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2. PDBe: improved accessibility of macromolecular structure data from PDB and EMDB.

Author

Sameer Velankar, Glen van Ginkel, Younes Alhroub, Gary M. Battle, John M. Berrisford, Matthew J. Conroy, Jose M. Dana, Swanand P. Gore, Aleksandras Gutmanas, Pauline Haslam, Pieter M. S. Hendrickx, Ingvar C. Lagerstedt, Saqib Mir, Manuel A. Fernandez Montecelo, Abhik Mukhopadhyay, Thomas J. Oldfield, Ardan Patwardhan, Eduardo Sanz-García, Sanchayita Sen, Robert A. Slowley, Michael E. Wainwright, Mandar S. Deshpande, Andrii Iudin, Gaurav Sahni, José Salavert Torres, Miriam Hirshberg, Lora Mak, Nurul Nadzirin, David R. Armstrong, Alice R. Clark, Oliver S. Smart, Paul K. Korir, and Gerard J. Kleywegt

Published
2016
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3. EMDataBank unified data resource for 3DEM.

Author

Catherine L. Lawson, Ardan Patwardhan, Matthew L. Baker, Corey Hryc, Eduardo Sanz-García, Brian P. Hudson, Ingvar C. Lagerstedt, Steven J. Ludtke, Grigore Pintilie, Raul Sala, John D. Westbrook, Helen M. Berman, Gerard J. Kleywegt, and Wah Chiu

Published
2016
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4. PDBe: Protein Data Bank in Europe.

Author

Aleksandras Gutmanas, Younes Alhroub, Gary M. Battle, John M. Berrisford, Estelle Bochet, Matthew J. Conroy, Jose M. Dana, Manuel A. Fernandez Montecelo, Glen van Ginkel, Swanand P. Gore, Pauline Haslam, Rowan Hatherley, Pieter M. S. Hendrickx, Miriam Hirshberg, Ingvar C. Lagerstedt, Saqib Mir, Abhik Mukhopadhyay, Thomas J. Oldfield, Ardan Patwardhan, Luana Rinaldi, Gaurav Sahni, Eduardo Sanz-García, Sanchayita Sen, Robert A. Slowley, Sameer Velankar, Michael E. Wainwright, and Gerard J. Kleywegt

Published
2014
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6. PDBe: Protein Data Bank in Europe.

Author

Sameer Velankar, Younes Alhroub, Christoph Best, Ségolène Caboche, Matthew J. Conroy, Jose M. Dana, Manuel A. Fernandez Montecelo, Glen van Ginkel, Adel Golovin, Swanand P. Gore, Aleksandras Gutmanas, Pauline Haslam, Pieter M. S. Hendrickx, Egon Heuson, Miriam Hirshberg, Melford John, Ingvar C. Lagerstedt, Saqib Mir, Laurence E. Newman, Thomas J. Oldfield, Ardan Patwardhan, Luana Rinaldi, Gaurav Sahni, Eduardo Sanz-García, Sanchayita Sen, Robert A. Slowley, Antonio Suarez-Uruena, G. J. Swaminathan, Martyn F. Symmons, Wim F. Vranken, Michael E. Wainwright, and Gerard J. Kleywegt

Published
2012
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8. EMDataBank.org: unified data resource for CryoEM.

Author

Catherine L. Lawson, Matthew L. Baker, Christoph Best, Chunxiao Bi, Matthew T. Dougherty, Powei Feng, Glen van Ginkel, Batsal Devkota, Ingvar C. Lagerstedt, Steven J. Ludtke, Richard H. Newman, Thomas J. Oldfield, Ian Rees, Gaurav Sahni, Raul Sala, Sameer Velankar, Joe D. Warren, John D. Westbrook, Kim Henrick, Gerard J. Kleywegt, Helen M. Berman, and Wah Chiu

Published
2011
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9. PDBe: Protein Data Bank in Europe.

Author

Sameer Velankar, Younes Alhroub, Anaëlle Alili, Christoph Best, Harry Boutselakis, Ségolène Caboche, Matthew J. Conroy, Jose M. Dana, Glen van Ginkel, Adel Golovin, Swanand P. Gore, Aleksandras Gutmanas, Pauline Haslam, Miriam Hirshberg, Melford John, Ingvar C. Lagerstedt, Saqib Mir, Laurence E. Newman, Thomas J. Oldfield, Christopher J. Penkett, Jorge Pineda-Castillo, Luana Rinaldi, Gaurav Sahni, Grégoire Sawka, Sanchayita Sen, Robert A. Slowley, Alan W. Sousa da Silva, Antonio Suarez-Uruena, Jawahar Swaminathan, Martyn F. Symmons, Wim F. Vranken, Michael E. Wainwright, and Gerard J. Kleywegt

Published
2011
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12. Survival in 31 670 patients with thin melanomas: a Swedish population-based study

Author

Isaksson, K., Mikiver, R., Eriksson, H., Lapins, J., Nielsen, K., Ingvar, C., Lyth, Johan, Isaksson, K., Mikiver, R., Eriksson, H., Lapins, J., Nielsen, K., Ingvar, C., and Lyth, Johan

Abstract

Background The incidence of cutaneous malignant melanoma (CMM) continues to increase in most countries worldwide and the majority are diagnosed with thin tumours (<= 1 mm). Objectives The aim of the present study was to investigate the melanoma-specific survival (MSS) as well as conditional MSS (CMSS) in patients with thin CMM in Sweden. Patients and methods Clinical and histological parameters were obtained from the Swedish Melanoma Registry for patients diagnosed with thin CMM between 1990 and 2017. Patients were followed until the end of 2017. MSS as well as CMSS for different thickness groups were calculated using the Kaplan-Meier method and Cox regression analyses were used to calculate for survival differences between thickness groups. Results There were 31 670 patients included for final analyses. The overall 10- and 20-year MSS for thin CMMs was 97% [95% confidence interval (CI) 97-97] and 95% (95% CI 95-96), respectively. From 0 center dot 7 mm and above, MSS decreased significantly with increasing thickness level. All thickness groups had an increased survival over time. The lowest CMSS was confirmed for men with 1 center dot 0 mm in thickness but their 10-year CMSS increased steadily over time. Women had overall better MSS as well as CMSS than men. However, the relation between MSS and CMSS was similar for both sexes. Conclusions MSS was confirmed as excellent for patients with thin CMMs in Sweden. Although we could show a decreased MSS for patients with 0 center dot 7 mm thickness and above, the long-term survival and, in addition, a very favourable CMSS for those patients do not support more extended follow-up programmes than the current recommendations in Sweden. What is already known about this topic? The majority of patients with cutaneous malignant melanoma are diagnosed with thin melanomas (<= 1 mm) and the survival is generally reported as favourable. What does this study add? Our national population-based designed study, including 3, Funding Agencies|M. Paulsson Fund; Gorthon Foundation; S. Paulsson Fund; LMK Foundation; Welander Finsen Foundation

Published
2021
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16. Overlapping genetic architecture between Parkinson disease and melanoma

Author

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

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

Author

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

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

Author

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

Abstract

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

Published
2020

19. Long-term outcome of pT1a-b, cN0 breast cancer without axillary dissection or staging : a prospective observational study of 1543 women

Author

Ingvar, C., Ahlgren, J., Emdin, Stefan, Lofgren, L., Nordander, M., Nimeus, E., Arnesson, L-G, Ingvar, C., Ahlgren, J., Emdin, Stefan, Lofgren, L., Nordander, M., Nimeus, E., and Arnesson, L-G

Abstract

Background: The implementation of screening programmes in Sweden during the mid‐1990s increased the number of small node‐negative breast cancers. In this era before staging by sentinel node biopsy, routine axillary dissection for staging of early breast cancer was questioned owing to the increased morbidity and lack of perceived benefit. The long‐term risk of axillary recurrence when axillary staging is omitted remains unclear. Methods: This prospective observational multicentre cohort study included Swedish women diagnosed with breast cancer between 1997 and 2002. The patients had clinically node‐negative, pT1a–b, grade I–II tumours. No axillary staging or dissection was performed. The primary outcome was ipsilateral axillary recurrence and survival. Results: A total of 1543 patients were included. Breast‐conserving surgery (BCS) was performed in 94·0 per cent and the rest underwent mastectomy. After surgery, 58·1 per cent of the women received adjuvant radiotherapy, 11·9 per cent adjuvant endocrine therapy and 31·5 per cent did not receive any adjuvant treatment. After a median follow‐up of 15·5 years, 6·4 per cent developed contralateral breast cancer and 16·5 per cent experienced a recurrence. The first recurrence was local in 116, regional in 47 and distant in 59 patients. The breast cancer‐specific survival rate was 93·7 per cent after 15 years. There were no differences in overall or breast cancer‐specific survival between patients who received adjuvant radiotherapy and those who did not. Only 3·0 per cent of patients had an axillary recurrence, which was isolated in only 1·0 per cent. Conclusion: Axillary surgery can safely be omitted in patients with low‐grade, T1a–b, cN0 breast cancers. This large prospective cohort with 15‐year follow‐up had a very low incidence of axillary recurrences and high breast cancer‐specific survival rate.

Published
2020
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20. Overlapping genetic architecture between Parkinson disease and melanoma

Author

Dube, Umber, Ibanez, Laura, Budde, John P., Benitez, Bruno A., Davis, Albert A., Harari, Oscar, Iles, M. M., Law, Matthew H., Brown, Kevin M., Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Furlotte, Nicholas A., Hinds, David A., Huber, Karen E., Kleinman, Aaron, Litterman, Nadia K., McCreight, Jennifer C., McIntyre, Matthew H., Mountain, Joanna L., 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., Vacic, Vladimir, Wilson, Catherine 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., Scarrà, G. B., Brown, K. M., 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., Hočevar, M., Höiom, V., Ingvar, C., Kanetsky, P. A., Chen, W. V., Landi, M. T., Lang, J., Lathrop, G. M., Lubiński, J., Mackie, R. M., Mann, G. J., Molven, A., Montgomery, G. W., Novaković, 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., Cruchaga, Carlos, other, and, Dube, Umber, Ibanez, Laura, Budde, John P., Benitez, Bruno A., Davis, Albert A., Harari, Oscar, Iles, M. M., Law, Matthew H., Brown, Kevin M., Agee, Michelle, Alipanahi, Babak, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Elson, Sarah L., Fontanillas, Pierre, Furlotte, Nicholas A., Hinds, David A., Huber, Karen E., Kleinman, Aaron, Litterman, Nadia K., McCreight, Jennifer C., McIntyre, Matthew H., Mountain, Joanna L., 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., Vacic, Vladimir, Wilson, Catherine 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., Scarrà, G. B., Brown, K. M., 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., Hočevar, M., Höiom, V., Ingvar, C., Kanetsky, P. A., Chen, W. V., Landi, M. T., Lang, J., Lathrop, G. M., Lubiński, J., Mackie, R. M., Mann, G. J., Molven, A., Montgomery, G. W., Novaković, 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., Cruchaga, Carlos, and other, and

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 × 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 × 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

30. Association of MC1R Variants and Host Phenotypes With Melanoma Risk in CDKN2A Mutation Carriers: A GenoMEL Study

Author

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
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32. Overlapping genetic architecture between Parkinson disease and melanoma

Author

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.

Subjects
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

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

Author

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

Published
2019

36. Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways

Author

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

Subjects
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.

Published
2018

37. Cell-type–specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes

Author

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.

Subjects
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.

Published
2018

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

Author

Duffy, DL, Zhu, G, Li, X, Sanna, M, Iles, MM, Jacobs, LC, Evans, DM, Yazar, S, Beesley, J, Law, MH, Kraft, P, Visconti, A, Taylor, JC, Liu, F, Wright, MJ, Henders, AK, Bowdler, L, Glass, D, Ikram, MA, Uitterlinden, AG, Madden, PA, Heath, AC, Nelson, EC, Green, AC, Chanock, S, Barrett, JH, Brown, MA, Hayward, NK, MacGregor, S, Sturm, RA, Hewitt, AW, Kayser, M, Hunter, DJ, Bishop, JAN, Spector, TD, Montgomery, GW, Mackey, DA, Smith, GD, Nijsten, TE, Bishop, DT, Bataille, V, Falchi, M, Han, J, Martin, NG, 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, M-F, Azizi, E, Scarra, GB, Brown, KM, Debniak, T, Elder, DE, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, EM, Goldstein, AM, Gruis, NA, Hansson, J, Helsing, P, Hocevar, M, Hoiom, V, Ingvar, C, Kanetsky, PA, Chen, WV, Landi, MT, Lang, J, Lathrop, GM, Lubinski, J, Mackie, RM, Mann, GJ, Molven, A, Novakovic, 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, H-J, Dunning, AM, Demenais, F, Amos, CI, Duffy, DL, Zhu, G, Li, X, Sanna, M, Iles, MM, Jacobs, LC, Evans, DM, Yazar, S, Beesley, J, Law, MH, Kraft, P, Visconti, A, Taylor, JC, Liu, F, Wright, MJ, Henders, AK, Bowdler, L, Glass, D, Ikram, MA, Uitterlinden, AG, Madden, PA, Heath, AC, Nelson, EC, Green, AC, Chanock, S, Barrett, JH, Brown, MA, Hayward, NK, MacGregor, S, Sturm, RA, Hewitt, AW, Kayser, M, Hunter, DJ, Bishop, JAN, Spector, TD, Montgomery, GW, Mackey, DA, Smith, GD, Nijsten, TE, Bishop, DT, Bataille, V, Falchi, M, Han, J, Martin, NG, 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, M-F, Azizi, E, Scarra, GB, Brown, KM, Debniak, T, Elder, DE, Fang, S, Friedman, E, Galan, P, Ghiorzo, P, Gillanders, EM, Goldstein, AM, Gruis, NA, Hansson, J, Helsing, P, Hocevar, M, Hoiom, V, Ingvar, C, Kanetsky, PA, Chen, WV, Landi, MT, Lang, J, Lathrop, GM, Lubinski, J, Mackie, RM, Mann, GJ, Molven, A, Novakovic, 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, H-J, Dunning, AM, Demenais, F, and Amos, CI

Abstract

The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.

Published
2019

45. Abstract P2-08-26: High expression of CYP27A1 in breast cancer is associated with poor tumor pathological features and may differentially predict prognosis depending on menopausal status

Author

Kimbung, S, primary, Stålhammar, T, additional, Inasu, M, additional, Nodin, B, additional, Elebro, K, additional, Tryggvadottir, H, additional, Jirström, K, additional, Rose, C, additional, Ingvar, C, additional, Jernström, H, additional, and Borgquist, S, additional

Published
2019
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48. Primary Melanoma Tumors from CDKN2A Mutation Carriers Do Not Belong to a Distinct Molecular Subclass

Author

Staaf, J., Harbst, K., Lauss, M., Ringner, M., Masback, A., Howlin, J., Jirstrom, K., Harland, M., Zebary, A., Palmer, J.M., Ingvar, C., Olsson, H., Newton-Bishop, J., Hansson, J., Hayward, N., Gruis, N., Jonsson, G., and Melanoma Genetics Consortium

Subjects
Adult, Male, Proto-Oncogene Proteins B-raf, Heterozygote, CDKN2A Mutation, Pathology, medicine.medical_specialty, Skin Neoplasms, Adolescent, Dermatology, Biology, Biochemistry, Subclass, GTP Phosphohydrolases, Young Adult, medicine, Humans, Melanoma, Nevus, Molecular Biology, Cyclin-Dependent Kinase Inhibitor p16, Aged, Aged, 80 and over, Gene Expression Profiling, Australia, Membrane Proteins, Cancer, Cell Biology, Middle Aged, medicine.disease, Europe, Phenotype, Case-Control Studies, Mutation, Cancer research, Immunohistochemistry, Female
Abstract

Abbreviations: AJCC, American Joint Committee on Cancer; CMM, cutaneous malignant melanoma; IHC, immunohistochemical; PCA, principal component analysis

Published
2014
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49. Germline variation at CDKN2A and associations with nevus phenotypes among members of melanoma families

Author

Taylor, N.J., Mitra, N., Goldstein, A.M., Tucker, M.A., Avil, M.F., Azizi, E., Bergman, W., Bishop, D.T., Bressac-de Paillerets, B., Bruno, W., Calista, D., Cannon-Albright, L.A., Cuellar, F., Cust, A.E., Demenais, F., Elder, D.E., Gerdes, A.M., Ghiorzo, P., Grazziotin, T.C., Hansson, J., Harland, M., Hayward, N.K., Hocevar, M., Hoiom, V., Ingvar, C., Landi, M.T., Landman, G., Larre-Borges, A., Leachman, S.A., Mann, G.J., Nagore, E., Olsson, H., Palmer, J.M., Peric, B., Pjanova, D., Pritchard, A., Puig, S., Stoep, N. van der, Wadt, K.A.W., Whitaker, L., Yang, X.R., Bishop, J.A.N., Gruis, N.A., Kanetsky, P.A., and GenoMEL Study Grp

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Skin Neoplasms, Genotype, DNA Mutational Analysis, Dermatology, Biology, Biochemistry, Article, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, CDKN2A, medicine, Odds Ratio, Nevus, Cyclin-Dependent Kinase Inhibitor p18, Humans, Registries, skin and connective tissue diseases, Molecular Biology, neoplasms, Melanoma, Cyclin-Dependent Kinase Inhibitor p16, Germ-Line Mutation, Genetics, Family Health, Nevus, Pigmented, Cell Biology, Odds ratio, medicine.disease, Atypical nevus, Confidence interval, 030104 developmental biology, Phenotype, 030220 oncology & carcinogenesis, Medical genetics, Female
Abstract

Germline mutations in CDKN2A are frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18–2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92–1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94–1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75–4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2A and may influence carcinogenesis.

Published
2017

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

Author

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.

Subjects
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.

Published
2017

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