72 results on '"Randerson-Moor J"'
Search Results
2. HFE Genotype Modifies the Influence of Heme Iron Intake on Iron Status
- Author
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Greenwood, D. C., Cade, J. E., Moreton, J. A., O'Hara, B., Burley, V. J., Randerson-Moor, J. A., Kukalizch, K., Thompson, D., Worwood, M., and Bishop, D. T.
- Published
- 2005
- Full Text
- View/download PDF
3. Overlapping genetic architecture between Parkinson disease and melanoma
- Author
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Dube, Umber Ibanez, Laura Budde, John P. Benitez, Bruno A. and Davis, Albert A. Harari, Oscar Iles, Mark M. Law, Matthew H. Brown, Kevin M. Agee, Michelle Alipanahi, Babak and Auton, Adam Bell, Robert K. Bryc, Katarzyna Elson, Sarah L. Fontanillas, Pierre Furlotte, Nicholas A. Hinds, David A. and Huber, Karen E. Kleinman, Aaron Litterman, Nadia K. and McCreight, Jennifer C. McIntyre, Matthew H. Mountain, Joanna L. and Noblin, Elizabeth S. Northover, Carrie A. M. Pitts, Steven J. Sathirapongsasuti, J. Fah Sazonova, Olga V. Shelton, Janie F. Shringarpure, Suyash Tian, Chao Tung, Joyce Y. and Vacic, Vladimir Wilson, Catherine H. Law, M. H. Law, M. H. and Bishop, D. T. Lee, J. E. Brossard, M. Martin, N. G. and Moses, E. K. Song, F. Barrett, J. H. Kumar, R. Easton, D. F. Pharoah, P. D. Swerdlow, A. J. Kypreou, K. P. and Taylor, J. C. Harland, M. Randerson-Moor, J. Akslen, L. A. and Andresen, P. A. Avril, M. F. Azizi, E. Scarra, G. B. and Brown, K. M. Debniak, T. Duffy, D. L. Elder, D. E. Fang, S. Friedman, E. Galan, P. Ghiorzo, P. Gillanders, E. M. and Goldstein, A. M. Gruis, N. A. Hansson, J. Helsing, P. and Hocevar, M. Hoiom, V. Ingvar, C. Kanetsky, P. A. and Chen, W. V. Landi, M. T. Lang, J. Lathrop, G. M. and Lubinski, J. Mackie, R. M. Mann, G. J. Molven, A. and Montgomery, G. W. Novakovic, S. Olsson, H. Puig, S. and Puig-Butille, J. A. Wu, W. Qureshi, A. A. Radford-Smith, G. L. Van der Stoep, N. Van Doorn, R. Whiteman, D. C. and Craig, J. E. Schadendorf, E. Simms, L. A. Burdon, K. P. and Nyholt, D. R. Pooley, K. A. Orr, N. Stratigos, A. J. and Cust, A. E. Ward, S. V. Hayward, N. K. Han, J. Schulze, H. J. Dunning, A. M. Bishop, J. A. Demenais, F. Amos, C. I. MacGregor, S. Iles, M. M. Cruchaga, Carlos 23andMe Research Team Melanoma Meta Analysis Consortium
- Abstract
Epidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here, we apply polygenic, linkage disequilibrium-informed methods to the largest available case-control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10-0.24; P = 4.09 x 10(-06)) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22; P = 7.87 x 10(-04)) and highlight seven genes including PIEZO1, TRAPPC2L, and SOX6 as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression.
- Published
- 2020
4. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility
- Author
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Landi MT, Bishop DT, MacGregor S, Machiela MJ, Stratigos AJ, Ghiorzo P, Brossard M, Calista D, Choi J, Fargnoli MC, Zhang T, Rodolfo M, Trower AJ, Menin C, Martinez J, Hadjisavvas A, Song L, Stefanaki I, Scolyer R, Yang R, Goldstein AM, Potrony M, Kypreou KP, Pastorino L, Queirolo P, Pellegrini C, Cattaneo L, Zawistowski M, Gimenez-Xavier P, Rodriguez A, Elefanti L, Manoukian S, Rivoltini L, Smith BH, Loizidou MA, Del Regno L, Massi D, Mandala M, Khosrotehrani K, Akslen LA, Amos CI, Andresen PA, Avril MF, Azizi E, Soyer HP, Bataille V, Dalmasso B, Bowdler LM, Burdon KP, Chen WV, Codd V, Craig JE, Debniak T, Falchi M, Fang S, Friedman E, Simi S, Galan P, Garcia-Casado Z, Gillanders EM, Gordon S, Green A, Gruis NA, Hansson J, Harland M, Harris J, Helsing P, Henders A, Hocevar M, Höiom V, Hunter D, Ingvar C, Kumar R, Lang J, Lathrop GM, Lee JE, Li X, Lubinski J, Mackie RM, Malt M, Malvehy J, McAloney K, Mohamdi H, Molven A, Moses EK, Neale RE, Novakovic S, Nyholt DR, Olsson H, Orr N, Fritsche LG, Puig-Butille JA, Qureshi AA, Radford-Smith GL, Randerson-Moor J, Requena C, Rowe C, Samani NJ, Sanna M, Schadendorf D, Schulze HJ, Simms LA, Smithers M, Song F, Swerdlow AJ, van der Stoep N, Kukutsch NA, Visconti A, Wallace L, Ward SV, Wheeler L, Sturm RA, Hutchinson A, Jones K, Malasky M, Vogt A, Zhou W, Pooley KA, Elder DE, Han J, Hicks B, Hayward NK, Kanetsky PA, Brummett C, Montgomery GW, Olsen CM, Hayward C, Dunning AM, Martin NG, Evangelou E, Mann GJ, Long G, Pharoah PDP, Easton DF, Barrett JH, Cust AE, Abecasis G, Duffy DL, Whiteman DC, Gogas H, De Nicolo A, Tucker MA, Newton-Bishop JA, GenoMEL Consortium, Q-MEGA and QTWIN Investigators, ATHENS Melanoma Study Group, 23andMe, SDH Study Group, IBD Investigators, Essen-Heidelberg Investigators, AMFS Investigators, MelaNostrum Consortium, Peris K, Chanock SJ, Demenais F, Brown KM, Puig S, Nagore E, Shi J, Iles MM, and Law MH
- Abstract
Meta-analysis of 36,760 cases and 375,188 controls identifies 54 loci associated with susceptibility to cutaneous melanoma. Further analysis combining nevus count and hair color GWAS results provide insights into the genetic architecture of melanoma. 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 x 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.
- Published
- 2020
5. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility
- Author
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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
6. Association of MC1R Variants and Host Phenotypes With Melanoma Risk in CDKN2A Mutation Carriers: A GenoMEL Study
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Demenais, F., Mohamdi, H., Chaudru, V., Goldstein, A. M., Newton Bishop, J. A., Bishop, D. T., Kanetsky, P. A., Hayward, N. K., Gillanders, E., Elder, D. E., Avril, M. F., Azizi, E., van Belle, P., Bergman, W., Bianchi-Scarrà, G., Bressac-de Paillerets, B., Calista, D., Carrera, C., Hansson, J., Harland, M., Hogg, D., Höiom, V., Holland, E. A., Ingvar, C., Landi, M. T., Lang, J. M., Mackie, R. M., Mann, G. J., Ming, M. E., Njauw, C. J., Olsson, H., Palmer, J., Pastorino, L., Puig, S., Randerson-Moor, J., Stark, M., Tsao, H., Tucker, M. A., van der Velden, P., Yang, X. R., and Gruis, N.
- Published
- 2010
- Full Text
- View/download PDF
7. Overlapping genetic architecture between Parkinson disease and melanoma
- Author
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Dube, U., Ibanez, L., Budde, J. P., Benitez, B. A., Davis, A. A., Harari, O., Iles, M. M., Law, M. H., Brown, K. M., Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., Mccreight, J. C., Mcintyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A. M., Pitts, S. J., Sathirapongsasuti, J. F., Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Bishop, D. T., Lee, J. E., Brossard, M., Martin, N. G., Moses, E. K., Song, F., Barrett, J. H., Kumar, R., Easton, D. F., Pharoah, P. D., Swerdlow, A. J., Kypreou, K. P., Taylor, J. C., Harland, M., Randerson-Moor, J., Akslen, L. A., Andresen, P. A., Avril, M. F., Azizi, E., Scarra, G. B., Debniak, T., Duffy, D. L., Elder, D. E., Fang, S., 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., Montgomery, G. W., Novakovic, S., Olsson, H., Puig, S., Puig-Butille, J. A., Wu, W., Qureshi, A. A., Radford-Smith, G. L., van der Stoep, N., van Doorn, R., Whiteman, D. C., Craig, J. E., Schadendorf, E., Simms, L. A., Burdon, K. P., Nyholt, D. R., Pooley, K. A., Orr, N., Stratigos, A. J., Cust, A. E., Ward, S. V., Hayward, N. K., Han, J., Schulze, H. J., Dunning, A. M., Bishop, J. A., Demenais, F., Amos, C. I., Macgregor, S., and Cruchaga, C.
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Genetic correlation ,Multifactorial Inheritance ,Skin Neoplasms ,Medizin ,TWAS ,Disease ,Melanoma ,Parkinson disease ,Polygenic ,Shared genetic architecture ,Pathology and Forensic Medicine ,Correlation ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Internal medicine ,Gene expression ,Medicine ,Humans ,Gene ,business.industry ,Parkinson Disease ,medicine.disease ,Genetic architecture ,030104 developmental biology ,Case-Control Studies ,Cutaneous melanoma ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Epidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here, we apply polygenic, linkage disequilibrium-informed methods to the largest available case-control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10-0.24; P = 4.09 x 10(-06)) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22; P = 7.87 x 10(-04)) and highlight seven genes including PIEZO1, TRAPPC2L, and SOX6 as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression.
- Published
- 2019
8. High-Resolution Copy Number Patterns From Clinically Relevant FFPE Material
- Author
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Filia, A, Droop, A, Harland, M, Thygesen, H, Randerson-Moor, J, Snowden, H, Taylor, C, Diaz, JMS, Pozniak, J, Nsengimana, J, Laye, J, Newton-Bishop, JA, and Bishop, DT
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Paraffin Embedding ,Tissue Fixation ,Science & Technology ,Molecular medicine ,DNA Copy Number Variations ,IDENTIFICATION ,MUTATIONS ,lcsh:R ,High-Throughput Nucleotide Sequencing ,Reproducibility of Results ,lcsh:Medicine ,MELANOMA ,AMPLIFICATION ,Article ,VALIDATION ,Multidisciplinary Sciences ,GENOME ,Neoplasms ,Humans ,Science & Technology - Other Topics ,TOOL ,lcsh:Q ,lcsh:Science ,Melanoma ,Cancer - Abstract
Systematic tumour profiling is essential for biomarker research and clinically for assessing response to therapy. Solving the challenge of delivering informative copy number (CN) profiles from formalin-fixed paraffin embedded (FFPE) material, the only likely readily available biospecimen for most cancers, involves successful processing of small quantities of degraded DNA. To investigate the potential for analysis of such lesions, whole-genome CNVseq was applied to 300 FFPE primary tumour samples, obtained from a large-scale epidemiological study of melanoma. The quality and the discriminatory power of CNVseq was assessed. Libraries were successfully generated for 93% of blocks, with input DNA quantity being the only predictor of success (success rate dropped to 65% if
- Published
- 2019
9. Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways (vol 9, 4774, 2018)
- Author
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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
10. Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways
- Author
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Duffy, David L, Zhu, Gu, Xin, Li, Sanna, Marianna, Iles, Mark M, Jacobs, Leonie C, Evans, David M, Yazar, Seyhan, Beesley, Jonathan, Law, Matthew H, Kraft, Peter, Visconti, Alessia, Taylor, John C, Lui, Fan, Wright, Margaret J, Henders, Anjali K, Bowdler, Lisa, Glass, Dan, Ikram, Arfan M, Uitterlinden, André G, Madden, Pamela A, Heath, Andrew C, Nelson, Elliot C, Green, Adele C, Chanock, Stephen, Barrett, Jennifer H, Brown, Matthew A, Hayward, Nicholas K, Macgregor, Stuart, Sturm, Richard A, Hewitt, Alex W, Kayser, Manfred, Hunter, David J, Newton Bishop, Julia A, Spector, Timothy D, Montgomery, Grant W, Mackey, David A, Smith, George Davey, Nijsten, Tamar E, Bishop, D Timothy, Bataille, Veronique, Falchi, Mario, Han, Jiali, Martin, Nicholas, G, Lee, Je, Brossard, M, Moses, Ek, Song, F, Kumar, R, Easton, Df, Pharoah, Pdp, Swerdlow, Aj, Kypreou, Kp, Harland, M, Randerson-Moor, J, Akslen, La, Andresen, Pa, Avril, Mf, Azizi, E, Scarrà, Gb, Brown, Km, Dębniak, T, Elder, De, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, Em, Goldstein, Am, Gruis, Na, Hansson, J, Helsing, P, Hočevar, M, Höiom, V, Ingvar, C, Kanetsky, Pa, Chen, Wv, Landi, Mt, Lang, J, Lathrop, Gm, Lubiński, J, Mackie, Rm, Mann, Gj, Molven, A, Novaković, S, Olsson, H, Puig, S, Puig-Butille, Ja, Radford-Smith, Gl, van der Stoep, N, van Doorn, R, Whiteman, Dc, Craig, Je, Schadendorf, D, Simms, La, Burdon, Kp, Nyholt, Dr, Pooley, Ka, Orr, N, Stratigos, Aj, Cust, Ae, Ward, Sv, Schulze, Hj, Dunning, Am, Demenais, F, Amos, Ci., Apollo - University of Cambridge Repository, Dermatology, Genetic Identification, Epidemiology, Internal Medicine, and Consortium, Melanoma Gwas
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0301 basic medicine ,Skin Neoplasms ,Medizin ,General Physics and Astronomy ,Genome-wide association study ,Receptors, G-Protein-Coupled ,0302 clinical medicine ,Guanine Nucleotide Exchange Factors ,lcsh:Science ,skin and connective tissue diseases ,Melanoma ,Telomerase ,Genetics ,0303 health sciences ,Nevus, Pigmented ,Stem Cell Factor ,Multidisciplinary ,Microfilament Proteins ,Nuclear Proteins ,RNA-Binding Proteins ,Genetic Pleiotropy ,Microphthalmia-associated transcription factor ,3. Good health ,030220 oncology & carcinogenesis ,Cytochrome P-450 CYP1B1 ,Interferon Regulatory Factors ,Medical genetics ,PPARGC1B ,Dock8 ,medicine.medical_specialty ,Science ,Telomere-Binding Proteins ,Single-nucleotide polymorphism ,Nerve Tissue Proteins ,Biology ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Histone Deacetylases ,White People ,Group VI Phospholipases A2 ,03 medical and health sciences ,Genetic predisposition ,Pigmented Nevus ,medicine ,Nevus ,Humans ,Genetic Predisposition to Disease ,neoplasms ,030304 developmental biology ,General Chemistry ,medicine.disease ,Repressor Proteins ,MicroRNAs ,030104 developmental biology ,Cutaneous melanoma ,RNA ,lcsh:Q ,Carrier Proteins ,IRF4 ,Genome-Wide Association Study - Abstract
The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, United Kingdom, and United States, comprising a total of 52,506 phenotyped individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs at a genome-wide level of significance in KITLG, DOCK8, and a broad region of 9q32. In a bivariate analysis combining the nevus results with those from a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level of significance. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis via genes we can show to be expressed under control of the MITF melanocytic cell lineage regulator.
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- 2018
11. Cell-type–specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes
- Author
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Zhang, Tongwu, Choi, Jiyeon, Kovacs, Michael A., Shi, Jianxin, Mai, Xu, Goldstein, Alisa M., Trower, Adam J., Bishop, D. Timothy, Iles, Mark M., Duffy, David L., Macgregor, Stuart, Amundadottir, Laufey T., Law, Matthew H., Loftus, Stacie K., Pavan, William J., Brown, Kevin M., Lee, Je, Brossard, M, Martin, Ng, Moses, Ek, Song, F, Barrett, Jh, Kumar, R, Easton, Df, Pharoah, Pdp, Swerdlow, Aj, Kypreou, Kp, Taylor, Jc, Harland, M, Randerson-Moor, J, Akslen, La, Andresen, Pa, Avril, Mf, Azizi, E, Bianchi Scarrà, G, Dȩbniak, T, Duffy, Dl, Elder, De, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, Em, Goldstein, Am, Gruis, Na, Hansson, J, Helsing, P, Hočevar, M, Höiom, V, Ingvar, C, Kanetsky, Pa, Chen, Wv, Landi, Mt, Lang, J, Lathrop, Gm, Lubiński, J, Mackie, Rm, Mann, Gj, Molven, A, Montgomery, Gw, Novaković, S, Olsson, H, Puig, S, Puig-Butille, Ja, Wu, W, Qureshi, Aa, Radford-Smith, Gl, van der Stoep, N, van Doorn, R, Whiteman, Dc, Craig, Je, Schadendorf, D, Simms, La, Burdon, Kp, Nyholt, Dr, Pooley, Ka, Orr, N, Stratigos, Aj, Cust, Ae, Ward, Sv, Hayward, Nk, Han, J, Schulze, Hj, Dunning, Am, Bishop, Jan, Demenais, F, Amos, Ci, Macgregor, S, Iles, Mm, Barnabas, Bb, Bouffard, Gg, Brooks, Sy, Coleman, H, Dekhtyar, L, Guan, X, Ho, Sl, Legaspi, R, Maduro, Ql, Masiello, Ca, Mcdowell, Jc, Montemayor, C, Mullikin, Jc, Park, M, Riebow, Nl, Schandler, K, Schmidt, B, Sison, C, Smith, R, Stantripop, S, Thomas, Jw, Thomas, Pj, Vemulapalli, M, and Young, Ac.
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0301 basic medicine ,Hemeproteins ,Linkage disequilibrium ,Quantitative Trait Loci ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Quantitative trait locus ,Melanocyte ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,03 medical and health sciences ,Heme-Binding Proteins ,0302 clinical medicine ,Genetics ,medicine ,Basic Helix-Loop-Helix Transcription Factors ,Humans ,Genetic Predisposition to Disease ,Melanoma ,Genetics (clinical) ,Cells, Cultured ,Genetic association ,Research ,medicine.disease ,Repressor Proteins ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Expression quantitative trait loci ,Interferon Regulatory Factors ,Melanocytes ,Carrier Proteins - Abstract
Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type–specific regulatory landscape of human melanocytes, which give rise to melanoma but account for cis-eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans-eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis-regulation of IRF4. Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant P-values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.
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- 2018
12. The Relationship Between the Epidermal Growth Factor (EGF) 5′UTR Variant A61G and Melanoma/Nevus Susceptibility
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Randerson-Moor, J. A., Gaut, R., Turner, F., Whitaker, L., Barrett, J. H., dos Santos Silva, I., Swerdlow, A., Bishop, D. T., and Newton Bishop, J. A.
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- 2004
13. β-catenin-mediated immune evasion pathway frequently operates in primary cutaneous melanomas
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Nsengimana, J, Laye, J, Filia, A, O'Shea, S, Muralidhar, S, Poźniak, J, Droop, A, Chan, M, Walker, C, Parkinson, L, Gascoyne, J, Mell, T, Polso, M, Jewell, R, Randerson-Moor, J, Cook, GP, Bishop, DT, and Newton-Bishop, J
- Abstract
Immunotherapy prolongs survival in only a subset of melanoma patients, highlighting the need to better understand the driver tumor microenvironment. We conducted bioinformatic analyses of 703 transcriptomes to probe the immune landscape of primary cutaneous melanomas in a population-ascertained cohort. We identified and validated 6 immunologically distinct subgroups, with the largest having the lowest immune scores and the poorest survival. This poor-prognosis subgroup exhibited expression profiles consistent with β-catenin–mediated failure to recruit CD141+ DCs. A second subgroup displayed an equally bad prognosis when histopathological factors were adjusted for, while 4 others maintained comparable survival profiles. The 6 subgroups were replicated in The Cancer Genome Atlas (TCGA) melanomas, where β-catenin signaling was also associated with low immune scores predominantly related to hypomethylation. The survival benefit of high immune scores was strongest in patients with double-WT tumors for BRAF and NRAS, less strong in BRAF-V600 mutants, and absent in NRAS (codons 12, 13, 61) mutants. In summary, we report evidence for a β-catenin–mediated immune evasion in 42% of melanoma primaries overall and in 73% of those with the worst outcome. We further report evidence for an interaction between oncogenic mutations and host response to melanoma, suggesting that patient stratification will improve immunotherapeutic outcomes.
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- 2018
14. Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148
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Fang, J, Jia, J, Makowski, M, Xu, M, Wang, Z, Zhang, T, Hoskins, Jw, Choi, J, Han, Y, Zhang, M, Thomas, J, Kovacs, M, Collins, I, Dzyadyk, M, Thompson, A, O'Neill, M, Das, S, Lan, Q, Koster, R, Solomon, Rs, Kraft, P, Wolpin, Bm, Jansen, Pwtc, Olson, S, Mcglynn, Ka, Kanetsky, Pa, Chatterjee, N, Barrett, Jh, Dunning, Am, Taylor, Jc, Newton Bishop, Ja, Bishop, Dt, Andresson, T, Petersen, Gm, Amos, Ci, Iles, Mm, Nathanson, Kl, Landi, Mt, Vermeulen, M, Brown, Km, Amundadottir, Lt, Canzian, F, Kooperberg, C, Arslan, Aa, Bracci, Pm, Buring, J, Duell, Ej, Gallinger, S, Jacobs, Ej, Kamineni, A, Van Den Eeden, S, Klein, Ap, Kolonel, Ln, Li, D, Olson, Sh, Risch, Ha, Sesso, Hd, Visvanathan, K, Zheng, W, Albanes, D, Austin, Ma, Boutron Ruault, Mc, Bueno de Mesquita, Hb, Cotterchio, M, Gaziano, Jm, Giovannucci, El, Goggins, M, Gross, M, Hassan, M, Helzlsouer, Kj, Holly, Ea, Hunter, Dj, Jenab, M, Kaaks, R, Key, Tj, Khaw, Kt, Krogh, V, Kurtz, Rc, Lacroix, A, Le Marchand, L, Mannisto, S, Patel, Av, Peeters, Phm, Riboli, E, Shu, Xo, Sund, M, Thornquist, M, Tjønneland, A, Tobias, Gs, Trichopoulos, D, Wactawski Wende, J, Yu, H, Yu, K, Zeleniuch Jacquotte, A, Hoover, R, Hartge, P, Fuchs, C, Chanock, Sj, Stevens, V, Caporaso, Ne, Brennan, P, Mckay, J, Wu, X, Hung, Rj, Mclaughlin, Jr, Bickeboller, H, Risch, A, Wichmann, E, Houlston, R, Mann, G, Hopper, J, Aitken, J, Armstrong, B, Giles, G, Holland, E, Kefford, R, Cust, A, Jenkins, M, Schmid, H, Puig, S, Aguilera, P, Badenas, C, Barreiro, A, Carrera, C, Gabriel, D, Xavier, Pg, Iglesias Garcia, P, Malvehy, J, Mila, M, Pigem, R, Potrony, M, Batille, Ja, Marti, Gt, Hayward, N, Martin, N, Montgomery, G, Duffy, D, Whiteman, D, Gregor, Sm, Calista, D, Landi, G, Minghetti, P, Arcangeli, F, Bertazzi, Pa, Ghiorzo, Paola, Bianchi, Giovanna, Pastorino, Lorenza, Bruno, William, Andreotti, Virginia, Queirolo, P, Spagnolo, Francesco, Mackie, R, Lang, J, Gruis, N, van Nieuwpoort, Fa, Out, C, Bergman, W, Kukutsch, N, Bavinck, Jnb, Bakker, B, van der Stoep, N, Ter Huurne, J, van der Rhee, H, Bekkenk, M, Snels, D, van Praag, M, Brochez, L, Gerritsen, R, Crijns, M, Vasen, H, Janssen, B, Ingvar, C, Olsson, H, Jonsson, G, Borg, A, Harbst, K, Nielsen, K, Zander, As, Molvern, A, Helsing, P, Andresen, Pa, Rootwelt, H, Akslen, La, Bressac de Paillerets, B, Demenais, F, Avril, Mf, Chaudru, V, Jeannin, P, Lesueur, F, Maubec, E, Mohamdi, H, Bossard, M, Vaysse, A, Boitier, F, Caron, O, Caux, F, Dalle, S, Dereure, O, Leroux, D, Martin, L, Mateus, C, Robert, C, Stoppa Lyonnet, D, Thomas, L, Wierzbicka, E, Elder, D, Ming, M, Mitra, N, Debniak, T, Lubinski, J, Hocevar, M, Novakovic, S, Peric, B, Skerl, P, Hansson, J, Hoiom, V, Freidman, E, Azizi, E, Baron Epel, O, Scope, A, Pavlotsky, F, Cohen Manheim, I, Laitman, Y, Harland, M, Randerson Moor, J, Laye, J, Davies, J, Nsengimana, J, O'Shea, S, Chan, M, Gascoyne, J, Tucker, Ma, Goldstein, Am, and Yang, X. r.
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0301 basic medicine ,Male ,Lung Neoplasms ,Skin Neoplasms ,General Physics and Astronomy ,Genome-wide association study ,VARIANTS ,Histones ,Skin cancer ,RNA, Small Interfering ,Melanoma ,Telomerase ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,Pancreas cancer ,Regulation of gene expression ,Genetics ,Zinc finger ,Gene knockdown ,Multidisciplinary ,Proteomics and Chromatin Biology ,TRICL Consortium ,Chromosome Mapping ,GenoMEL Consortium ,PANCREATIC-CANCER ,Multidisciplinary Sciences ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Science & Technology - Other Topics ,Chromosomes, Human, Pair 5 ,Female ,Lung cancer ,Signal Transduction ,SUSCEPTIBILITY LOCI ,Science ,Locus (genetics) ,Single-nucleotide polymorphism ,PROMOTES GROWTH ,Biology ,Polymorphism, Single Nucleotide ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,LUNG-CANCER ,Testicular Neoplasms ,Cell Line, Tumor ,MD Multidisciplinary ,Humans ,Genetic Predisposition to Disease ,QUANTITATIVE PROTEOMICS ,GENOME-WIDE ASSOCIATION ,Gene ,PanScan Consortium ,Càncer de pell ,Càncer de pàncrees ,Alleles ,Science & Technology ,Kirurgi ,HUMAN-CELLS ,Telomere Homeostasis ,Correction ,General Chemistry ,Molecular biology ,TERT-CLPTM1L LOCUS ,Telomere ,Pancreatic Neoplasms ,030104 developmental biology ,Genetic Loci ,TELOMERE LENGTH ,Càncer de pulmó ,Surgery ,Genètica ,Genome-Wide Association Study ,Transcription Factors - 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., Genetic variants at multiple loci of chr5p15.33 have been associated with susceptibility to numerous cancers. Here the authors show that the association of one of these loci may be explained by a variant, rs36115365, influencing telomerase reverse transcriptase (TERT) expression via ZNF148.
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- 2017
15. Genome-wide association study identifies novel loci predisposing to cutaneous melanoma†
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Amos, Ci, Wang, Le, Lee, Je, Gershenwald, Je, Chen, Wv, Fang, S, Kosoy, R, Zhang, M, Qureshi, Aa, Vattathil, S, Schacherer, Cw, Gardner, Jm, Wang, Y, Bishop, Dt, Barrett, Jh, Macgregor, S, Hayward, Nk, Martin, Ng, Duffy, Dl, Mann, Gj, Cust, A, Hopper, J, Brown, Km, Grimm, Ea, Xu, Y, Han, Y, Jing, K, Mchugh, C, Laurie, Cc, Doheny, Kf, Pugh, Ew, Seldin, Mf, Han, J, Wei, Q, Genomel, Investigators, Mega Investigators, Q., AMFS Investigators Mann GJ, Hopper, Jl, Aitken, Jf, Armstrong, Bk, Giles, Gg, Kefford, Rf, Cust, Ae, Jenkins, Ma, Schmid, H, Aguilera, P, Badenas, C, Carrera, C, Cuellar, F, Gabriel, D, Martinez, E, Gonzalez, M, Iglesias, P, Malvehy, J, Marti Laborda, R, Mila, M, Ogbah, Z, Butille, Ja, Puig, S, Alós, L, Arance, A, Arguís, P, Campo, A, Castel, T, Conill, C, Palou, J, Rull, R, Sánchez, M, Vidal Sicart, S, Vilalta, A, Vilella, R, Montgomery, Gw, Whiteman, Dc, Whiteman, D, Webb, P, Green, A, Parsons, P, Purdie, D, Hayward, N, Landi, Mt, Calista, D, Landi, G, Minghetti, P, Arcangeli, F, Bertazzi, Pa, Bianchi, Giovanna, Ghiorzo, Paola, Pastorino, Lorenza, Bruno, William, Battistuzzi, Linda, Gargiulo, Sara, Nasti, Sabina, Gliori, S, Origone, Paola, Andreotti, V, Queirolo, P, Mackie, R, Lang, J, Bishop, Ja, Affleck, P, Harrison, J, Iles, Mm, Randerson Moor, J, Harland, M, Taylor, Jc, Whittaker, L, Kukalizch, K, Leake, S, Karpavicius, B, Haynes, S, Mack, T, Chan, M, Taylor, Y, Davies, J, King, P, Gruis, Na, van Nieuwpoort FA, Out, C, van der Drift, C, Bergman, W, Kukutsch, N, Bavinck, Jn, Bakker, B, van der Stoep, N, ter Huurne, J, van der Rhee, H, Bekkenk, M, Snels, D, van Praag, M, Brochez, L, Gerritsen, R, Crijns, M, Vasen, H, Olsson, H, Ingvar, C, Jönsson, G, Borg, Å, Måsbäck, A, Lundgren, L, Baeckenhorn, K, Nielsen, K, Casslén, As, Helsing, P, Andresen, Pa, Rootwelt, H, Akslen, La, Molven, A, Avril, Mf, Bressac de Paillerets, B, Chaudru, V, Chateigner, N, Corda, E, Jeannin, P, Lesueur, F, de Lichy, M, Maubec, E, Mohamdi, H, Demenais, F, Andry Benzaquen, P, Bachollet, B, Bérard, F, Berthet, P, Boitier, F, Bonadona, V, Bonafé, Jl, Bonnetblanc, Jm, Cambazard, F, Caron, O, Caux, F, Chevrant Breton, J, Chompret, A, Dalle, S, Demange, L, Dereure, O, Doré, Mx, Doutre, Ms, Dugast, C, Faivre, L, Grange, F, Humbert, P, Joly, P, Kerob, D, Lasset, C, Leccia, Mt, Lenoir, G, Leroux, D, Levang, J, Lipsker, D, Mansard, S, Martin, L, Martin Denavit, T, Mateus, C, Michel, Jl, Morel, P, Olivier Faivre, L, Perrot, Jl, Robert, C, Ronger Savle, S, Sassolas, B, Souteyrand, P, Stoppa Lyonnet, D, Thomas, L, Vabres, P, Wierzbicka, E, Elder, D, Kanetsky, P, Knorr, J, Ming, M, Mitra, N, Ruffin, A, Van Belle, P, Debniak, T, Lubiński, J, Mirecka, A, Ertmański, S, Novakovic, S, Hocevar, M, Peric, B, Cerkovnik, P, Höiom, V, Hansson, J, Holland, Ea, Azizi, E, Galore Haskel, G, Friedman, E, Baron Epel, O, Scope, A, Pavlotsky, F, Yakobson, E, Cohen Manheim, I, Laitman, Y, Milgrom, R, Shimoni, I, and Kozlovaa, E.
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Genetic Markers ,Candidate gene ,Skin Neoplasms ,Ubiquitin-Protein Ligases ,Locus (genetics) ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,0302 clinical medicine ,Meta-Analysis as Topic ,Genetics ,Eye color ,Guanine Nucleotide Exchange Factors ,Humans ,SNP ,Genetic Predisposition to Disease ,Melanoma ,Molecular Biology ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Pigmentation ,Association Studies Articles ,General Medicine ,3. Good health ,Chromosomes, Human, Pair 1 ,Genetic Loci ,Genetic marker ,Case-Control Studies ,030220 oncology & carcinogenesis ,Cutaneous melanoma ,Genome-Wide Association Study - Abstract
We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 × 10(-10)). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma.
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- 2011
16. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma
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Law, M, Bishop, DT, Lee, JE, Brossard, M, Martin, NG, Moses, EK, Song, F, Barrett, JH, Kumar, R, Easton, DF, Pharoah, PDP, Swerdlow, AJ, Kypreou, KP, Taylor, JC, Harland, M, Randerson-Moor, J, Akslen, LA, Andresen, PA, Avril, MF, Azizi, E, Scarra, GB, Brown, KM, Debniak, T, Duffy, DL, Elder, DE, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, EM, Goldstein, AM, Gruis, NE, Hansson, J, Helsing, P, Hocevar, M, Hoiom, V, Ingvar, C, Kanetsky, PA, Chen, WV, GenoMEL Consortium, Essen-Heidelberg Investigators, The SDH Study Group, Q-MEGA and QTWIN Investigators, AMFS Investigators, ATHENS Melanoma Study Group, Landi, MT, Lang, J, Lathrop, M, Lubinski, J, Mackie, RM, Mann, GJ, Molvern, A, Montgomery, GW, Novakovic, S, Olsson, H, Puig, S, Puig-Butille, JA, Qureshi, AA, Radford-Smith, GL, van der Stoep, N, van Doorn, R, Whiteman, DC, Craig, JE, Schadendorf, D, Simms, LA, Burdon, KP, Nyholt, DR, Pooley, KA, Orr, N, Stratigos, AJ, Cust, AE, Ward, SV, Hayward, NK, Han, J, Schulze, HJ, Dunning, AM, Newton-Bishop, JA, Demenais, F, Amos, CI, MacGregor, S, Iles, MM, Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Pooley, Karen [0000-0002-1274-9460], Dunning, Alison [0000-0001-6651-7166], and Apollo - University of Cambridge Repository
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Candidate gene ,Skin Neoplasms ,Medizin ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Genome ,Polymorphism, Single Nucleotide ,Article ,Polymorphism (computer science) ,ATHENS Melanoma Study Group ,Genetics ,Chromosomes, Human ,Humans ,Genetic Predisposition to Disease ,AMFS Investigators ,Melanoma ,Genetic association ,11 Medical And Health Sciences ,06 Biological Sciences ,GenoMEL Consortium ,Human genetics ,3. Good health ,Genetic Loci ,Case-Control Studies ,SDH Study Group ,Expression quantitative trait loci ,Q-MEGA and QTWIN Investigators ,Essen-Heidelberg Investigators ,Developmental Biology ,Genome-Wide Association Study - Abstract
© 2015 Nature America, Inc. All rights reserved.Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10-8), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.
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- 2015
17. Genome-wide association study identifies three new melanoma susceptibility loci
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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
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- 2011
18. The determinants of serum vitamin D levels in participants in a melanoma case-control study living in a temperate climate
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Davies, J R, Chang, Y M, Snowden, H, Chan, M, Leake, S, Karpavicius, B, Haynes, S, Kukalizch, K, Randerson-Moor, J, Elliott, F, Barth, J, Kanetzky, P A, Harland, M, Bishop, D T, Barrett, J H, Newton-Bishop, J A, Leeds, Leeds Teaching Hospitals Trust, and Pennsylvania, Philadelphia
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- 2011
19. Genome-wide association study identifies three loci associated with melanoma risk
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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.
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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.
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- 2009
20. Plasma osteopontin concentrations in patients with cutaneous melanoma
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FILIA, A., primary, ELLIOTT, F., additional, WIND, T., additional, FIELD, S., additional, DAVIES, J., additional, KUKALIZCH, K., additional, RANDERSON-MOOR, J., additional, HARLAND, M., additional, BISHOP, D.T., additional, BANKS, R.E., additional, and NEWTON-BISHOP, J.A., additional
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- 2013
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21. Melanoma risk for CDKN2A mutation carriers who are relatives of population-based case carriers in Australia and the UK
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Cust, A. E., primary, Harland, M., additional, Makalic, E., additional, Schmidt, D., additional, Dowty, J. G., additional, Aitken, J. F., additional, Agha-Hamilton, C., additional, Armstrong, B. K., additional, Barrett, J. H., additional, Chan, M., additional, Chang, Y.-M., additional, Gascoyne, J., additional, Giles, G. G., additional, Holland, E. A., additional, Kefford, R. F., additional, Kukalizch, K., additional, Lowery, J., additional, Randerson-Moor, J. A., additional, Schmid, H., additional, Taylor, C. F., additional, Whitaker, L., additional, Hopper, J. L., additional, Newton-Bishop, J. A., additional, Mann, G. J., additional, Bishop, D. T., additional, and Jenkins, M. A., additional
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- 2011
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22. Melanoma-Astrocytoma syndrome
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Randerson-Moor, J, primary, Kukalizch, K, additional, and Bishop, DT, additional
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- 2011
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23. Serum vitamin D levels, VDR, and survival from melanoma
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Newton Bishop, J. A., primary, Beswick, S., additional, Randerson-Moor, J., additional, Chang, Y., additional, Affleck, P., additional, Elliott, F., additional, Elder, D., additional, Barrett, J., additional, and Bishop, T., additional
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- 2009
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24. Vitamin D and survival from melanoma
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Newton Bishop, J., primary, Beswick, S., additional, Jackson, S., additional, Randerson Moor, J., additional, Elliott, F., additional, Barrett, J., additional, Affleck, P., additional, Marsden, J., additional, and Bishop, T., additional
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- 2006
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25. A germline deletion of p14ARF but not CDKN2A in a melanoma-neural system tumour syndrome family
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Randerson-Moor, J. A., primary
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- 2001
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26. Prevalence and predictors of germline CDKN2A mutations for melanoma cases from Australia
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Harland, M, Cust, A E, Badenas, C, Chang, Y M, Holland, E A, Aguilera, P, Aitken, J F, Armstrong, B K, Barrett, J H, Carrera, C, Chan, M, Gascoyne, J, Giles, G G, Agha-Hamilton, C, Hopper, J L, Jenkins, M A, Kanetsky, P A, Kefford, R F, Kolmn, I, Lowery, J, Malvehy, J, Ogbah, Z, Puig-Butille, J A, Orihuela-Segales, J, Randerson-Moor, J A, Schmid, H, Taylor, C F, Whitaker, L, Bishop, D T, Mann, G J, Newton-Bishop, J A, and Puig, S
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neoplasms
27. The effect on melanoma risk of genes previously associated with telomere length
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Iles, M. M., Bishop, D. T., Taylor, J. C., Hayward, N. K., Brossard, M., Cust, A. E., Dunning, A. M., Lee, J. E., Moses, E. K., Akslen, L. A., Amfs, Investigators, Andresen, P. A., Avril, M. F., Azizi, E., Scarrà, G. B., Brown, K. M., Debniak, T., Elder, D. E., Friedman, E., Ghiorzo, P., Gillanders, E. M., Goldstein, A. M., Gruis, N. A., Hansson, J., Harland, M., Helsing, P., Hočevar, M., Höiom, V., Ibd, Investigators, Ingvar, C., Kanetsky, P. A., Landi, M. T., Lang, J., Lathrop, G. M., Lubiński, J., Mackie, R. M., Nicholas Martin, Molven, A., Montgomery, G. W., Novaković, S., Olsson, H., Puig, S., Puig-Butille, J. A., Qmega Qtwin, And Investigators, Radford-Smith, G. L., Randerson-Moor, J., Sdh, Study Group, Stoep, N., Doorn, R., Whiteman, D. C., Macgregor, S., Pooley, K. A., Ward, S. V., Mann, G. J., Amos, C. I., Pharoah, P. D., Demenais, F., Law, M. H., Newton Bishop, J. A., Barrett, J. H., GenoMEL Consortium, Dunning, Alison [0000-0001-6651-7166], Pooley, Karen [0000-0002-1274-9460], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
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Skin Neoplasms ,Telomere-Binding Proteins ,Australia ,DNA Helicases ,Confounding Factors, Epidemiologic ,Zinc Fingers ,Telomere ,Polymorphism, Single Nucleotide ,United States ,Europe ,Ribonucleoproteins ,Predictive Value of Tests ,Research Design ,Humans ,RNA ,Israel ,Melanoma ,Telomerase ,Germ-Line Mutation - Abstract
Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10(-9), two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.
28. Pathway-Based Analysis of a Melanoma Genome-Wide Association Study: Analysis of Genes Related to Tumour-Immunosuppression
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Schoof, N, Iles, Mm, Bishop, Dt, Newton Bishop JA, Barrett, Jh, Mann, Gj, Hopper, Jl, Aitken, Jf, Armstrong, Bk, Giles, Gg, Kefford, Rf, Cust, A, Jenkins, M, Aguilera, P, Badenas, C, Carrera, C, Cuellar, F, Gabriel, D, Martinez, E, Gonzalez, M, Iglesias, P, Malvehy, J, Marti Laborda, R, Mila, M, Ogbah, Z, Butille, Ja, Puig, S, Alós, L, Arance, A, Arguís, P, Campo, A, Castel, T, Conill, C, Palou, J, Rull, R, Sánchez, M, Vidal Sicart, S, Vilalta, A, Vilella, R, Martin, Ng, Montgomery, Gw, Duffy, D, Whiteman, D, Macgregor, S, Hayward, Nk, Webb, P, Parsons, P, Purdie, D, Hayward, N, Landi, Mt, Calista, D, Landi, G, Minghetti, P, Arcangeli, F, Bertazzi, Pa, Bianchi, Giovanna, Ghiorzo, Paola, Pastorino, Lorenza, Bruno, William, Battistuzzi, Linda, Gargiulo, Sara, Nasti, Sabina, Gliori, S, Origone, Paola, Queirolo, P, Mackie, R, Lang, J, Bishop, Ja, Affleck, P, Harrison, J, Randerson Moor, J, Harland, M, Taylor, Jc, Whittaker, L, Kukalizch, K, Leake, S, Karpavicius, B, Haynes, S, Mack, T, Chan, M, Taylor, Y, Davies, J, King, P, Gruis, Na, van Nieuwpoort FA, Out, C, van der Drift, C, Bergman, W, Kukutsch, N, Bavinck, Jn, Bakker, B, van der Stoep, N, ter Huurne, J, van der Rhee, H, Bekkenk, M, Snels, D, van Praag, M, Brochez, L, Gerritsen, R, Crijns, M, Vasen, H, Olsson, H, Ingvar, C, Jönsson, G, Borg, Å, Måsbäck, A, Lundgren, L, Baeckenhorn, K, Nielsen, K, Casslén, As, Helsing, P, Andresen, Pa, Rootwelt, H, Akslen, La, Molven, A, Avril, Mf, Bressac de Paillerets, B, Chaudru, V, Chateigner, N, Corda, E, Jeannin, P, Lesueur, F, de Lichy, M, Maubec, E, Mohamdi, H, Demenais, F, Andry Benzaquen, P, Bachollet, B, Bérard, F, Berthet, P, Boitier, F, Bonadona, V, Bonafé, Jl, Bonnetblanc, Jm, Cambazard, F, Caron, O, Caux, F, Chevrant Breton, J, Chompret, A, Dalle, S, Demange, L, Dereure, O, Doré, Mx, Doutre, Ms, Dugast, C, Faivre, L, Grange, F, Humbert, P, Joly, P, Kerob, D, Lasset, C, Leccia, Mt, Lenoir, G, Leroux, D, Levang, J, Lipsker, D, Mansard, S, Martin, L, Martin Denavit, T, Mateus, C, Michel, Jl, Morel, P, Olivier Faivre, L, Perrot, Jl, Robert, C, Ronger Savle, S, Sassolas, B, Souteyrand, P, Stoppa Lyonnet, D, Thomas, L, Vabres, P, Wierzbicka, E, Elder, D, Kanetsky, P, Knorr, J, Ming, M, Mitra, N, Ruffin, A, Van Belle, P, Dębniak, T, Lubiński, J, Mirecka, A, Ertmański, S, Novakovic, S, Hocevar, M, Peric, B, Cerkovnik, P, Höiom, V, Hansson, J, Schmid, H, Holland, Ea, Azizi, E, Galore Haskel, G, Friedman, E, Baron Epel, O, Scope, A, Pavlotsky, F, Yakobson, E, Cohen Manheim, I, Laitman, Y, Milgrom, R, Shimoni, I, Kozlovaa, E., Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Martí Laborda, Rosa Ma., and Universitat de Barcelona
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Melanomas ,Skin Neoplasms ,Epidemiology ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,lcsh:Medicine ,Genome-wide association study ,0302 clinical medicine ,Polymorphism (computer science) ,Genetics of the Immune System ,lcsh:Science ,Melanoma ,Genetics ,0303 health sciences ,Multidisciplinary ,Cancer Risk Factors ,Statistics ,Immunosuppression ,Genomics ,Oncology ,Genetic Epidemiology ,030220 oncology & carcinogenesis ,Medicine ,Research Article ,medicine.medical_specialty ,Immunology ,Genetic Causes of Cancer ,Malignant Skin Neoplasms ,Single-nucleotide polymorphism ,Dermatology ,Biostatistics ,Biology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Genome Analysis Tools ,Molecular genetics ,Genome-Wide Association Studies ,medicine ,Humans ,SNP ,Genetic Predisposition to Disease ,Statistical Methods ,Gene ,030304 developmental biology ,Immunosuppression Therapy ,Evolutionary Biology ,Population Biology ,Immunosupressió ,lcsh:R ,Computational Biology ,Human Genetics ,medicine.disease ,Genetic Polymorphism ,Clinical Immunology ,lcsh:Q ,Population Genetics ,Mathematics ,Genome-Wide Association Study - Abstract
Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA) studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs) in 43 genes (39 genomic regions) related to immunosuppression have been analysed using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (pemp = 0.002), as well as the subgroups related to the generation of tolerogenic dendritic cells (pemp = 0.006) and secretion of suppressive factors (pemp = 0.0004), thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges.
29. Management of familial melanoma.
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Bishop JN, Harland M, Randerson-Moor J, and Bishop DT
- Abstract
Relatives of patients with melanoma are at increased risk of melanoma. We review the evidence that this risk may be attributed both to shared susceptibility genes (both high-penetrance and lower-penetrance genes) and shared environment. The most frequent high-penetrance susceptibility gene is CDKN2A, and environmental effects on the risk to gene carriers are evident in that CDKN2A penetrance is higher in CDKN2A-mutation-positive families living in Australia than those in Europe. We review the approaches to managing melanoma families, in which the likelihood of there being detectable CDKN2A mutations is positively correlated with the number of cases of melanoma in the family. Within families, risk that an individual carries a germline mutation can be estimated by pedigree analysis for autosomal dominant genes with incomplete penetrance. Prevention advice to families relates to moderation of sun exposure and self-examination of naevi, although there are few supportive data. [ABSTRACT FROM AUTHOR]
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- 2007
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30. Systemic Inflammation, the Peripheral Blood Transcriptome, and Primary Melanoma.
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Randerson-Moor J, Davies J, Harland M, Nsengimana J, Bigirumurame T, Walker C, Laye J, Appleton ES, Ball G, Cook GP, Bishop DT, Salmond RJ, and Newton-Bishop J
- Abstract
Peripheral blood transcriptomes from 383 patients with newly diagnosed melanoma were subjected to differential gene expression analysis. The hypotheses were that impaired systemic immunity is associated with poorer prognosis (thicker tumors and fewer tumor-infiltrating lymphocytes) and evidence of systemic inflammation (high-sensitivity CRP and fibrinogen levels). Higher fibrinogen levels were associated with thicker primary tumors. In single-gene analysis, high-sensitivity CRP levels were significantly associated with higher blood CD274 expression (coding for PD-L1), but each was independently prognostic, with high-sensitivity CRP associated with increased mortality and higher CD274 protective, independent of age. Pathway analysis identified downregulation of immune cell signaling pathways in the blood of people with thicker tumors and notable upregulation of signal transducer and activator of transcription 1 gene STAT1 in people with brisk tumor-infiltrating lymphocytes. Transcriptomic data provided evidence for increased NF-kB signaling with higher inflammatory markers but with reduction in expression of HLA class II molecules and higher CD274, suggesting that aberrant systemic inflammation is a significant mediator of reduced immune function in melanoma. In summary, transcriptomic data revealed evidence of reduced immune function in patients with thicker tumors and fewer tumor-infiltrating lymphocytes at diagnosis. Inflammatory markers were associated with thicker primaries and independently with death from melanoma, suggesting that systemic inflammation contributes to that reduced immune function., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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31. Ulcerated melanoma: Systems biology evidence of inflammatory imbalance towards pro-tumourigenicity.
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Davies J, Muralidhar S, Randerson-Moor J, Harland M, O'Shea S, Diaz J, Walker C, Nsengimana J, Laye J, Mell T, Chan M, Appleton L, Birkeälv S, Adams DJ, Cook GP, Ball G, Bishop DT, and Newton-Bishop JA
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- Humans, Inflammation genetics, Systems Biology, Ulcer pathology, Melanoma metabolism, Skin Neoplasms genetics, Skin Neoplasms metabolism
- Abstract
Microscopic ulceration is an independent predictor of melanoma death. Here, we used systems biology to query the role of host and tumour-specific processes in defining the phenotype. Albumin level as a measure of systemic inflammation was predictive of fewer tumour-infiltrating lymphocytes and poorer survival in the Leeds Melanoma Cohort. Ulcerated melanomas were thicker and more mitotically active (with corresponding transcriptomic upregulated cell cycle pathways). Sequencing identified tumoural p53 and APC mutations, and TUBB2B amplification as associated with the phenotype. Ulcerated tumours had perturbed expression of cytokine genes, consistent with protumourigenic inflammation and histological and transcriptomic evidence for reduced adaptive immune cell infiltration. Pathway/network analysis of multiomic data using neural networks highlighted a role for the β-catenin pathway in the ulceration, linking genomic changes in the tumour to immunosuppression and cell proliferation. In summary, the data suggest that ulceration is in part associated with genomic changes but that host factors also predict melanoma death with evidence of reduced immune responses to the tumour., (© 2021 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)
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- 2022
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32. A Recessively Inherited Risk Locus on Chromosome 13q22-31 Conferring Susceptibility to Schizophrenia.
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Mahmood T, El-Asrag ME, Poulter JA, Cardno AG, Tomlinson A, Ahmed S, Al-Amri A, Nazari J, Neill J, Chamali RS, Kiwan N, Ghuloum S, Alhaj HA, Randerson Moor J, Khan S, Al-Amin H, Johnson CA, Woodruff P, Wilkinson ID, Ali M, Clapcote SJ, and Inglehearn CF
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- Endophenotypes, Female, Genetic Loci, Humans, Male, Pedigree, Psychotic Disorders physiopathology, Schizophrenia physiopathology, Chromosomes, Human, Pair 13 genetics, Consanguinity, Genes, Recessive genetics, Genetic Predisposition to Disease genetics, Psychotic Disorders genetics, Schizophrenia genetics
- Abstract
We report a consanguineous family in which schizophrenia segregates in a manner consistent with recessive inheritance of a rare, partial-penetrance susceptibility allele. From 4 marriages between 2 sets of siblings who are half first cousins, 6 offspring have diagnoses of psychotic disorder. Homozygosity mapping revealed a 6.1-Mb homozygous region on chromosome 13q22.2-31.1 shared by all affected individuals, containing 13 protein-coding genes. Microsatellite analysis confirmed homozygosity for the affected haplotype in 12 further apparently unaffected members of the family. Psychiatric reports suggested an endophenotype of milder psychiatric illness in 4 of these individuals. Exome and genome sequencing revealed no potentially pathogenic coding or structural variants within the risk haplotype. Filtering for noncoding variants with a minor allele frequency of <0.05 identified 17 variants predicted to have significant effects, the 2 most significant being within or adjacent to the SCEL gene. RNA sequencing of blood from an affected homozygote showed the upregulation of transcription from NDFIP2 and SCEL. NDFIP2 is highly expressed in brain, unlike SCEL, and is involved in determining T helper (Th) cell type 1 and Th2 phenotypes, which have previously been implicated with schizophrenia., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)
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- 2021
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33. MX 2 is a novel regulator of cell cycle in melanoma cells.
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Juraleviciute M, Pozniak J, Nsengimana J, Harland M, Randerson-Moor J, Wernhoff P, Bassarova A, Øy GF, Trøen G, Flørenes VA, Bishop DT, Herlyn M, Newton-Bishop J, and Slipicevic A
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- Animals, Cell Line, Tumor, Cell Proliferation, Down-Regulation genetics, Gene Expression Regulation, Neoplastic, Humans, Kaplan-Meier Estimate, Melanoma genetics, Mice, Nude, Myxovirus Resistance Proteins genetics, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction, Cell Cycle genetics, Melanoma pathology, Myxovirus Resistance Proteins metabolism
- Abstract
MX2 protein is a dynamin-like GTPase2 that has recently been identified as an interferon-induced restriction factor of HIV-1 and other primate lentiviruses. A single nucleotide polymorphism (SNP), rs45430, in an intron of the MX2 gene, was previously reported as a novel melanoma susceptibility locus in genome-wide association studies. Functionally, however, it is still unclear whether and how MX2 contributes to melanoma susceptibility and tumorigenesis. Here, we show that MX2 is differentially expressed in melanoma tumors and cell lines, with most metastatic cell lines showing lower MX2 expression than primary melanoma cell lines and melanocytes. Furthermore, high expression of MX2 RNA in primary melanoma tumors is associated with better patient survival. Overexpression of MX2 reduces in vivo proliferation partially through inhibition of AKT activation, suggesting that it can act as a tumor suppressor in melanoma. However, we have also identified a subset of melanoma cell lines with high endogenous MX2 expression where downregulation of MX2 leads to reduced proliferation. In these cells, MX2 downregulation interfered with DNA replication and cell cycle processes. Collectively, our data for the first time show that MX2 is functionally involved in the regulation of melanoma proliferation but that its function is context-dependent., (© 2019 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)
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- 2020
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34. High-Resolution Copy Number Patterns From Clinically Relevant FFPE Material.
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Filia A, Droop A, Harland M, Thygesen H, Randerson-Moor J, Snowden H, Taylor C, Diaz JMS, Pozniak J, Nsengimana J, Laye J, Newton-Bishop JA, and Bishop DT
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- High-Throughput Nucleotide Sequencing, Humans, Neoplasms pathology, Reproducibility of Results, Tissue Fixation, DNA Copy Number Variations, Neoplasms genetics, Paraffin Embedding
- Abstract
Systematic tumour profiling is essential for biomarker research and clinically for assessing response to therapy. Solving the challenge of delivering informative copy number (CN) profiles from formalin-fixed paraffin embedded (FFPE) material, the only likely readily available biospecimen for most cancers, involves successful processing of small quantities of degraded DNA. To investigate the potential for analysis of such lesions, whole-genome CNVseq was applied to 300 FFPE primary tumour samples, obtained from a large-scale epidemiological study of melanoma. The quality and the discriminatory power of CNVseq was assessed. Libraries were successfully generated for 93% of blocks, with input DNA quantity being the only predictor of success (success rate dropped to 65% if <20 ng available); 3% of libraries were dropped because of low sequence alignment rates. Technical replicates showed high reproducibility. Comparison with targeted CN assessment showed consistency with the Next Generation Sequencing (NGS) analysis. We were able to detect and distinguish CN changes with a resolution of ≤10 kb. To demonstrate performance, we report the spectrum of genomic CN alterations (CNAs) detected at 9p21, the major site of CN change in melanoma. This successful analysis of CN in FFPE material using NGS provides proof of principle for intensive examination of population-based samples.
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- 2019
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35. β-Catenin-mediated immune evasion pathway frequently operates in primary cutaneous melanomas.
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Nsengimana J, Laye J, Filia A, O'Shea S, Muralidhar S, Poźniak J, Droop A, Chan M, Walker C, Parkinson L, Gascoyne J, Mell T, Polso M, Jewell R, Randerson-Moor J, Cook GP, Bishop DT, and Newton-Bishop J
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- Female, GTP Phosphohydrolases genetics, Humans, Male, Melanoma genetics, Melanoma pathology, Membrane Proteins genetics, Proto-Oncogene Proteins B-raf genetics, Skin Neoplasms genetics, Skin Neoplasms pathology, Tumor Microenvironment genetics, beta Catenin genetics, GTP Phosphohydrolases immunology, Melanoma immunology, Membrane Proteins immunology, Mutation, Proto-Oncogene Proteins B-raf immunology, Skin Neoplasms immunology, Tumor Microenvironment immunology, beta Catenin immunology
- Abstract
Immunotherapy prolongs survival in only a subset of melanoma patients, highlighting the need to better understand the driver tumor microenvironment. We conducted bioinformatic analyses of 703 transcriptomes to probe the immune landscape of primary cutaneous melanomas in a population-ascertained cohort. We identified and validated 6 immunologically distinct subgroups, with the largest having the lowest immune scores and the poorest survival. This poor-prognosis subgroup exhibited expression profiles consistent with β-catenin-mediated failure to recruit CD141+ DCs. A second subgroup displayed an equally bad prognosis when histopathological factors were adjusted for, while 4 others maintained comparable survival profiles. The 6 subgroups were replicated in The Cancer Genome Atlas (TCGA) melanomas, where β-catenin signaling was also associated with low immune scores predominantly related to hypomethylation. The survival benefit of high immune scores was strongest in patients with double-WT tumors for BRAF and NRAS, less strong in BRAF-V600 mutants, and absent in NRAS (codons 12, 13, 61) mutants. In summary, we report evidence for a β-catenin-mediated immune evasion in 42% of melanoma primaries overall and in 73% of those with the worst outcome. We further report evidence for an interaction between oncogenic mutations and host response to melanoma, suggesting that patient stratification will improve immunotherapeutic outcomes.
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- 2018
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36. Changes in plasma chemokine C-C motif ligand 2 levels during treatment with eicosapentaenoic acid predict outcome in patients undergoing surgery for colorectal cancer liver metastasis.
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Volpato M, Perry SL, Marston G, Ingram N, Cockbain AJ, Burghel H, Mann J, Lowes D, Wilson E, Droop A, Randerson-Moor J, Coletta PL, and Hull MA
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- Animals, Biomarkers, Tumor blood, Disease-Free Survival, Female, Humans, Kaplan-Meier Estimate, Male, Mice, Mice, Inbred C57BL, Treatment Outcome, Antineoplastic Agents therapeutic use, Chemokine CCL2 blood, Colorectal Neoplasms drug therapy, Colorectal Neoplasms mortality, Colorectal Neoplasms pathology, Eicosapentaenoic Acid therapeutic use, Liver Neoplasms drug therapy, Liver Neoplasms secondary, Liver Neoplasms surgery
- Abstract
The mechanism of the anti-colorectal cancer (CRC) activity of the omega-3 fatty acid eicosapentaenoic acid (EPA) is not understood. We tested the hypothesis that EPA reduces expression of chemokine C-C motif ligand 2 (CCL2), a pro-inflammatory chemokine with known roles in metastasis.We measured CCL2 in clinical samples from a randomized trial of EPA in patients undergoing liver surgery for CRC liver metastasis (LM) and preclinical models. Genome-wide transcriptional profiling of tumors from EPA-treated patients was performed.EPA decreased CCL2 synthesis by CRC cells in a dose-dependent manner. CCL2 was localized to malignant epithelial cells in human CRCLM. EPA did not reduce CCL2 content in human or mouse tumors compare to control. However, EPA treatment was associated with decreased plasma CCL2 levels compared with controls (P=0.04). Reduction in plasma CCL2 following EPA treatment predicted improved disease-free survival (HR 0.32; P=0.003). Lack of 'CCL2 response' was associated with a specific CRCLM gene expression signature.In conclusion, reduction in plasma CCL2 in patients with CRCLM treated with EPA predicts better clinical outcome and a specific tumor gene expression profile. Further work is needed to validate CCL2 as a therapeutic response biomarker for omega-3 fatty acid treatment of CRC patients., Competing Interests: None of the authors have any potential conflicts of interest to disclose.
- Published
- 2016
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37. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma.
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Law MH, Bishop DT, Lee JE, Brossard M, Martin NG, Moses EK, Song F, Barrett JH, Kumar R, Easton DF, Pharoah PDP, Swerdlow AJ, Kypreou KP, Taylor JC, Harland M, Randerson-Moor J, Akslen LA, Andresen PA, Avril MF, Azizi E, Scarrà GB, Brown KM, Dębniak T, Duffy DL, Elder DE, Fang S, Friedman E, Galan P, Ghiorzo P, Gillanders EM, Goldstein AM, Gruis NA, Hansson J, Helsing P, Hočevar M, Höiom V, Ingvar C, Kanetsky PA, Chen WV, Landi MT, Lang J, Lathrop GM, Lubiński J, Mackie RM, Mann GJ, Molven A, Montgomery GW, Novaković S, Olsson H, Puig S, Puig-Butille JA, Qureshi AA, Radford-Smith GL, van der Stoep N, van Doorn R, Whiteman DC, Craig JE, Schadendorf D, Simms LA, Burdon KP, Nyholt DR, Pooley KA, Orr N, Stratigos AJ, Cust AE, Ward SV, Hayward NK, Han J, Schulze HJ, Dunning AM, Bishop JAN, Demenais F, Amos CI, MacGregor S, and Iles MM
- Subjects
- Case-Control Studies, Chromosomes, Human genetics, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Melanoma, Cutaneous Malignant, Melanoma genetics, Skin Neoplasms genetics
- Abstract
Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.
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- 2015
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38. 25-Hydroxyvitamin D2 /D3 levels and factors associated with systemic inflammation and melanoma survival in the Leeds Melanoma Cohort.
- Author
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Newton-Bishop JA, Davies JR, Latheef F, Randerson-Moor J, Chan M, Gascoyne J, Waseem S, Haynes S, O'Donovan C, and Bishop DT
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Aspirin therapeutic use, Comorbidity, Female, Follow-Up Studies, Humans, Inflammation drug therapy, Inflammation epidemiology, Male, Melanoma drug therapy, Melanoma epidemiology, Middle Aged, Multivariate Analysis, Smoking blood, Smoking epidemiology, Survival Analysis, Treatment Outcome, Ulcer blood, Ulcer epidemiology, United Kingdom epidemiology, Young Adult, 25-Hydroxyvitamin D 2 blood, Calcifediol blood, Inflammation blood, Melanoma blood
- Abstract
Lower 25-hydroxyvitamin D2 /D3 levels at melanoma diagnosis are associated with thicker primaries and poorer survival. We postulated that this might relate to the deleterious effect of systemic inflammation as 25-hydroxyvitamin D2 /D3 levels are inversely associated with levels of C-reactive protein. 2,182 participants in the Leeds Melanoma Cohort (median follow-up 7.98 years) provided data on drug exposure, comorbidities and a serum 25-hydroxyvitamin D2 /D3 level at recruitment. Factors reported to modify systemic inflammation (low vitamin D levels, high body mass index, use of aspirin or nonsteroidal anti-inflammatory drugs or smoking were tested as predictors of microscopic ulceration (in which primary tumors are inflamed) and melanoma-specific survival (MSS). Ulceration was independently associated with lower 25-hydroxyvitamin D2 /D3 levels (odds ratio (OR) = 0.94 per 10 nmol/L, 95% CI 0.88-1.00, p = 0.05) and smoking at diagnosis (OR = 1.47, 95% CI 1.00-2.15, p = 0.04). In analyses adjusted for age and sex, a protective effect was seen of 25-hydroxyvitamin D2 /D3 levels at diagnosis on melanoma death (OR = 0.89 per 10 nmol/L, 95% CI 0.83-0.95, p < 0.001) and smoking increased the risk of death (OR = 1.13 per 10 years, 95% CI 1.05-1.22, p = 0.001). In multivariable analyses (adjusted for tumor thickness) the associations with death from melanoma were low 25-hydroxyvitamin D2 /D3 level at recruitment (<20 nmol/L vs. 20-60 nmol/L, hazard ratio (HR) = 1.52, 95% CI 0.97-2.40, p = 0.07) and smoking duration at diagnosis (HR = 1.11, 95% CI 1.03-1.20, p = 0.009). The study shows evidence that lower vitamin D levels and smoking are associated with ulceration of primary melanomas and poorer MSS. Further analyses are necessary to understand any biological mechanisms that underlie these findings., (© 2014 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.)
- Published
- 2015
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39. Inherited variation in the PARP1 gene and survival from melanoma.
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Davies JR, Jewell R, Affleck P, Anic GM, Randerson-Moor J, Ozola A, Egan KM, Elliott F, García-Casado Z, Hansson J, Harland M, Höiom V, Jian G, Jönsson G, Kumar R, Nagore E, Wendt J, Olsson H, Park JY, Patel P, Pjanova D, Puig S, Schadendorf D, Sivaramakrishna Rachakonda P, Snowden H, Stratigos AJ, Bafaloukos D, Ogbah Z, Sucker A, Van den Oord JJ, Van Doorn R, Walker C, Okamoto I, Wolter P, Barrett JH, Timothy Bishop D, and Newton-Bishop J
- Subjects
- DNA, Neoplasm genetics, Follow-Up Studies, Humans, Poly (ADP-Ribose) Polymerase-1, Polymerase Chain Reaction, Prognosis, Retrospective Studies, Survival Rate, Genetic Predisposition to Disease, Melanoma genetics, Melanoma mortality, Poly(ADP-ribose) Polymerases genetics, Polymorphism, Single Nucleotide genetics, Quantitative Trait Loci
- Abstract
We report the association of an inherited variant located upstream of the poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) gene (rs2249844), with survival in 11 BioGenoMEL melanoma cohorts. The gene encodes a protein involved in a number of cellular processes including single-strand DNA repair. Survival analysis was conducted for each cohort using proportional hazards regression adjusting for factors known to be associated with survival. Survival was measured as overall survival (OS) and, where available, melanoma-specific survival (MSS). Results were combined using random effects meta-analysis. Evidence for a role of the PARP1 protein in melanoma ulceration and survival was investigated by testing gene expression levels taken from formalin-fixed paraffin-embedded tumors. A significant association was seen for inheritance of the rarer variant of PARP1, rs2249844 with OS (hazard ratio (HR) = 1.16 per allele, 95% confidence interval (CI) 1.04-1.28, p = 0.005, eleven cohorts) and MSS (HR = 1.20 per allele, 95% CI 1.01-1.39, p = 0.03, eight cohorts). We report bioinformatic data supportive of a functional effect for rs2249844. Higher levels of PARP1 gene expression in tumors were shown to be associated with tumor ulceration and poorer OS., (© 2014 UICC. Published by Wiley Periodicals, Inc. on behalf of UICC.)
- Published
- 2014
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40. The effect on melanoma risk of genes previously associated with telomere length.
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Iles MM, Bishop DT, Taylor JC, Hayward NK, Brossard M, Cust AE, Dunning AM, Lee JE, Moses EK, Akslen LA, Andresen PA, Avril MF, Azizi E, Scarrà GB, Brown KM, Dębniak T, Elder DE, Friedman E, Ghiorzo P, Gillanders EM, Goldstein AM, Gruis NA, Hansson J, Harland M, Helsing P, Hočevar M, Höiom V, Ingvar C, Kanetsky PA, Landi MT, Lang J, Lathrop GM, Lubiński J, Mackie RM, Martin NG, Molven A, Montgomery GW, Novaković S, Olsson H, Puig S, Puig-Butille JA, Radford-Smith GL, Randerson-Moor J, van der Stoep N, van Doorn R, Whiteman DC, MacGregor S, Pooley KA, Ward SV, Mann GJ, Amos CI, Pharoah PD, Demenais F, Law MH, Newton Bishop JA, and Barrett JH
- Subjects
- Australia, Confounding Factors, Epidemiologic, DNA Helicases genetics, Europe, Humans, Israel, Predictive Value of Tests, RNA genetics, Research Design, Ribonucleoproteins genetics, Telomerase genetics, United States, Zinc Fingers genetics, Germ-Line Mutation, Melanoma genetics, Polymorphism, Single Nucleotide, Skin Neoplasms genetics, Telomere genetics, Telomere-Binding Proteins genetics
- Abstract
Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10(-9), two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk., (© The Author 2014. Published by Oxford University Press.)
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- 2014
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41. An inherited variant in the gene coding for vitamin D-binding protein and survival from cutaneous melanoma: a BioGenoMEL study.
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Davies JR, Field S, Randerson-Moor J, Harland M, Kumar R, Anic GM, Nagore E, Hansson J, Höiom V, Jönsson G, Gruis NA, Park JY, Guan J, Sivaramakrishna Rachakonda P, Wendt J, Pjanova D, Puig S, Schadendorf D, Okamoto I, Olsson H, Affleck P, García-Casado Z, Puig-Butille JA, Stratigos AJ, Kodela E, Donina S, Sucker A, Hosen I, Egan KM, Barrett JH, van Doorn R, Bishop DT, and Newton-Bishop J
- Subjects
- Adolescent, Adult, Aged, Alleles, Cohort Studies, Genetic Association Studies, Haplotypes genetics, Humans, Kaplan-Meier Estimate, Melanoma blood, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide genetics, Skin Neoplasms, Sun Protection Factor, Treatment Outcome, Vitamin D blood, Young Adult, Melanoma, Cutaneous Malignant, Genetic Predisposition to Disease, Inheritance Patterns genetics, Melanoma genetics, Vitamin D-Binding Protein genetics
- Abstract
An association between low serum vitamin D levels and poorer melanoma survival has been reported. We have studied inheritance of a polymorphism of the GC gene, rs2282679, coding for the vitamin D-binding protein, which is associated with lower serum levels of vitamin D, in a meta-analysis of 3137 melanoma patients. The aim was to investigate evidence for a causal relationship between vitamin D and outcome (Mendelian randomization). The variant was not associated with reduced overall survival (OS) in the UK cohort, per-allele hazard ratio (HR) for death 1.23 (95% confidence interval (CI) 0.93, 1.64). In the smaller cohorts, HR in OS analysis was 1.07 (95% CI 0.88, 1.3) and for all cohorts combined, HR for OS was 1.09 (95% CI 0.93, 1.29). There was evidence of increased melanoma-specific deaths in the seven cohorts for which these data were available. The lack of unequivocal findings despite the large sample size illustrates the difficulties of implementing Mendelian randomization., (© 2013 The Authors. Pigment Cell & Melanoma Research Published by John Wiley & Sons Ltd.)
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- 2014
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42. Do vitamin A serum levels moderate outcome or the protective effect of vitamin D on outcome from malignant melanoma?
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Field S, Elliott F, Randerson-Moor J, Kukalizch K, Barrett JH, Bishop DT, and Newton-Bishop JA
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- Adult, Aged, Cohort Studies, Dietary Supplements, Female, Humans, Linear Models, Male, Melanoma complications, Melanoma drug therapy, Middle Aged, Vitamin A administration & dosage, Vitamin A adverse effects, Vitamin D administration & dosage, Vitamin D Deficiency blood, Vitamin D Deficiency complications, Melanoma blood, Vitamin A blood, Vitamin D blood
- Abstract
Background & Aims: Low serum vitamin D levels (25-OH-vit D2/3) are reported to be associated with thicker melanomas and poorer outcome. Vitamin A metabolites and vitamin D bind to the same heterodimeric receptor. We report a study testing the hypothesis that high vitamin A levels may reduce the protective effect of vitamin D on outcome., Methods: Serum vitamin A levels were measured in 795 melanoma cases and assessed for association with Breslow thickness, overall (OS) and melanoma-specific survival (MSS), and modification of the effect of vitamin D levels on survival., Results: Higher vitamin A levels (≥ 2.2 μmol/l) conferred a non-significant increased risk of melanoma-specific death (adjusted HR = 1.11, 95%CI(0.74-1.67), p = 0.60) but not for death overall (adjusted HR = 0.95, 95%CI(0.65-1.39), p = 0.79). There was reduction in the protective effect of vitamin D on OS in patients with high vitamin A levels (≥ 2.2 μmol/l)(HR = 0.99, 95%CI(0.72-1.36),p = 0.93) compared to patients with low levels (<2.2 μmol)(HR = 0.77, 95%CI(0.64-0.93),p = 0.007), although the difference was not statistically significant (p = 0.26)., Conclusions: High vitamin A levels may reduce the protective effect of vitamin D. As sub-optimal levels of vitamin D are common in temperate climates, and are usually managed by dietary supplementation, we suggest vitamin D3 supplementation alone might be preferable for melanoma patients than preparations containing vitamin D and A., (Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)
- Published
- 2013
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43. Evaluation of PAX3 genetic variants and nevus number.
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Ogbah Z, Badenas C, Harland M, Puig-Butille JA, Elliot F, Bonifaci N, Guino E, Randerson-Moor J, Chan M, Iles MM, Glass D, Brown AA, Carrera C, Kolm I, Bataille V, Spector TD, Malvehy J, Newton-Bishop J, Pujana MA, Bishop T, and Puig S
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Case-Control Studies, Female, Genetic Association Studies, Humans, Male, Middle Aged, PAX3 Transcription Factor, Spain, United Kingdom, Young Adult, Genetic Predisposition to Disease, Nevus genetics, Nevus pathology, Paired Box Transcription Factors genetics, Polymorphism, Single Nucleotide genetics, Skin Neoplasms genetics
- Abstract
The presence of a high nevus number is the strongest phenotypic predictor of melanoma risk. Here, we describe the results of a three-stage study directed at identifying risk variants for the high nevus phenotype. At the first stage, 263 melanoma cases from Barcelona were genotyped for 223 single-nucleotide polymorphisms (SNPs) in 39 candidate genes. Seven SNPs in the PAX3 gene were found to be significantly associated with nevus number under the additive model. Next, the associations for seven PAX3 variants were evaluated in 1217 melanoma cases and 475 controls from Leeds; and in 3054 healthy twins from TwinsUK. Associations with high nevus number were detected for rs6754024 (P values < 0.01) in the Barcelona and Leeds datasets and for rs2855268 (P values < 0.01) in the Barcelona and the TwinsUK sets. Associations (P values < 0.001) in the opposite direction were detected for rs7600206 and rs12995399 in the Barcelona and TwinsUK sets. This study suggests that SNPs in PAX3 are associated with nevus number, providing support for PAX3 as a candidate nevus gene. Further studies are needed to examine the role of PAX3 in melanoma susceptibility., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2013
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44. A variant in FTO shows association with melanoma risk not due to BMI.
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Iles MM, Law MH, Stacey SN, Han J, Fang S, Pfeiffer R, Harland M, Macgregor S, Taylor JC, Aben KK, Akslen LA, Avril MF, Azizi E, Bakker B, Benediktsdottir KR, Bergman W, Scarrà GB, Brown KM, Calista D, Chaudru V, Fargnoli MC, Cust AE, Demenais F, de Waal AC, Dębniak T, Elder DE, Friedman E, Galan P, Ghiorzo P, Gillanders EM, Goldstein AM, Gruis NA, Hansson J, Helsing P, Hočevar M, Höiom V, Hopper JL, Ingvar C, Janssen M, Jenkins MA, Kanetsky PA, Kiemeney LA, Lang J, Lathrop GM, Leachman S, Lee JE, Lubiński J, Mackie RM, Mann GJ, Martin NG, Mayordomo JI, Molven A, Mulder S, Nagore E, Novaković S, Okamoto I, Olafsson JH, Olsson H, Pehamberger H, Peris K, Grasa MP, Planelles D, Puig S, Puig-Butille JA, Randerson-Moor J, Requena C, Rivoltini L, Rodolfo M, Santinami M, Sigurgeirsson B, Snowden H, Song F, Sulem P, Thorisdottir K, Tuominen R, Van Belle P, van der Stoep N, van Rossum MM, Wei Q, Wendt J, Zelenika D, Zhang M, Landi MT, Thorleifsson G, Bishop DT, Amos CI, Hayward NK, Stefansson K, Bishop JA, and Barrett JH
- Subjects
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Case-Control Studies, Cooperative Behavior, Female, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Obesity, Risk Factors, Body Mass Index, Genetic Loci genetics, Genetic Predisposition to Disease, Melanoma etiology, Polymorphism, Single Nucleotide genetics, Proteins genetics
- Abstract
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 × 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.
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- 2013
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45. Inherited variants in the MC1R gene and survival from cutaneous melanoma: a BioGenoMEL study.
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Davies JR, Randerson-Moor J, Kukalizch K, Harland M, Kumar R, Madhusudan S, Nagore E, Hansson J, Höiom V, Ghiorzo P, Gruis NA, Kanetsky PA, Wendt J, Pjanova D, Puig S, Saiag P, Schadendorf D, Soufir N, Okamoto I, Affleck P, García-Casado Z, Ogbah Z, Ozola A, Queirolo P, Sucker A, Barrett JH, van Doorn R, Bishop DT, and Newton-Bishop J
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Follow-Up Studies, Genetic Predisposition to Disease, Hair Color genetics, Humans, Inheritance Patterns genetics, Male, Middle Aged, Survival Analysis, Young Adult, Genetic Variation, Melanoma genetics, Melanoma mortality, Receptor, Melanocortin, Type 1 genetics, Skin Neoplasms genetics, Skin Neoplasms mortality
- Abstract
Inherited MC1R variants modulate MITF transcription factor signaling, which in turn affects tumor cell proliferation, apoptosis, and DNA repair. The aim of this BioGenoMEL collaborative study in 10 melanoma cohorts was to test the hypothesis that inherited variants thereby moderate survival expectation. A survival analysis in the largest cohort (Leeds) was carried out adjusting for factors known to impact on survival. The results were then compared with data from nine smaller cohorts. The absence of any consensus MC1R alleles was associated with a significantly lower risk of death in the Leeds set (HR, 0.64; 95% CI, 0.46-0.89) and overall in the 10 data sets (HR, 0.78; 95% CI, 0.65-0.94) with some support from the nine smaller data sets considered together (HR, 0.83; 95% CI, 0.67-1.04). The data are suggestive of a survival benefit for inherited MC1R variants in melanoma patients., (© 2012 John Wiley & Sons A/S.)
- Published
- 2012
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46. Genome-wide association study identifies three new melanoma susceptibility loci.
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Barrett JH, Iles MM, Harland M, Taylor JC, Aitken JF, Andresen PA, Akslen LA, Armstrong BK, Avril MF, Azizi E, Bakker B, Bergman W, Bianchi-Scarrà G, Bressac-de Paillerets B, Calista D, Cannon-Albright LA, Corda E, Cust AE, Dębniak T, Duffy D, Dunning AM, Easton DF, Friedman E, Galan P, Ghiorzo P, Giles GG, Hansson J, Hocevar M, Höiom V, Hopper JL, Ingvar C, Janssen B, Jenkins MA, Jönsson G, Kefford RF, Landi G, Landi MT, Lang J, Lubiński J, Mackie R, Malvehy J, Martin NG, Molven A, Montgomery GW, van Nieuwpoort FA, Novakovic S, Olsson H, Pastorino L, Puig S, Puig-Butille JA, Randerson-Moor J, Snowden H, Tuominen R, Van Belle P, van der Stoep N, Whiteman DC, Zelenika D, Han J, Fang S, Lee JE, Wei Q, Lathrop GM, Gillanders EM, Brown KM, Goldstein AM, Kanetsky PA, Mann GJ, Macgregor S, Elder DE, Amos CI, Hayward NK, Gruis NA, Demenais F, Bishop JA, and Bishop DT
- Subjects
- Case-Control Studies, Humans, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Genome-Wide Association Study, Melanoma genetics, Skin Neoplasms genetics
- Abstract
We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 × 10(-9)), an SNP in MX2 (rs45430, P = 2.9 × 10(-9)) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10(-7) under a fixed-effects model and P = 1.2 × 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.
- Published
- 2011
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47. The determinants of serum vitamin D levels in participants in a melanoma case-control study living in a temperate climate.
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Davies JR, Chang YM, Snowden H, Chan M, Leake S, Karpavicius B, Haynes S, Kukalizch K, Randerson-Moor J, Elliott F, Barth J, Kanetsky PA, Harland M, Bishop DT, Barrett JH, and Newton-Bishop JA
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Calcifediol administration & dosage, Case-Control Studies, Child, Child, Preschool, Climate, Dietary Supplements, Female, Genetic Variation, Genotype, Heterozygote, Humans, Infant, Infant, Newborn, Male, Melanoma genetics, Melanoma metabolism, Middle Aged, Seasons, Skin Neoplasms genetics, Skin Neoplasms metabolism, Sunlight, United Kingdom, Vitamin D Deficiency blood, Vitamin D Deficiency genetics, Vitamin D-Binding Protein blood, Vitamin D-Binding Protein genetics, Young Adult, Calcifediol blood, Melanoma blood, Skin Neoplasms blood
- Abstract
Background: We report the determinants of serum levels of vitamin D in a U.K. melanoma case-control study benefitting from detailed exposure and genotyping data., Methods: Sun exposure, supplemental vitamin D, and SNPs reported to be associated with serum levels were assessed as predictors of a single serum 25-hydroxyvitamin D3 measurement adjusted for season, age, sex, and body mass index., Results: Adjusted analyses showed that vitamin D levels were sub-optimal especially in the sun-sensitive individuals (-2.61 nmol/L, p = 0.03) and for inheritance of a genetic variant in the GC gene coding for the vitamin D-binding protein (-5.79 for heterozygotes versus wild type, p = <0.0001). Higher levels were associated with sun exposure at the weekend in summer (+4.71 nmol/L per tertile, p = <0.0001), and on hot holidays (+4.17 nmol/L per tertile, p = <0.0001). In smoothed scatter plots, vitamin D levels of 60 nmol/L in the non-sun-sensitive individuals were achieved after an average 6 h/day summer weekend sun exposure but not in the sun-sensitive individuals. Users of supplements had levels on average 11.0 nmol/L higher, p = <0.0001, and achieved optimal levels irrespective of sun exposure., Conclusions: Sun exposure was associated with increased vitamin D levels, but levels more than 60 nmol/L were reached on average only in individuals reporting lengthy exposure (≥12 h/weekend). The sun-sensitive individuals did not achieve optimal levels without supplementation, which therefore should be considered for the majority of populations living in a temperate climate and melanoma patients in particular. Inherited variation in genes such as GC is a strong factor, and carriers of variant alleles may therefore require higher levels of supplementation.
- Published
- 2011
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48. Relationship between sun exposure and melanoma risk for tumours in different body sites in a large case-control study in a temperate climate.
- Author
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Newton-Bishop JA, Chang YM, Elliott F, Chan M, Leake S, Karpavicius B, Haynes S, Fitzgibbon E, Kukalizch K, Randerson-Moor J, Elder DE, Bishop DT, and Barrett JH
- Subjects
- Adaptation, Physiological, Adult, Aged, Case-Control Studies, England, Environmental Exposure adverse effects, Environmental Exposure statistics & numerical data, Eye Color physiology, Female, Humans, Hydroxycholecalciferols blood, Male, Melanoma etiology, Middle Aged, Phenotype, Risk Factors, Skin Neoplasms etiology, Skin Pigmentation physiology, Sunburn complications, Sunburn epidemiology, Young Adult, Melanoma epidemiology, Skin Neoplasms epidemiology, Sunlight adverse effects
- Abstract
Aim: A melanoma case-control study was conducted to elucidate the complex relationship between sun exposure and risk., Methods: Nine hundred and sixty population-ascertained cases, 513 population and 174 sibling controls recruited in England provided detailed sun exposure and phenotype data; a subset provided serum 25-hydroxyvitamin D(2)+D(3) levels., Results: Phenotypes associated with a tendency to sunburn and reported sunburn at ≥ 20 years of age were associated with increased melanoma risk (odds ratio (OR) 1.56, 95% confidence intervals (CI) 1.23-1.99). Holiday sun exposure was not associated with an increased melanoma risk although this may be in part because reported sun exposure overall was much lower in those with a sun-sensitive phenotype, particularly among controls. Head and neck melanoma was associated with less sun exposure on holidays at low latitudes (OR 0.39, 95% CI (0.23-0.68) for >13 h/year compared to <3.1). Overall the clearest relationship between reported sun exposure and risk was for average weekend sun exposure in warmer months, which was protective (OR 0.67, 95% CI 0.50-0.89 for highest versus lowest tertile of exposure). Serum vitamin D levels were strongly associated with increased weekend and holiday sun exposure., Conclusions: Sun-sensitive phenotypes and reported sunburn were associated with an increased risk of melanoma. Although no evidence was seen of a causal relationship between holiday sun exposure and increased risk, this is consistent with the view that intense sun exposure is causal for melanoma in those prone to sunburn. A protective effect of regular weekend sun exposure was seen, particularly for limb tumours, which could be mediated by photoadaptation or higher vitamin D levels., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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49. Patterns of expression of DNA repair genes and relapse from melanoma.
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Jewell R, Conway C, Mitra A, Randerson-Moor J, Lobo S, Nsengimana J, Harland M, Marples M, Edward S, Cook M, Powell B, Boon A, de Kort F, Parker KA, Cree IA, Barrett JH, Knowles MA, Bishop DT, and Newton-Bishop J
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Pharmacological analysis, Biomarkers, Pharmacological metabolism, Cohort Studies, Disease-Free Survival, Female, Gene Expression Profiling, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Male, Melanoma drug therapy, Melanoma pathology, Recurrence, Skin Neoplasms drug therapy, Skin Neoplasms pathology, DNA Repair genetics, DNA Repair Enzymes genetics, Melanoma genetics, Skin Neoplasms genetics
- Abstract
Purpose: To use gene expression profiling of formalin-fixed primary melanoma samples to detect expression patterns that are predictive of relapse and response to chemotherapy., Experimental Design: Gene expression profiles were identified in samples from two studies (472 tumors). Gene expression data for 502 cancer-related genes from these studies were combined for analysis., Results: Increased expression of DNA repair genes most strongly predicted relapse and was associated with thicker tumors. Increased expression of RAD51 was the most predictive of relapse-free survival in unadjusted analysis (hazard ratio, 2.98; P = 8.80 × 10(-6)). RAD52 (hazard ratio, 4.73; P = 0.0004) and TOP2A (hazard ratio, 3.06; P = 0.009) were independent predictors of relapse-free survival in multivariable analysis. These associations persisted when the analysis was further adjusted for demographic and histologic features of prognostic importance (RAD52 P = 0.01; TOP2A P = 0.02). Using principal component analysis, expression of DNA repair genes was summarized into one variable. Genes whose expression correlated with this variable were predominantly associated with the cell cycle and DNA repair. In 42 patients treated with chemotherapy, DNA repair gene expression was greater in tumors from patients who progressed on treatment. Further data supportive of a role for increased expression of DNA repair genes as predictive biomarkers are reported, which were generated using multiplex PCR., Conclusions: Overexpression of DNA repair genes (predominantly those involved in double-strand break repair) was associated with relapse. These data support the hypothesis that melanoma progression requires maintenance of genetic stability and give insight into mechanisms of melanoma drug resistance and potential therapies., (©2010 AACR.)
- Published
- 2010
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50. Deletion at chromosome arm 9p in relation to BRAF/NRAS mutations and prognostic significance for primary melanoma.
- Author
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Conway C, Beswick S, Elliott F, Chang YM, Randerson-Moor J, Harland M, Affleck P, Marsden J, Sanders DS, Boon A, Knowles MA, Bishop DT, and Newton-Bishop JA
- Subjects
- Chromosome Mapping, Cluster Analysis, Cyclin-Dependent Kinase Inhibitor p15 genetics, Cyclin-Dependent Kinase Inhibitor p16 genetics, Cyclin-Dependent Kinase Inhibitor p16 metabolism, DNA Mutational Analysis, Gene Dosage, Histocytochemistry, Humans, Melanoma diagnosis, Melanoma metabolism, Nucleic Acid Amplification Techniques, Prognosis, Purine-Nucleoside Phosphorylase genetics, Purine-Nucleoside Phosphorylase metabolism, Statistics, Nonparametric, Tumor Suppressor Protein p14ARF genetics, Chromosomes, Human, Pair 9, Gene Deletion, Genes, ras, Melanoma genetics, Proto-Oncogene Proteins B-raf genetics
- Abstract
We report an investigation of gene dosage at 9p21.3 and mutations in BRAF and NRAS, as predictors of relapse and histological markers of poor melanoma prognosis. Formalin-fixed primary melanomas from 74 relapsed and 42 nonrelapsed patients were sequenced for common BRAF and NRAS mutations (N = 71 results) and gene dosage at 9p21.3 including the genes CDKN2A (which encodes CDKN2A and P14ARF), CDKN2B (CDKN2B), and MTAP was measured using multiplexed ligation-dependant probe amplification (MLPA), (N = 75 results). BRAF/NRAS mutations were detected in 77% of relapsers and 58% of nonrelapsers (Fisher's exact P = 0.17), and did not predict ulceration or mitotic rate. There was no relationship between BRAF/NRAS mutations and gene dosage at 9p21.3. Reduced gene dosage at MTAP showed a borderline association with BRAF mutation (P = 0.04) and reduced gene dosage at the interferon gene cluster was borderline associated with wild type NRAS (P = 0.05). Reduced gene dosage in the CDKN2A regions coding for CDKN2A was associated with an increased risk of relapse (P = 0.03). Reduced gene dosage across 9p21.3 was associated with increased tumor thickness, mitotic rate, and ulceration (P = 0.02, 0.02, and 0.002, respectively), specifically in coding regions impacting on CDKN2B and P14ARF and CDKN2A. Loss at MTAP (P = 0.05) and the interferon gene cluster (P = 0.03) on 9p21 was also associated with tumor ulceration. There was no association between reduced gene dosage at 9p21.3 and subtype or site of tumor. This study presents supportive evidence that CDKN2B, P14ARF, and CDKN2A may all play a tumor suppressor role in melanoma progression., ((c) 2010 Wiley-Liss, Inc.)
- Published
- 2010
- Full Text
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