep, N. van der, Doorn, R. van, Whiteman, D.C., Craig, J.E., Schadendorf, D., Simms, L.A., Burdon, K.P., Nyholt, D.R., Pooley, K.A., Orr, N., Stratigos, A.J., Cust, A.E., Ward, S.V., Schulze, H.J., Dunning, A.M., Demenais, F., Amos, C.I., and Melanoma GWAS Consortium

Published
2019

19. A Summary of ODP Leg 141 Hydrogeologic, Geochemical, and Thermal Results

Author

Brown, K.M., primary, Bangs, N., additional, Marsaglia, K., additional, Froelich, P.N., additional, Zheng, Y., additional, Didyk, B.M., additional, Prior, D., additional, Rochford, E.L., additional, Torres, M.E., additional, Kurnosov, V.B., additional, Lindsley-Griffin, N., additional, Osozawa, S., additional, and Waseda, A., additional

Published
1995
Full Text
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27. Combining common genetic variants and non-genetic risk factors to predict risk of cutaneous melanoma

Author

Gu, F. Chen, T.-H. Pfeiffer, R.M. Fargnoli, M.C. Calista, D. Ghiorzo, P. Peris, K. Puig, S. Menin, C. De Nicolo, A. Rodolfo, M. Pellegrini, C. Pastorino, L. Evangelou, E. Zhang, T. Hua, X. DellaValle, C.T. Timothy Bishop, D. MacGregor, S. Iles, M.I. Law, M.H. Cust, A. Brown, K.M. Stratigos, A.J. Nagore, E. Chanock, S. Shi, J. Consortium, M.M.-A. Consortium, M. Landi, M.T.

Abstract

Melanoma heritability is among the highest for cancer and single nucleotide polymorphisms (SNPs) contribute to it. To date, only SNPs that reached statistical significance in genome-wide association studies or few candidate SNPs have been included in melanoma risk prediction models. We compared four approaches for building polygenic risk scores (PRS) using 12 874 melanoma cases and 23 203 controls from Melanoma Meta-Analysis Consortium as a training set, and newly genotyped 3102 cases and 2301 controls from the MelaNostrum consortium for validation. We estimated adjusted odds ratios (ORs) for melanoma risk using traditional melanoma risk factors and the PRS with the largest area under the receiver operator characteristics curve (AUC). We estimated absolute risks combining the PRS and other risk factors, with age- and sex-specific melanoma incidence and competing mortality rates from Italy as an example. The best PRS, including 204 SNPs (AUC = 64.4%; 95% confidence interval (CI) = 63-65.8%), developed using winner's curse estimate corrections, had a per-quintile OR = 1.35 (95% CI = 1.30-1.41), corresponding to a 3.33-fold increase comparing the 5th to the 1st PRS quintile. The AUC improvement by adding the PRS was up to 7%, depending on adjusted factors and country. The 20-year absolute risk estimates based on the PRS, nevus count and pigmentation characteristics for a 60-year-old Italian man ranged from 0.5 to 11.8% (relative risk = 26.34), indicating good separation. © 2018 Lippincott Williams and Wilkins.All Rights Reserved.

Published
2018

28. Germline TERT promoter mutations are rare in familial melanoma

Author

Harland, M., Petljak, M., Robles-Espinoza, C.D., Ding, Z.H., Gruis, N.A., Doorn, R. van, Pooley, K.A., Dunning, A.M., Aoude, L.G., Wadt, K.A.W., Gerdes, A.M., Brown, K.M., Hayward, N.K., Newton-Bishop, J.A., Adams, D.J., Bishop, D.T., Petljak, M, Robles-Espinoza, CD, Ding, Z, Gruis, NA, van Doorn, R, Pooley, KA, Dunning, AM, Aoude, LG, Wadt, KAW, Gerdes, A-M, Brown, KM, Hayward, N, Newton-Bishop, JA, Adams, DJ, Bishop, DT, Pooley, Karen [0000-0002-1274-9460], Dunning, Alison [0000-0001-6651-7166], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Cancer Research, Skin Neoplasms, TERT, Polymerase Chain Reaction, Pedigree, Young Adult, Familial, Oncology, Genetic, Mutation, Genetics, Humans, Female, Genetic Predisposition to Disease, Genetics(clinical), Promoter Regions, Genetic, Telomerase, Melanoma, Germ-Line Mutation
Abstract

Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP, POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.-57 T>G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated in carriers. The c.-57 T>G TERT promoter variant was identified in one 7-case family with multiple primaries and early age of onset (earliest, 15 years) but not among population cases or controls. One family member had multiple primary melanomas, basal cell carcinomas and a bladder tumour. The blood leukocyte telomere length of a carrier was similar to wild-type cases. We provide evidence confirming that a rare promoter variant of TERT (c.-57 T>G) is associated with high penetrance, early onset melanoma and potentially other cancers, and explains

Published
2016

30. SDHD promoter mutations ablate GABP transcription factor binding in melanoma

Author

Zhang, T., Xu, M., Makowski, M.M., Lee, C., Kovacs, M., Fang, J., Willems, E., Trent, J.M., Hayward, N.K., Vermeulen, M., Brown, K.M., Zhang, T., Xu, M., Makowski, M.M., Lee, C., Kovacs, M., Fang, J., Willems, E., Trent, J.M., Hayward, N.K., Vermeulen, M., and Brown, K.M.

Abstract

Contains fulltext : 168904.pdf (publisher's version ) (Closed access)

Published
2017

32. A common intronic variant of PARP1 confers melanoma risk and mediates melanocyte growth via regulation of MITF

Author

Choi, J.Y., Xu, M., Makowski, M.M., Zhang, T.W., Law, M.H., Kovacs, M.A., Granzhan, A., Kim, W.D.J., Parikh, H., Gartside, M., Trent, J.M., Teulade-Fichou, M.P., Iles, M.M., Newton-Bishop, J.A., Bishop, D.T., MacGregor, S., Hayward, N.K., Vermeulen, M., Brown, K.M., Choi, J.Y., Xu, M., Makowski, M.M., Zhang, T.W., Law, M.H., Kovacs, M.A., Granzhan, A., Kim, W.D.J., Parikh, H., Gartside, M., Trent, J.M., Teulade-Fichou, M.P., Iles, M.M., Newton-Bishop, J.A., Bishop, D.T., MacGregor, S., Hayward, N.K., Vermeulen, M., and Brown, K.M.

Abstract

Contains fulltext : 177722.pdf (publisher's version ) (Closed access)

Published
2017

33. Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Author

Fang, J. (Jun), Jia, J. (Jinping), Makowski, M. (Matthew), Xu, M. (Mai), Wang, Z. (Zhaoming), Zhang, T. (Tongwu), Hoskins, J.W. (Jason W.), Choi, J. (Jiyeon), Han, Y. (Younghun), Zhang, M. (Mingfeng), Thomas, J. (Janelle), Kovacs, M. (Michael), Collins, I. (Irene), Dzyadyk, M. (Marta), Thompson, A. (Abbey), O'Neill, M. (Maura), Das, S. (Sudipto), Lan, Q. (Qi), Koster, R. (Roelof), Stolzenberg-Solomon, R.S. (Rachael S.), Kraft, P. (Peter), Wolpin, B.M. (Brian M.), Jansen, P., Olson, S. (Sara), McGlynn, K.A., Kanetsky, P.P. (Peter P.), Chatterjee, N. (Nilanjan), Barrett, J.H. (Jennifer H.), Dunning, A.M. (Alison), Taylor, J.C. (John C.), Newton Bishop, J.A. (Julia), Timothy Bishop, D. (D.), Andresson, T. (Thorkell), Petersen, G.M. (Gloria M.), Amos, W., Iles, M.M. (Mark M.), Nathanson, K.L. (Katherine), Landi, M.T. (Maria Teresa), Vermeulen, M. (Michiel), Brown, K.M. (Kevin M.), Amundadottir, L.T. (Laufey T.), Fang, J. (Jun), Jia, J. (Jinping), Makowski, M. (Matthew), Xu, M. (Mai), Wang, Z. (Zhaoming), Zhang, T. (Tongwu), Hoskins, J.W. (Jason W.), Choi, J. (Jiyeon), Han, Y. (Younghun), Zhang, M. (Mingfeng), Thomas, J. (Janelle), Kovacs, M. (Michael), Collins, I. (Irene), Dzyadyk, M. (Marta), Thompson, A. (Abbey), O'Neill, M. (Maura), Das, S. (Sudipto), Lan, Q. (Qi), Koster, R. (Roelof), Stolzenberg-Solomon, R.S. (Rachael S.), Kraft, P. (Peter), Wolpin, B.M. (Brian M.), Jansen, P., Olson, S. (Sara), McGlynn, K.A., Kanetsky, P.P. (Peter P.), Chatterjee, N. (Nilanjan), Barrett, J.H. (Jennifer H.), Dunning, A.M. (Alison), Taylor, J.C. (John C.), Newton Bishop, J.A. (Julia), Timothy Bishop, D. (D.), Andresson, T. (Thorkell), Petersen, G.M. (Gloria M.), Amos, W., Iles, M.M. (Mark M.), Nathanson, K.L. (Katherine), Landi, M.T. (Maria Teresa), Vermeulen, M. (Michiel), Brown, K.M. (Kevin M.), and Amundadottir, L.T. (Laufey T.)

Abstract

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365- C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele.

Published
2017
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41. Genome-wide association study identifies novel loci predisposing to cutaneous melanoma

Author

Amos, C.I., Wang, L.E., Lee, J.E., Gershenwald, J.E., Chen, W.V., Fang, S.Y., Kosoy, R., Zhang, M.F., Qureshi, A.A., Vattathil, S., Schacherer, C.W., Gardner, J.M., Wang, Y.L., Bishop, D.T., Barrett, J.H., MacGregor, S., Hayward, N.K., Martin, N.G., Duffy, D.L., Mann, G.J., Cust, A., Hopper, J., Brown, K.M., Grimm, E.A., Xu, Y.J., Han, Y.H., Jing, K.Y., McHugh, C., Laurie, C.C., Doheny, K.F., Pugh, E.W., Seldin, M.F., Han, J.L., Wei, Q.Y., GenoMEL Investigators, Q-Mega Investigators, and AMFS Investigators

Published
2011

42. Genome-wide association study identifies three new melanoma susceptibility loci

Author

Barrett, J.H., Iles, M.M., Harland, M., Taylor, J.C., Aitken, J.F., Andresen, P.A., Akslen, L.A., Armstrong, B.K., Avril, M.F., Azizi, E., Bakker, B., Bergman, W., Bianchi-Scarra, G., Bressac-de Paillerets, B., Calista, D., Cannon-Albright, L.A., Corda, E., Cust, A.E., Debniak, T., Duffy, D., Dunning, A.M., Easton, D.F., Friedman, E., Galan, P., Ghiorzo, P., Giles, G.G., Hansson, J., Hocevar, M., Hoiom, V., Hopper, J.L., Ingvar, C., Janssen, B., Jenkins, M.A., Jonsson, G., Kefford, R.F., Landi, G., Landi, M.T., Lang, J., Lubinski, J., Mackie, R., Malvehy, J., Martin, N.G., Molven, A., Montgomery, G.W., Nieuwpoort, F.A. van, Novakovic, S., Olsson, H., Pastorino, L., Puig, S., Puig-Butille, J.A., Randerson-Moor, J., Snowden, H., Tuominen, R., VanBelle, P., Stoep, N. van der, Whiteman, D.C., Zelenika, D., Han, J.L., Fang, S.Y., Lee, J.E., Wei, Q.Y., Lathrop, G.M., Gillanders, E.M., Brown, K.M., Goldstein, A.M., Kanetsky, P.A., Mann, G.J., MacGregor, S., Elder, D.E., Amos, C.I., Hayward, N.K., Gruis, N.A., Demenais, F., Bishop, J.A.N., Bishop, D.T., and GenoMEL Consortium

Published
2011

43. Genome-wide association study identifies three loci associated with melanoma risk

Author

Bishop, D.T., Demenais, F., Iles, M.M., Harland, M., Taylor, J.C., Corda, E., Randerson-Moor, J., Aitken, J.F, Avril, M.-F., Azizi, E., Bakker, B., Bianchi-Scarrà, G., Bressac-de Paillerets, B., Calista, D., Cannon-Albright, L.A., Chin-A-Woeng, T., Dębniak, T., Galore-Haskel, G., Ghiorzo, P., Gut, I., Hansson, J., Hočevar, M., Höiom, V., Hopper, J.L., Ingvar, C., Kanetsky, P.A., Kefford, R.F., Landi, M.T., Lang, J., Lubiński, J., Mackie, R., Malvehy, J., Mann, G.J., Martin, N.G., Montgomery, G.W., van Nieuwpoort, F.A., Novakovic, S., Olsson, H., Puig, S., Weiss, M., van Workum, W., Zelenika, D., Brown, K.M., Goldstein, A.M., Gillanders, E.M., Boland, A., Galan, P., Elder, D.E., Gruis, N.A., Hayward, N.K., Lathrop, G.M., Barrett, J.H., and Newton Bishop, J.A.

Subjects
RC0254
Abstract

We report a genome-wide association study of melanoma conducted by the GenoMEL consortium based on 317K tagging SNPs for 1,650 selected cases and 4,336 controls, with replication in an additional two cohorts (1,149 selected cases and 964 controls from GenoMEL, and a population-based case-control study in Leeds of 1,163 cases and 903 controls). The genome-wide screen identified five loci with genotyped or imputed SNPs reaching P < 5 times 10-7. Three of these loci were replicated: 16q24 encompassing MC1R (combined P = 2.54 times 10-27 for rs258322), 11q14-q21 encompassing TYR (P = 2.41 times 10-14 for rs1393350) and 9p21 adjacent to MTAP and flanking CDKN2A (P = 4.03 times 10-7 for rs7023329). MC1R and TYR are associated with pigmentation, freckling and cutaneous sun sensitivity, well-recognized melanoma risk factors. Common variants within the 9p21 locus have not previously been associated with melanoma. Despite wide variation in allele frequency, these genetic variants show notable homogeneity of effect across populations of European ancestry living at different latitudes and show independent association to disease risk.

Published
2009

45. Levetiracetam reduces spike-wave density and duration during continuous EEG monitoring in patients with idiopathic generalized epilepsy

Author

Gallagher, M.J., Eisenman, L.N., Brown, K.M., Erbayat-Altay, E., Hecimović, Hrvoje, Fessler, A.J., Attarian, H.P., and Gilliam, F.G.

Subjects
Levetiracetam, continuous EEG monitoring, idiopathic generalized epilepsy
Abstract

Levetiracetam reduces spike-wave density and duration during continuous EEG monitoring in patients with idiopathic generalized epilepsy.

Published
2004

46. A recurrent germlineBAP1mutation and extension of theBAP1tumor predisposition spectrum to include basal cell carcinoma

Author

Wadt, K.A.W., primary, Aoude, L.G., additional, Johansson, P., additional, Solinas, A., additional, Pritchard, A., additional, Crainic, O., additional, Andersen, M.T., additional, Kiilgaard, J.F., additional, Heegaard, S., additional, Sunde, L., additional, Federspiel, B., additional, Madore, J., additional, Thompson, J.F., additional, McCarthy, S.W., additional, Goodwin, A., additional, Tsao, H., additional, Jönsson, G., additional, Busam, K., additional, Gupta, R., additional, Trent, J.M., additional, Gerdes, A.-M., additional, Brown, K.M., additional, Scolyer, R.A., additional, and Hayward, N.K., additional

Published
2014
Full Text
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48. A variant in FTO shows association with melanoma risk not due to BMI

Author

Iles, M.M., Law, M.H., Stacey, S.N., Han, J., Fang, S., Pfeiffer, R., Harland, M., MacGregor, S., Taylor, J.C., Aben, K.K.H., Akslen, L.A., Avril, M.F., Azizi, E., Bakker, B., Benediktsdottir, K.R., Bergman, W., Scarra, G.B., Brown, K.M., Calista, D., Chaudru, V., Fargnoli, M.C., Cust, A.E., Demenais, F., Waal, A.C. de, Debniak, T., Elder, D.E., Friedman, E., Galan, P., Ghiorzo, P., Gillanders, E.M., Goldstein, A.M., Gruis, N.A., Hansson, J., Helsing, P., Hocevar, M., Hoiom, V., Hopper, J.L., Ingvar, C., Janssen, M., Jenkins, M.A., Kanetsky, P.A., Kiemeney, L.A.L.M., Lang, J., Lathrop, G.M., Leachman, S., Lee, J.E., Lubinski, J., Mackie, R.M., Mann, G.J., Martin, N.G., Mayordomo, J.I., Molven, A., Mulder, S., Nagore, E., Novakovic, S., Okamoto, I., Olafsson, J.H., Olsson, H., Pehamberger, H., Peris, K., Grasa, M.P., Planelles, D., Puig, S., Puig-Butille, J.A., Randerson-Moor, J., Requena, C., Rivoltini, L., Rodolfo, M., Santinami, M., Sigurgeirsson, B., Snowden, H., Song, F., Sulem, P., Thorisdottir, K., Tuominen, R., Belle, P. Van, Stoep, N. van der, Rossum, M.M. van, Wei, Q., Wendt, J., Zelenika, D., Zhang, M., Landi, M.T., Thorleifsson, G., Bishop, D.T., Amos, C.I., Hayward, N.K., Stefansson, K., Bishop, J.A., Barrett, J.H., et al., Iles, M.M., Law, M.H., Stacey, S.N., Han, J., Fang, S., Pfeiffer, R., Harland, M., MacGregor, S., Taylor, J.C., Aben, K.K.H., Akslen, L.A., Avril, M.F., Azizi, E., Bakker, B., Benediktsdottir, K.R., Bergman, W., Scarra, G.B., Brown, K.M., Calista, D., Chaudru, V., Fargnoli, M.C., Cust, A.E., Demenais, F., Waal, A.C. de, Debniak, T., Elder, D.E., Friedman, E., Galan, P., Ghiorzo, P., Gillanders, E.M., Goldstein, A.M., Gruis, N.A., Hansson, J., Helsing, P., Hocevar, M., Hoiom, V., Hopper, J.L., Ingvar, C., Janssen, M., Jenkins, M.A., Kanetsky, P.A., Kiemeney, L.A.L.M., Lang, J., Lathrop, G.M., Leachman, S., Lee, J.E., Lubinski, J., Mackie, R.M., Mann, G.J., Martin, N.G., Mayordomo, J.I., Molven, A., Mulder, S., Nagore, E., Novakovic, S., Okamoto, I., Olafsson, J.H., Olsson, H., Pehamberger, H., Peris, K., Grasa, M.P., Planelles, D., Puig, S., Puig-Butille, J.A., Randerson-Moor, J., Requena, C., Rivoltini, L., Rodolfo, M., Santinami, M., Sigurgeirsson, B., Snowden, H., Song, F., Sulem, P., Thorisdottir, K., Tuominen, R., Belle, P. Van, Stoep, N. van der, Rossum, M.M. van, Wei, Q., Wendt, J., Zelenika, D., Zhang, M., Landi, M.T., Thorleifsson, G., Bishop, D.T., Amos, C.I., Hayward, N.K., Stefansson, K., Bishop, J.A., Barrett, J.H., and et al.

Abstract

Contains fulltext : 118658.pdf (publisher's version ) (Closed access), We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 x 10(-12), per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanoma-susceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.

Published
2013

49. A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma.

Author

Wadt, K., Choi, J., Chung, J.Y., Kiilgaard, Jens Folke, Heegaard, Steffen, Drzewiecki, Krzysztof Tadeusz M, Trent, J.M., Hewitt, S.M., Hayward, N.K., Gerdes, Anne-Marie Axø, Brown, K.M., Wadt, K., Choi, J., Chung, J.Y., Kiilgaard, Jens Folke, Heegaard, Steffen, Drzewiecki, Krzysztof Tadeusz M, Trent, J.M., Hewitt, S.M., Hayward, N.K., Gerdes, Anne-Marie Axø, and Brown, K.M.

Published
2012

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