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

Author

Landi, Maria Teresa, Bishop, D. Timothy, MacGregor, Stuart, Machiela, Mitchell J., Stratigos, Alexander J., Ghiorzo, Paola, Brossard, Myriam, Calista, Donato, Choi, Jiyeon, Fargnoli, Maria Concetta, Zhang, Tongwu, Rodolfo, Monica, Trower, Adam J., Menin, Chiara, Martinez, Jacobo, Hadjisavvas, Andreas, Song, Lei, Stefanaki, Irene, Scolyer, Richard, Yang, Rose, Goldstein, Alisa M., Potrony, Miriam, Kypreou, Katerina P., Pastorino, Lorenza, Queirolo, Paola, Pellegrini, Cristina, Cattaneo, Laura, Zawistowski, Matthew, Gimenez-Xavier, Pol, Rodriguez, Arantxa, Elefanti, Lisa, Manoukian, Siranoush, Rivoltini, Licia, Smith, Blair H., Loizidou, Maria A., Del Regno, Laura, Massi, Daniela, Mandala, Mario, Khosrotehrani, Kiarash, Akslen, Lars A., Amos, Christopher I., Andresen, Per A., Avril, Marie-Françoise, Azizi, Esther, Soyer, H. Peter, Bataille, Veronique, Dalmasso, Bruna, Bowdler, Lisa M., Burdon, Kathryn P., Chen, Wei V., Codd, Veryan, Craig, Jamie E., Dębniak, Tadeusz, Falchi, Mario, Fang, Shenying, Friedman, Eitan, Simi, Sarah, Galan, Pilar, Garcia-Casado, Zaida, Gillanders, Elizabeth M., Gordon, Scott, Green, Adele, Gruis, Nelleke A., Hansson, Johan, Harland, Mark, Harris, Jessica, Helsing, Per, Henders, Anjali, Hočevar, Marko, Höiom, Veronica, Hunter, David, Ingvar, Christian, Kumar, Rajiv, Lang, Julie, Lathrop, G. Mark, Lee, Jeffrey E., Li, Xin, Lubiński, Jan, Mackie, Rona M., Malt, Maryrose, Malvehy, Josep, McAloney, Kerrie, Mohamdi, Hamida, Molven, Anders, Moses, Eric K., Neale, Rachel E., Novaković, Srdjan, Nyholt, Dale R., Olsson, Håkan, Orr, Nicholas, Fritsche, Lars G., Puig-Butille, Joan Anton, Qureshi, Abrar A., Radford-Smith, Graham L., Randerson-Moor, Juliette, Requena, Celia, Rowe, Casey, Samani, Nilesh J., Sanna, Marianna, Schadendorf, Dirk, Schulze, Hans-Joachim, Simms, Lisa A., Smithers, Mark, Song, Fengju, Swerdlow, Anthony J., van der Stoep, Nienke, Kukutsch, Nicole A., Visconti, Alessia, Wallace, Leanne, Ward, Sarah V., Wheeler, Lawrie, Sturm, Richard A., Hutchinson, Amy, Jones, Kristine, Malasky, Michael, Vogt, Aurelie, Zhou, Weiyin, Pooley, Karen A., Elder, David E., Han, Jiali, Hicks, Belynda, Hayward, Nicholas K., Kanetsky, Peter A., Brummett, Chad, Montgomery, Grant W., Olsen, Catherine M., Hayward, Caroline, Dunning, Alison M., Martin, Nicholas G., Evangelou, Evangelos, Mann, Graham J., Long, Georgina, Pharoah, Paul D. P., Easton, Douglas F., Barrett, Jennifer H., Cust, Anne E., Abecasis, Goncalo, Duffy, David L., Whiteman, David C., Gogas, Helen, De Nicolo, Arcangela, Tucker, Margaret A., Newton-Bishop, Julia A., Peris, Ketty, Chanock, Stephen J., Demenais, Florence, Brown, Kevin M., Puig, Susana, Nagore, Eduardo, Shi, Jianxin, Iles, Mark M., and Law, Matthew H.

Published
2020
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2. Gene-Level Associations in Patients With and Without Pathogenic Germline Variants in CDKN2A and Pancreatic Cancer

Author

Astiazaran-Symonds, Esteban, Graham, Cole, Kim, Jung, Tucker, Margaret A., Ingvar, Christian, Helgadottir, Hildur, Pastorino, Lorenza, van Doorn, Remco, Sampson, Joshua N., Zhu, Bin, Bruno, William, Queirolo, Paola, Fornarini, Giuseppe, Sciallero, Stefania, Carter, Brian, Hicks, Belynda, Hutchinson, Amy, Jones, Kristine, Stewart, Douglas R., Chanock, Stephen J., Freedman, Neal D., Landi, Maria Teresa, Höiom, Veronica, Puig, Susana, Gruis, Nelleke, Yang, Xiaohong R., Ghiorzo, Paola, and Goldstein, Alisa M.

Published
2022
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4. Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families

Author

Taylor, Nicholas J., Mitra, Nandita, Goldstein, Alisa M., Tucker, Margaret A., Avril, Marie-Françoise, Azizi, Esther, Bergman, Wilma, Bishop, D. Timothy, Bressac-de Paillerets, Brigitte, Bruno, William, Calista, Donato, Cannon-Albright, Lisa A., Cuellar, Francisco, Cust, Anne E., Demenais, Florence, Elder, David E., Gerdes, Anne-Marie, Ghiorzo, Paola, Grazziotin, Thais C., Hansson, Johan, Harland, Mark, Hayward, Nicholas K., Hocevar, Marko, Höiom, Veronica, Ingvar, Christian, Landi, Maria Teresa, Landman, Gilles, Larre-Borges, Alejandra, Leachman, Sancy A., Mann, Graham J., Nagore, Eduardo, Olsson, Håkan, Palmer, Jane M., Perić, Barbara, Pjanova, Dace, Pritchard, Antonia, Puig, Susana, van der Stoep, Nienke, Wadt, Karin A.W., Whitaker, Linda, Yang, Xiaohong R., Newton Bishop, Julia A., Gruis, Nelleke A., and Kanetsky, Peter A.

Published
2017
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7. Supplementary Methods, Tables 1-5, Figures 1-4 from Development and Validation of a Melanoma Risk Score Based on Pooled Data from 16 Case–Control Studies

Author

Davies, John R., primary, Chang, Yu-mei, primary, Bishop, D. Timothy, primary, Armstrong, Bruce K., primary, Bataille, Veronique, primary, Bergman, Wilma, primary, Berwick, Marianne, primary, Bracci, Paige M., primary, Elwood, J. Mark, primary, Ernstoff, Marc S., primary, Green, Adele, primary, Gruis, Nelleke A., primary, Holly, Elizabeth A., primary, Ingvar, Christian, primary, Kanetsky, Peter A., primary, Karagas, Margaret R., primary, Lee, Tim K., primary, Le Marchand, Loïc, primary, Mackie, Rona M., primary, Olsson, Håkan, primary, Østerlind, Anne, primary, Rebbeck, Timothy R., primary, Reich, Kristian, primary, Sasieni, Peter, primary, Siskind, Victor, primary, Swerdlow, Anthony J., primary, Titus, Linda, primary, Zens, Michael S., primary, Ziegler, Andreas, primary, Gallagher, Richard P., primary, Barrett, Jennifer H., primary, and Newton-Bishop, Julia, primary

Published
2023
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8. Data from Development and Validation of a Melanoma Risk Score Based on Pooled Data from 16 Case–Control Studies

Author

Davies, John R., primary, Chang, Yu-mei, primary, Bishop, D. Timothy, primary, Armstrong, Bruce K., primary, Bataille, Veronique, primary, Bergman, Wilma, primary, Berwick, Marianne, primary, Bracci, Paige M., primary, Elwood, J. Mark, primary, Ernstoff, Marc S., primary, Green, Adele, primary, Gruis, Nelleke A., primary, Holly, Elizabeth A., primary, Ingvar, Christian, primary, Kanetsky, Peter A., primary, Karagas, Margaret R., primary, Lee, Tim K., primary, Le Marchand, Loïc, primary, Mackie, Rona M., primary, Olsson, Håkan, primary, Østerlind, Anne, primary, Rebbeck, Timothy R., primary, Reich, Kristian, primary, Sasieni, Peter, primary, Siskind, Victor, primary, Swerdlow, Anthony J., primary, Titus, Linda, primary, Zens, Michael S., primary, Ziegler, Andreas, primary, Gallagher, Richard P., primary, Barrett, Jennifer H., primary, and Newton-Bishop, Julia, primary

Published
2023
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11. Multiple rare variants in high-risk pancreatic cancer-related genes may increase risk for pancreatic cancer in a subset of patients with and without germline CDKN2A mutations

Author

Yang, Xiaohong R., Rotunno, Melissa, Xiao, Yanzi, Ingvar, Christian, Helgadottir, Hildur, Pastorino, Lorenza, van Doorn, Remco, Bennett, Hunter, Graham, Cole, Sampson, Joshua N., Malasky, Michael, Vogt, Aurelie, Zhu, Bin, Bianchi-Scarra, Giovanna, Bruno, William, Queirolo, Paola, Fornarini, Giuseppe, Hansson, Johan, Tuominen, Rainer, Burdett, Laurie, Hicks, Belynda, Hutchinson, Amy, Jones, Kristine, Yeager, Meredith, Chanock, Stephen J., Landi, Maria Teresa, Höiom, Veronica, Olsson, Håkan, Gruis, Nelleke, Ghiorzo, Paola, Tucker, Margaret A., and Goldstein, Alisa M.

Published
2016
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12. Germline TERT promoter mutations are rare in familial melanoma

Author

Harland, Mark, Petljak, Mia, Robles-Espinoza, Carla Daniela, Ding, Zhihao, Gruis, Nelleke A., van Doorn, Remco, Pooley, Karen A., Dunning, Alison M., Aoude, Lauren G., Wadt, Karin A. W., Gerdes, Anne-Marie, Brown, Kevin M., Hayward, Nicholas K., Newton-Bishop, Julia A., Adams, David J., and Bishop, D. Timothy

Published
2016
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13. Germline CDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma

Author

Jouenne, Fanélie, Chauvot de Beauchene, Isaure, Bollaert, Emeline, Avril, Marie-Françoise, Caron, Olivier, Ingster, Olivier, Lecesne, Axel, Benusiglio, Patrick, Terrier, Philippe, Caumette, Vincent, Pissaloux, Daniel, de la Fouchardière, Arnaud, Cabaret, Odile, N’Diaye, Birama, Velghe, Amélie, Bougeard, Gaelle, Mann, Graham J, Koscielny, Serge, Barrett, Jennifer H, Harland, Mark, Newton-Bishop, Julia, Gruis, Nelleke, Van Doorn, Remco, Gauthier-Villars, Marion, Pierron, Gaelle, Stoppa-Lyonnet, Dominique, Coupier, Isabelle, Guimbaud, Rosine, Delnatte, Capucine, Scoazec, Jean-Yves, Eggermont, Alexander M, Feunteun, Jean, Tchertanov, Luba, Demoulin, Jean-Baptiste, Frebourg, Thierry, and Bressac-de Paillerets, Brigitte

Published
2017
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14. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma

Author

Law, Matthew H, Bishop, D Timothy, Lee, Jeffrey E, Brossard, Myriam, Martin, Nicholas G, Moses, Eric K, Song, Fengju, Barrett, Jennifer H, Kumar, Rajiv, Easton, Douglas F, Pharoah, Paul D P, Swerdlow, Anthony J, Kypreou, Katerina P, Taylor, John C, Harland, Mark, Randerson-Moor, Juliette, Akslen, Lars A, Andresen, Per A, Avril, Marie-Françoise, Azizi, Esther, Scarrà, Giovanna Bianchi, Brown, Kevin M, Dȩbniak, Tadeusz, Duffy, David L, Elder, David E, Fang, Shenying, Friedman, Eitan, Galan, Pilar, Ghiorzo, Paola, Gillanders, Elizabeth M, Goldstein, Alisa M, Gruis, Nelleke A, Hansson, Johan, Helsing, Per, Hočevar, Marko, Höiom, Veronica, Ingvar, Christian, Kanetsky, Peter A, Chen, Wei V, Landi, Maria Teresa, Lang, Julie, Lathrop, G Mark, Lubiński, Jan, Mackie, Rona M, Mann, Graham J, Molven, Anders, Montgomery, Grant W, Novaković, Srdjan, Olsson, Håkan, Puig, Susana, Puig-Butille, Joan Anton, Qureshi, Abrar A, Radford-Smith, Graham L, van der Stoep, Nienke, van Doorn, Remco, Whiteman, David C, Craig, Jamie E, Schadendorf, Dirk, Simms, Lisa A, Burdon, Kathryn P, Nyholt, Dale R, Pooley, Karen A, Orr, Nick, Stratigos, Alexander J, Cust, Anne E, Ward, Sarah V, Hayward, Nicholas K, Han, Jiali, Schulze, Hans-Joachim, Dunning, Alison M, Bishop, Julia A Newton, Demenais, Florence, Amos, Christopher I, MacGregor, Stuart, and Iles, Mark M

Published
2015
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15. Nonsense Mutations in the Shelterin Complex Genes ACD and TERF2IP in Familial Melanoma

Author

Aoude, Lauren G., Pritchard, Antonia L., Robles-Espinoza, Carla Daniela, Wadt, Karin, Harland, Mark, Choi, Jiyeon, Gartside, Michael, Quesada, Víctor, Johansson, Peter, Palmer, Jane M., Ramsay, Andrew J., Zhang, Xijun, Jones, Kristine, Symmons, Judith, Holland, Elizabeth A., Schmid, Helen, Bonazzi, Vanessa, Woods, Susan, Dutton-Regester, Ken, Stark, Mitchell S., Snowden, Helen, van Doorn, Remco, Montgomery, Grant W., Martin, Nicholas G., Keane, Thomas M., López-Otín, Carlos, Gerdes, Anne-Marie, Olsson, Håkan, Ingvar, Christian, Borg, Åke, Gruis, Nelleke A., Trent, Jeffrey M., Jönsson, Göran, Bishop, D. Timothy, Mann, Graham J., Newton-Bishop, Julia A., Brown, Kevin M., Adams, David J., and Hayward, Nicholas K.

Published
2015
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18. Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions

Author

Barrett, Jennifer H., Taylor, John C., Bright, Chloe, Harland, Mark, Dunning, Alison M., Akslen, Lars A., Andresen, Per A., Avril, Marie-Françoise, Azizi, Esther, Bianchi Scarrà, Giovanna, Brossard, Myriam, Brown, Kevin M., Dębniak, Tadeusz, Elder, David E., Friedman, Eitan, Ghiorzo, Paola, Gillanders, Elizabeth M., Gruis, Nelleke A., Hansson, Johan, Helsing, Per, Hočevar, Marko, Höiom, Veronica, Ingvar, Christian, Landi, Maria Teresa, Lang, Julie, Lathrop, Mark G., Lubiński, Jan, Mackie, Rona M., Molven, Anders, Novaković, Srdjan, Olsson, Håkan, Puig, Susana, Puig-Butille, Joan Anton, van der Stoep, Nienke, van Doorn, Remco, van Workum, Wilbert, Goldstein, Alisa M., Kanetsky, Peter A., Pharoah, Paul D. P., Demenais, Florence, Hayward, Nicholas K., Newton Bishop, Julia A., Bishop, Timothy D., and Iles, Mark M.

Published
2015
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19. MC1R variants increased the risk of sporadic cutaneous melanoma in darker-pigmented Caucasians: A pooled-analysis from the M-SKIP project

Author

Pasquali, Elena, García-Borrón, José C., Fargnoli, Maria Concetta, Gandini, Sara, Maisonneuve, Patrick, Bagnardi, Vincenzo, Specchia, Claudia, Liu, Fan, Kayser, Manfred, Nijsten, Tamar, Nagore, Eduardo, Kumar, Rajiv, Hansson, Johan, Kanetsky, Peter A., Ghiorzo, Paola, Debniak, Tadeusz, Branicki, Wojciech, Gruis, Nelleke A., Han, Jiali, Dwyer, Terry, Blizzard, Leigh, Landi, Maria Teresa, Palmieri, Giuseppe, Ribas, Gloria, Stratigos, Alexander, Council, Laurin M., Autier, Philippe, Little, Julian, Newton-Bishop, Julia, Sera, Francesco, and Raimondi, Sara

Published
2015
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20. Additional file 1 of Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families

Author

Lacson, John Charles A., Zamani, Shawn A., Froes, Luis Alberto Ribeiro, Mitra, Nandita, Qian, Lu, Scarlet H. Doyle, Azizi, Esther, Balestrini, Claudia, D. Timothy Bishop, Bruno, William, Carlos-Ortega, Blanca, Cuellar, Francisco, Cust, Anne E., E., David, Gerdes, Anne-Marie, Ghiorzo, Paola, Thais C. Grazziotin, Gruis, Nelleke A., Hansson, Johan, Hočevar, Marko, Höiom, Veronica, Holland, Elizabeth A., Ingvar, Christian, Landman, Gilles, Larre-Borges, Alejandra, Mann, Graham J., Molgo, Montserrat, Moredo, Luciana Facure, Olsson, Håkan, Out-Luiting, Jacoba J., Perić, Barbara, Pjanova, Dace, Puig, Susana, Salas-Alanis, Julio, Schmid, Helen, Wadt, Karin A. W., Newton-Bishop, Julia A., and Kanetsky, Peter A.

Subjects
neoplasms
Abstract

Additional file 1 : Module 1. Residency calendar, demographics, phenotype, and history of melanoma.

Published
2021
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21. Additional file 2 of Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families

Author

Lacson, John Charles A., Zamani, Shawn A., Froes, Luis Alberto Ribeiro, Mitra, Nandita, Qian, Lu, Scarlet H. Doyle, Azizi, Esther, Balestrini, Claudia, D. Timothy Bishop, Bruno, William, Carlos-Ortega, Blanca, Cuellar, Francisco, Cust, Anne E., E., David, Gerdes, Anne-Marie, Ghiorzo, Paola, Thais C. Grazziotin, Gruis, Nelleke A., Hansson, Johan, Hočevar, Marko, Höiom, Veronica, Holland, Elizabeth A., Ingvar, Christian, Landman, Gilles, Larre-Borges, Alejandra, Mann, Graham J., Molgo, Montserrat, Moredo, Luciana Facure, Olsson, Håkan, Out-Luiting, Jacoba J., Perić, Barbara, Pjanova, Dace, Puig, Susana, Salas-Alanis, Julio, Schmid, Helen, Wadt, Karin A. W., Newton-Bishop, Julia A., and Kanetsky, Peter A.

Abstract

Additional file 2 : Module 2. Personal sun exposure

Published
2021
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22. The importance of motivation in selecting undergraduate medical students for extracurricular research programmes

Author

Ommering, Belinda, van Blankenstein, Floris, van Diepen, Merel, Gruis, Nelleke, Kool, Ada, Dekker, Friedo, Ommering, Belinda, van Blankenstein, Floris, van Diepen, Merel, Gruis, Nelleke, Kool, Ada, and Dekker, Friedo

Abstract

INTRODUCTION: Extracurricular research programmes (ERPs) may contribute to reducing the current shortage in physician-scientists, but usually select students based on grades only. The question arises if students should be selected based on their motivation, regardless of their previous academic performance. Focusing on grades and lacking to take motivation into account when selecting students for ERPs might exclude an important target group when aiming to cultivate future physician-scientists. Therefore, this study compared ERP students with lower and higher previous academic performance on subsequent academic performance, ERP performance, and motivational factors.METHODS: Prospective cohort study with undergraduate medical students who filled in a yearly questionnaire on motivational factors. Two student groups participating in an ERP were compared: students with first-year grade point average (GPA) ≥7 versus <7 on a 10-point grading scale. Linear and logistic regressions analyses were used to compare groups on subsequent academic performance (i.e. third-year GPA, in-time bachelor completion), ERP performance (i.e. drop-out, number of credits), and motivational factors (i.e. intrinsic motivation for research, research self-efficacy beliefs, perceptions of research, curiosity), while adjusting for gender and motivational factors at baseline.RESULTS: The <7 group had significantly lower third-year GPA, and significantly higher odds for ERP drop-out than the ≥7 group. However, there was no significant between-group difference on in-time bachelor completion and the <7 group was not inferior to the ≥7 group in terms of intrinsic motivation for research, perceptions of research, and curiosity.CONCLUSIONS: Since intrinsic motivation for research, perceptions of research, and curiosity are prerequisites of future research involvement, it seems beneficial to focus on motivation when selecting students for ERPS, allowing students with lower c

Published
2021

23. Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families

Author

Lacson, John Charles A., Zamani, Shawn A., Froes, Luis Alberto Ribeiro, Mitra, Nandita, Qian, Lu, Doyle, Scarlet H., Azizi, Esther, Balestrini, Claudia, Bishop, D. Timothy, Bruno, William, Carlos-ortega, Blanca, Cuellar, Francisco, Cust, Anne E., Elder, David E., Gerdes, Anne-marie, Ghiorzo, Paola, Grazziotin, Thais C., Gruis, Nelleke A., Hansson, Johan, Hočevar, Marko, Höiom, Veronica, Holland, Elizabeth A., Ingvar, Christian, Landman, Gilles, Larre-borges, Alejandra, Mann, Graham J., Molgo, Montserrat, Moredo, Luciana Facure, Olsson, Håkan, Out-luiting, Jacoba J., Perić, Barbara, Pjanova, Dace, Puig, Susana, Salas-alanis, Julio, Schmid, Helen, Wadt, Karin A. W., Newton-bishop, Julia A., Kanetsky, Peter A., Lacson, John Charles A., Zamani, Shawn A., Froes, Luis Alberto Ribeiro, Mitra, Nandita, Qian, Lu, Doyle, Scarlet H., Azizi, Esther, Balestrini, Claudia, Bishop, D. Timothy, Bruno, William, Carlos-ortega, Blanca, Cuellar, Francisco, Cust, Anne E., Elder, David E., Gerdes, Anne-marie, Ghiorzo, Paola, Grazziotin, Thais C., Gruis, Nelleke A., Hansson, Johan, Hočevar, Marko, Höiom, Veronica, Holland, Elizabeth A., Ingvar, Christian, Landman, Gilles, Larre-borges, Alejandra, Mann, Graham J., Molgo, Montserrat, Moredo, Luciana Facure, Olsson, Håkan, Out-luiting, Jacoba J., Perić, Barbara, Pjanova, Dace, Puig, Susana, Salas-alanis, Julio, Schmid, Helen, Wadt, Karin A. W., Newton-bishop, Julia A., and Kanetsky, Peter A.

Published
2021

25. Genome-wide analysis of constitutional DNA methylation in familial melanoma

Author

Salgado, Catarina, Gruis, Nelleke, Heijmans, Bastiaan T, Oosting, Jan, van Doorn, Remco, Pool, Renée, van Dongen, Jenny, Hottenga, Jouke Jan, Boomsma, Dorret, Human genetics, VU University medical center, Laboratory Medicine, Psychiatry, APH - Mental Health, Consortium, BIOS, van Duijn, C, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Biological Psychology, and APH - Methodology

Subjects
Skin Neoplasms, VARIANT, 0302 clinical medicine, GERMLINE EPIMUTATION, Imprinting (psychology), Promoter Regions, Genetic, Melanoma, Genetics (clinical), Genetics, 0303 health sciences, Genome, DNA methylation, Loss of imprinting, MLH1, Methylation, Middle Aged, Familial melanoma, CpG site, 030220 oncology & carcinogenesis, Human, Adult, Short Report, Biology, INHERITANCE, Promoter Regions, Melanoma/genetics, CDKN2A, 03 medical and health sciences, Genetic, SDG 3 - Good Health and Well-being, Skin Neoplasms/genetics, medicine, Humans, Epimutation, Epigenetics, Molecular Biology, Gene, Aged, 030304 developmental biology, Genome, Human, MUTATIONS, DNA Methylation, medicine.disease, GENE, Human genetics, MSH2, CpG Islands, Developmental Biology
Abstract

Background Heritable epigenetic alterations have been proposed as an explanation for familial clustering of melanoma. Here we performed genome-wide DNA methylation analysis on affected family members not carrying pathogenic variants in established melanoma susceptibility genes, compared with healthy volunteers. Results All melanoma susceptibility genes showed the absence of epimutations in familial melanoma patients, and no loss of imprinting was detected. Unbiased genome-wide DNA methylation analysis revealed significantly different levels of methylation in single CpG sites. The methylation level differences were small and did not affect reported tumour predisposition genes. Conclusion Our results provide no support for heritable epimutations as a cause of familial melanoma.

Published
2020

26. Additional file 3 of Genome-wide analysis of constitutional DNA methylation in familial melanoma

Author

Salgado, Catarina, Gruis, Nelleke, Heijmans, Bastiaan, Oosting, Jan, and Doorn, Remco

Abstract

Additional file 3: Figure S2. Methylation levels (β-value) across the entire sequence of all imprinted genes (http://www.geneimprint.com/site/genes-by-species, accessed August 2019) assessed by 450 K array. In the upper part of each plot, the gene structure is represented in red and promoter region in blue. The light grey arrow represents the transcription direction of the gene. For each CpG, the BIOS values are represented by the black vertical line with upper (average + 1 SD) and lower limits (average – 1SD). The families are represented as a X of different colours (Family I – green, Family II – blue, Family III – yellow, Family IV – light purple, Family V – dark blue). To be considered as significantly different from the BIOS, the families symbols must go beyond the small black horizontal line (average ± 5.65 SD). Genes with more than 10 CpG sites assessed by 450 K array, were represented by 10 randomly selected CpGs.

Published
2020
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28. Association of HERV-K and LINE-1 hypomethylation with reduced disease-free survival in melanoma patients

Author

Cardelli, Maurizio, primary, Doorn, Remco van, additional, Larcher, Lares, additional, Donato, Michela Di, additional, Piacenza, Francesco, additional, Pierpaoli, Elisa, additional, Giacconi, Robertina, additional, Malavolta, Marco, additional, Rachakonda, Sivaramakrishna, additional, Gruis, Nelleke A, additional, Molven, Anders, additional, Andresen, Per Arne, additional, Pjanova, Dace, additional, van den Oord, Joost J, additional, Provinciali, Mauro, additional, Nagore, Eduardo, additional, and Kumar, Rajiv, additional

Published
2020
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29. Association between a 46-SNP Polygenic Risk Score and melanoma risk in Dutch patients with familial melanoma

Author

Potjer, Thomas P, primary, van der Grinten, Tara W J, additional, Lakeman, Inge M M, additional, Bollen, Sander H, additional, Rodríguez-Girondo, Mar, additional, Iles, Mark M, additional, Barrett, Jennifer H, additional, Kiemeney, Lambertus A, additional, Gruis, Nelleke A, additional, van Asperen, Christi J, additional, and van der Stoep, Nienke, additional

Published
2020
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32. MC1R variants in childhood and adolescent melanoma: a retrospective pooled analysis of a multicentre cohort

Author

Pellegrini, Cristina, Botta, Francesca, Massi, Daniela, Martorelli, Claudia, Facchetti, Fabio, Gandini, Sara, Maisonneuve, Patrick, Avril, Marie-Françoise, Demenais, Florence, Bressac-de Paillerets, Brigitte, Hoiom, Veronica, Cust, Anne E, Anton-Culver, Hoda, Gruber, Stephen B, Gallagher, Richard P, Marrett, Loraine, Zanetti, Roberto, Dwyer, Terence, Thomas, Nancy E, Begg, Colin B, Berwick, Marianne, Puig, Susana, Potrony, Miriam, Nagore, Eduardo, Ghiorzo, Paola, Menin, Chiara, Manganoni, Ausilia Maria, Rodolfo, Monica, Brugnara, Sonia, Passoni, Emanuela, Sekulovic, Lidija Kandolf, Baldini, Federica, Guida, Gabriella, Stratigos, Alexandros, Ozdemir, Fezal, Ayala, Fabrizio, Fernandez-de-Misa, Ricardo, Quaglino, Pietro, Ribas, Gloria, Romanini, Antonella, Migliano, Emilia, Stanganelli, Ignazio, Kanetsky, Peter A, Pizzichetta, Maria Antonietta, García-Borrón, Jose Carlos, Nan, Hongmei, Landi, Maria Teresa, Little, Julian, Newton-Bishop, Julia, Sera, Francesco, Fargnoli, Maria Concetta, Raimondi, Sara, Alaibac, Mauro, Ferrari, Andrea, Valeri, Barbara, Sicher, Mariacristina, Mangiola, Daniela, Nazzaro, Gianluca, Tosti, Giulio, Mazzarol, Giovanni, Giudice, Giuseppe, Ribero, Simone, Astrua, Chiara, Mazzoni, Laura, Orlow, Irene, Mujumdar, Urvi, Hummer, Amanda, Busam, Klaus, Roy, Pampa, Canchola, Rebecca, Clas, Brian, Cotignola, Javiar, Monroe, Yvette, Armstrong, Bruce, Kricker, Anne, Litchfield, Melisa, Tucker, Paul, Stephens, Nicola, Switzer, Teresa, Theis, Beth, From, Lynn, Chowdhury, Noori, Vanasse, Louise, Purdue, Mark, Northrup, David, Rosso, Stefano, Sacerdote, Carlotta, Leighton, Nancy, Gildea, Maureen, Bonner, Joe, Jeter, Joanne, Klotz, Judith, Wilcox, Homer, Weiss, Helen, Millikan, Robert, Mattingly, Dianne, Player, Jon, Tse, Chiu-Kit, Rebbeck, Timothy, Walker, Amy, Panossian, Saarene, Setlow, Richard, Mohrenweiser, Harvey, Autier, Philippe, Han, Jiali, Caini, Saverio, Hofman, Albert, Kayser, Manfred, Liu, Fan, Nijsten, Tamar, Uitterlinden, Andre G., Kumar, Rajiv, Bishop, Tim, Elliott, Faye, Lazovich, Deann, Polsky, David, Hansson, Johan, Pastorino, Lorenza, Gruis, Nelleke A., Bouwes Bavinck, Jan Nico, Aguilera, Paula, Badenas, Celia, Carrera, Cristina, Gimenez-Xavier, Pol, Malvehy, Josep, Puig-Butille, Joan Anton, Tell-Marti, Gemma, Blizzard, Leigh, Cochrane, Jennifer, Branicki, Wojciech, Debniak, Tadeusz, Morling, Niels, Johansen, Peter, Mayne, Susan, Bale, Allen, Cartmel, Brenda, Ferrucci, Leah, Pfeiffer, Ruth, Palmieri, Giuseppe, Kypreou, Katerina, Bowcock, Anne, Cornelius, Lynn, Council, M. Laurin, Motokawa, Tomonori, Anno, Sumiko, Helsing, Per, Andresen, Per Arne, Guida, Stefania, Wong, Collaborators (98): Alaibac M, Terence H., Ferrari, A, Valeri, B, Et, Al., Pellegrini, C., Botta, F., Massi, D., Martorelli, C., Facchetti, F., Gandini, S., Maisonneuve, P., Avril, M. -F., Demenais, F., Bressac-de Paillerets, B., Hoiom, V., Cust, A. E., Anton-Culver, H., Gruber, S. B., Gallagher, R. P., Marrett, L., Zanetti, R., Dwyer, T., Thomas, N. E., Begg, C. B., Berwick, M., Puig, S., Potrony, M., Nagore, E., Ghiorzo, P., Menin, C., Manganoni, A. M., Rodolfo, M., Brugnara, S., Passoni, E., Sekulovic, L. K., Baldini, F., Guida, G., Stratigos, A., Ozdemir, F., Ayala, F., Fernandez-de-Misa, R., Quaglino, P., Ribas, G., Romanini, A., Migliano, E., Stanganelli, I., Kanetsky, P. A., Pizzichetta, M. A., Garcia-Borron, J. C., Nan, H., Landi, M. T., Little, J., Newton-Bishop, J., Sera, F., Fargnoli, M. C., Raimondi, S., Alaibac, M., Ferrari, A., Valeri, B., Sicher, M., Mangiola, D., Nazzaro, G., Tosti, G., Mazzarol, G., Giudice, G., Ribero, S., Astrua, C., Mazzoni, L., Orlow, I., Mujumdar, U., Hummer, A., Busam, K., Roy, P., Canchola, R., Clas, B., Cotignola, J., Monroe, Y., Armstrong, B., Kricker, A., Litchfield, M., Tucker, P., Stephens, N., Switzer, T., Theis, B., From, L., Chowdhury, N., Vanasse, L., Purdue, M., Northrup, D., Rosso, S., Sacerdote, C., Leighton, N., Gildea, M., Bonner, J., Jeter, J., Klotz, J., Wilcox, H., Weiss, H., Millikan, R., Mattingly, D., Player, J., Tse, C. -K., Rebbeck, T., Walker, A., Panossian, S., Setlow, R., Mohrenweiser, H., Autier, P., Han, J., Caini, S., Hofman, A., Kayser, M., Liu, F., Nijsten, T., Uitterlinden, A. G., Kumar, R., Bishop, T., Elliott, F., Lazovich, D., Polsky, D., Hansson, J., Pastorino, L., Gruis, N. A., Bouwes Bavinck, J. N., Aguilera, P., Badenas, C., Carrera, C., Gimenez-Xavier, P., Malvehy, J., Puig-Butille, J. A., Tell-Marti, G., Blizzard, L., Cochrane, J., Branicki, W., Debniak, T., Morling, N., Johansen, P., Mayne, S., Bale, A., Cartmel, B., Ferrucci, L., Pfeiffer, R., Palmieri, G., Kypreou, K., Bowcock, A., Cornelius, L., Council, M. L., Motokawa, T., Anno, S., Helsing, P., Andresen, P. A., Guida, S., Wong, T. H., Ege Üniversitesi, Epidemiology, Genetic Identification, and Dermatology

Subjects
Male, Skin Neoplasms, Pediatrics, Cohort Studies, 0302 clinical medicine, Odds Ratio, Developmental and Educational Psychology, Pediatrics, Perinatology and Child Health, 030212 general & internal medicine, Child, Cancer, Pediatric, Tumor, childhood disease, Middle Aged, Perinatology and Child Health, cohort analysis, Meta-analysis, Melanocortin, Cohort, Female, MC1R gene, Receptor, Melanocortin, Type 1, Receptor, Type 1, Cohort study, Adult, medicine.medical_specialty, adolescent, melanoma, cohort analysi, Subgroup analysis, Article, 03 medical and health sciences, Genetic, Clinical Research, 030225 pediatrics, Internal medicine, Genetics, Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, Polymorphism, Germ-Line Mutation, Aged, Retrospective Studies, Polymorphism, Genetic, business.industry, Prevention, Case-control study, Retrospective cohort study, GEM Study Group, Odds ratio, Logistic Models, M-SKIP Study Group, Case-Control Studies, Cutaneous melanoma, IMI Study Group, business, Biomarkers
Abstract

Ferrari, Andrea/0000-0002-4724-0517; Pellegrini, Cristina/0000-0003-2168-8097; Migliano, Emilia/0000-0002-5316-8937; Maisonneuve, Patrick/0000-0002-5309-4704; Guida, Stefania/0000-0002-8221-6694; Pastorino, Lorenza/0000-0002-2575-8331; CARRERA, CRISTINA/0000-0003-1608-8820; Paillerets, Brigitte Bressac-de/0000-0003-0245-8608; Sekulovic, Lidija Kandolf/0000-0002-5221-5068; Caini, Saverio/0000-0002-2262-1102; Potrony, Miriam/0000-0003-2766-0765; Pizzichetta, Maria Antonietta/0000-0002-4201-8490; Little, Julian/0000-0001-5026-5531; Nagore, Eduardo/0000-0003-3433-8707; Polsky, David/0000-0001-9554-5289; Demenais, Florence/0000-0001-8361-0936; Nazzaro, Gianluca/0000-0001-8534-6497; gandini, sara/0000-0002-1348-4548; Cornelius, Lynn A/0000-0002-6329-2819; Palmieri, Giuseppe/0000-0002-4350-2276; Cotignola, Javier/0000-0003-4473-9854; Ghiorzo, Paola/0000-0002-3651-8173; Autier, Philippe/0000-0003-1538-5321; Bishop, Tim/0000-0002-8752-8785; Sera, Francesco/0000-0002-8890-6848; Newton-Bishop, Julia/0000-0001-9147-6802; Litchfield, Melisa/0000-0003-0002-7724, WOS: 000464254100018, PubMed: 30872112, Background Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls. Methods in this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger. Findings We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1.54, 95% CI 1.02-2.33), including when analysis was restricted to patients aged 18 years or younger (1.80, 1.06-3.07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1.60, 95% CI 1.05-2.44; p=0.04) and Asp294His (2.15, 1.05-4.40; p=0.04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants. Interpretation Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies. Copyright (c) 2019 Elsevier Ltd. All rights reserved., [AIRC-MFAG-11831]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086] Funding Source: NIH RePORTER, SPD-Pilot/Project-Award-2015; AIRC-MFAG-11831.

Published
2019

33. Publisher Correction: Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways

Author

Duffy, David L., Zhu, Gu, Li, Xin, Sanna, Marianna, Jacobs, Leonie C., Evans, David M., Yazar, Seyhan, Beesley, Jonathan, Lawrence, 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., Leenhardt, Jeffrey E., Brossard, Myriam, Moses, Eric K., Song, Fengju, Kumar, Rajiv, Easton, Douglas F., Pharoah, Paul D. P., Swerdlow, Anthony J., Kypreou, Katerina P., Harland, Mark, Randerson-Moor, Juliette, Akslen, Lars A., Andresen, Per A., Avril, Marie-Françoise, Azizi, Esther, Scarrà, Giovanna Bianchi, Brown, Kevin M., Dębniak, Tadeusz, Elder, David E., Fang, Shenying, Friedman, Eitan, Galan, Pilar, Ghiorzo, Paola, Gillanders, Elizabeth M., Goldstein, Alisa M., Gruis, Nelleke A., Hansson, Johan, Helsing, Per, Hočevar, Marko, Höiom, Veronica, Ingvar, Christian, Kanetsky, Peter A., Chen, Wei V., Landi, Maria Teresa, Lang, Julie, Lathrop, G. Mark, Lubiński, Jan, Mackie, Rona M., Mann, Graham J., Molven, Anders, Novaković, Srdjan, Olsson, Håkan, Puig, Susana, Puig-Butille, Joan Anton, Radford-Smith, Graham L., van Doorn, Remco, Whiteman, David C., Craig, Jamie E., Schadendorf, Dirk, Simms, Lisa A., Burdon, Kathryn P., Nyholt, Dale R., Pooley, Karen A., Orr, Nicholas, Stratigos, Alexander J., Cust, Anne E., Ward, Sarah V., Schulze, Hans-Joachim, Dunning, Alison M., Demenais, Florence, Amos, Christopher I., 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, and Martin, Nicholas G.

Subjects
0301 basic medicine, Skin Neoplasms, Medizin, General Physics and Astronomy, 02 engineering and technology, Receptors, G-Protein-Coupled, Guanine Nucleotide Exchange Factors, skin and connective tissue diseases, lcsh:Science, Melanoma, Telomerase, Nevus, Pigmented, Stem Cell Factor, Multidisciplinary, Microfilament Proteins, Nuclear Proteins, RNA-Binding Proteins, Genetic Pleiotropy, 021001 nanoscience & nanotechnology, Publisher Correction, Spelling, Cytochrome P-450 CYP1B1, Interferon Regulatory Factors, 0210 nano-technology, Science, Telomere-Binding Proteins, Nerve Tissue Proteins, Computational biology, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Histone Deacetylases, White People, Group VI Phospholipases A2, 03 medical and health sciences, medicine, Nevus, Humans, Genetic Predisposition to Disease, General Chemistry, medicine.disease, Repressor Proteins, MicroRNAs, 030104 developmental biology, RNA, lcsh:Q, Carrier Proteins, 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, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. 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., Melanocytic nevus count is associated with melanoma risk. In this study, a meta-analysis of 11 nevus GWAS studies identifies novel SNPs in KITLG and 9q32, and bivariate analysis with melanoma GWAS meta-analysis reveals that most nevus genes affect melanoma risk, while melanoma risk loci do not alter the nevus count.

Published
2019

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

Author

Duffy, David L. Zhu, Gu Li, Xin Sanna, Marianna Iles, Mark M. Jacobs, Leonie C. Evans, David M. Yazar, Seyhan and Beesley, Jonathan Law, Matthew H. Kraft, Peter Visconti, Alessia Taylor, John C. Liu, Fan Wright, Margaret J. and Henders, Anjali K. Bowdler, Lisa Glass, Dan Ikram, M. Arfan and Uitterlinden, Andre G. Madden, Pamela A. Heath, Andrew C. and Nelson, Elliot C. Green, Adele C. Chanock, Stephen and Barrett, Jennifer H. Brown, Matthew A. Hayward, Nicholas K. and MacGregor, Stuart Sturm, Richard A. Hewitt, Alex W. Kayser, Manfred Hunter, David J. Bishop, Julia A. Newton 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. and Lee, Jeffrey E. Brossard, Myriam Moses, Eric K. Song, Fengju and Kumar, Rajiv Easton, Douglas F. Pharoah, Paul D. P. and Swerdlow, Anthony J. Kypreou, Katerina P. Harland, Mark and Randerson-Moor, Juliette Akslen, Lars A. Andresen, Per A. and Avril, Marie-Francoise Azizi, Esther Scarra, Giovanna Bianchi and Brown, Kevin M. Debniak, Tadeusz Elder, David E. Fang, Shenying Friedman, Eitan Galan, Pilar Ghiorzo, Paola and Gillanders, Elizabeth M. Goldstein, Alisa M. Gruis, Nelleke A. and Hansson, Johan Helsing, Per Hocevar, Marko Hoiom, Veronica Ingvar, Christian Kanetsky, Peter A. Chen, Wei V. and Landi, Maria Teresa Lang, Julie Lathrop, G. Mark and Lubinski, Jan Mackie, Rona M. Mann, Graham J. Molven, Anders and Novakovic, Srdjan Olsson, Hakan Puig, Susana and Puig-Butille, Joan Anton Radford-Smith, Graham L. van der Stoep, Nienke van Doorn, Remco Whiteman, David C. Craig, Jamie E. and Schadendorf, Dirk Simms, Lisa A. Burdon, Kathryn P. and Nyholt, Dale R. Pooley, Karen A. Orr, Nicholas Stratigos, Alexander J. Cust, Anne E. Ward, Sarah V. Schulze, Hans-Joachim Dunning, Alison M. Demenais, Florence Amos, Christopher I. Melanoma GWAS Consortium

Published
2019

35. MC1R variants as melanoma risk factors independent of at-risk phenotypic characteristics: a pooled analysis from the M-SKIP project

Author

Tagliabue, Elena, Gandini, Sara, Bellocco, Rino, Maisonneuve, Patrick, Newton-Bishop, Julia, Polsky, David, Lazovich, Deann, Kanetsky, Peter A., Ghiorzo, Paola, Gruis, Nelleke A., Landi, Maria Teresa, Menin, Chiara, Fargnoli, Maria Concetta, García-Borrón, Jose Carlos, Han, Jiali, Little, Julian, Sera, Francesco, Raimondi, Sara, M-SKIP sudy group, Pastorino, Lorenza, Tagliabue, E, Gandini, S, Bellocco, R, Maisonneuve, P, Newton-Bishop, J, Polsky, D, Lazovich, D, Kanetsky, P, Ghiorzo, P, Gruis, N, Landi, M, Menin, C, Fargnoli, M, Garcia-Borron, J, Han, J, Little, J, Sera, F, and Raimondi, S

Subjects
genetic epidemiology, Pigmentation, Pooled-analysis, Cutaneous melanoma, Genetic epidemiology, Melanocortin 1 receptor, Pooled analysis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, mc1r gene, cutaneous melanoma, melanocortin 1 receptor, Cutaneous melanoma, Genetic epidemiology, Melanocortin 1 receptor, Pigmentation, Pooled analysis, Oncology, Oncology, Cancer Management and Research, melanoma, pigmentation, Melanocortin-1 Receptor, pooled analysis, Original Research
Abstract

Elena Tagliabue,1 Sara Gandini,2 Rino Bellocco,3,4 Patrick Maisonneuve,2 Julia Newton-Bishop,5 David Polsky,6 DeAnn Lazovich,7 Peter A Kanetsky,8 Paola Ghiorzo,9,10 Nelleke A Gruis,11 Maria Teresa Landi,12 Chiara Menin,13 Maria Concetta Fargnoli,14 Jose Carlos García-Borrón,15,16 Jiali Han,17 Julian Little,18 Francesco Sera,19 Sara Raimondi2 On behalf of the M-SKIP Study Group 1Clinical Trial Center, Scientific Directorate, Fondazione IRCCS Istituto Nazionale dei Tumori, 2Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy; 3Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 4Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy; 5Section of Epidemiology and Biostatistics, Institute of Cancer and Pathology, University of Leeds, Leeds, UK; 6Ronald O. Perelman Department of Dermatology, New York University School of Medicine, NYU Langone Medical Center, New York, NY, 7Division of Epidemiology and Community Health, University of Minnesota, MN, 8Department of Cancer Epidemiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 9Department of Internal Medicine and Medical Specialties, University of Genoa, 10IRCCS AOU San Martino-IST, Genoa, Italy; 11Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands; 12Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA; 13Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, Padua, 14Department of Dermatology, University of L’Aquila, L’Aquila, Italy; 15Department of Biochemistry, Molecular Biology, and Immunology, University of Murcia, 16IMIB-Arrixaca, Murcia, Spain; 17Department of Epidemiology, Richard M Fairbanks School of Public Health, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, USA; 18School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada; 19Department of Social and Environmental Health Research, London School of Hygiene and Tropical Medicine, London, UK Purpose: Melanoma represents an important public health problem, due to its high case-fatality rate. Identification of individuals at high risk would be of major interest to improve early diagnosis and ultimately survival. The aim of this study was to evaluate whether MC1R variants predicted melanoma risk independently of at-risk phenotypic characteristics. Materials and methods: Data were collected within an international collaboration – the M-SKIP project. The present pooled analysis included data on 3,830 single, primary, sporadic, cutaneous melanoma cases and 2,619 controls from seven previously published case–control studies. All the studies had information on MC1R gene variants by sequencing analysis and on hair color, skin phototype, and freckles, ie, the phenotypic characteristics used to define the red hair phenotype. Results: The presence of any MC1R variant was associated with melanoma risk independently of phenotypic characteristics (OR 1.60; 95% CI 1.36–1.88). Inclusion of MC1R variants in a risk prediction model increased melanoma predictive accuracy (area under the receiver-operating characteristic curve) by 0.7% over a base clinical model (P=0.002), and 24% of participants were better assessed (net reclassification index 95% CI 20%–30%). Subgroup analysis suggested a possibly stronger role of MC1R in melanoma prediction for participants without the red hair phenotype (net reclassification index: 28%) compared to paler skinned participants (15%). Conclusion: The authors suggest that measuring the MC1R genotype might result in a benefit for melanoma prediction. The results could be a valid starting point to guide the development of scientific protocols assessing melanoma risk prediction tools incorporating the MC1R genotype. Keywords: pooled analysis, genetic epidemiology, cutaneous melanoma, melanocortin 1 receptor, pigmentation

Published
2018

36. Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT

Author

Taylor, Nicholas J., Mitra, Nandita, Qian, Lu, Avril, Marie Françoise, Bishop, D. Timothy, Bressac-de Paillerets, Brigitte, Bruno, William, Calista, Donato, Cuellar, Francisco, Cust, Anne E., Demenais, Florence, Elder, David E., Gerdes, Anne Marie, Ghiorzo, P., Goldstein, Alisa M., Grazziotin, Thais C., Gruis, Nelleke A., Hansson, J., Harland, Mark, Hayward, Nicholas K., Hocevar, M., Höiom, Veronica, Holland, Elizabeth A., Ingvar, Christian, Landi, Maria Teresa, Landman, Gilles, Larre-Borges, Alejandra, Mann, Graham J., Nagore, Eduardo, Olsson, Håkan, Palmer, Jane M., Perić, Barbara, Pjanova, Dace, Pritchard, Antonia L., Puig, Susana, Schmid, H., van der Stoep, Nienke, Tucker, Margaret A., Wadt, Karin A.W., Yang, Xiaohong R., Newton-Bishop, Julia A., Kanetsky, Peter A., Taylor, Nicholas J., Mitra, Nandita, Qian, Lu, Avril, Marie Françoise, Bishop, D. Timothy, Bressac-de Paillerets, Brigitte, Bruno, William, Calista, Donato, Cuellar, Francisco, Cust, Anne E., Demenais, Florence, Elder, David E., Gerdes, Anne Marie, Ghiorzo, P., Goldstein, Alisa M., Grazziotin, Thais C., Gruis, Nelleke A., Hansson, J., Harland, Mark, Hayward, Nicholas K., Hocevar, M., Höiom, Veronica, Holland, Elizabeth A., Ingvar, Christian, Landi, Maria Teresa, Landman, Gilles, Larre-Borges, Alejandra, Mann, Graham J., Nagore, Eduardo, Olsson, Håkan, Palmer, Jane M., Perić, Barbara, Pjanova, Dace, Pritchard, Antonia L., Puig, Susana, Schmid, H., van der Stoep, Nienke, Tucker, Margaret A., Wadt, Karin A.W., Yang, Xiaohong R., Newton-Bishop, Julia A., and Kanetsky, Peter A.

Abstract

Background: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved. Methods: In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics. Results: MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P < .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance. Conclusion: The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling.

Published
2019

37. Association between a 46-SNP Polygenic Risk Score and melanoma risk in Dutch patients with familial melanoma.

Author

Potjer, Thomas P., van der Grinten, Tara W. J., Lakeman, Inge M. M., Bollen, Sander H., Rodríguez-Girondo, Mar, Iles, Mark M., Barrett, Jennifer H., Kiemeney, Lambertus A., Gruis, Nelleke A., van Asperen, Christi J., and van der Stoep, Nienke

Abstract

Background: Familial clustering of melanoma suggests a shared genetic predisposition among family members, but only 10%-40% of familial cases carry a pathogenic variant in a known high-risk melanoma susceptibility gene. We investigated whether a melanoma-specific Polygenic Risk Score (PRS) is associated with melanoma risk in patients with genetically unexplained familial melanoma. Methods: Dutch familial melanoma cases (n=418) were genotyped for 46 SNPs previously identified as independently associated with melanoma risk. The 46-SNP PRS was calculated and standardised to 3423 healthy controls (sPRS) and the association between PRS and melanoma risk was modelled using logistic regression. Within the case series, possible differences were further explored by investigating the PRS in relation to (1) the number of primary melanomas in a patient and (2) the extent of familial clustering of melanoma. Results: The PRS was significantly associated with melanoma risk, with a per-SD OR of 2.12 (95% CI 1.90 to 2.35, p<0.001), corresponding to a 5.70-fold increased risk (95% CI 3.93 to 8.28) when comparing the top 90th to the middle 40-60th PRS percentiles. The mean PRS was significantly higher in cases with multiple primary melanomas than in cases with a single melanoma (sPRS 1.17 vs 0.71, p=0.001). Conversely, cases from high-density melanoma families had a lower (but non-significant) mean PRS than cases from low-density families (sPRS 0.60 vs 0.94, p=0.204). Conclusion: Our work underlines the significance of a PRS in determining melanoma susceptibility and encourages further exploration of the diagnostic value of a PRS in genetically unexplained melanoma families. [ABSTRACT FROM AUTHOR]

Published
2021
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40. Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT

Author

Taylor, Nicholas J., primary, Mitra, Nandita, additional, Qian, Lu, additional, Avril, Marie-Françoise, additional, Bishop, D. Timothy, additional, Bressac-de Paillerets, Brigitte, additional, Bruno, William, additional, Calista, Donato, additional, Cuellar, Francisco, additional, Cust, Anne E., additional, Demenais, Florence, additional, Elder, David E., additional, Gerdes, Anne-Marie, additional, Ghiorzo, Paola, additional, Goldstein, Alisa M., additional, Grazziotin, Thais C., additional, Gruis, Nelleke A., additional, Hansson, Johan, additional, Harland, Mark, additional, Hayward, Nicholas K., additional, Hocevar, Marko, additional, Höiom, Veronica, additional, Holland, Elizabeth A., additional, Ingvar, Christian, additional, Landi, Maria Teresa, additional, Landman, Gilles, additional, Larre-Borges, Alejandra, additional, Mann, Graham J., additional, Nagore, Eduardo, additional, Olsson, Håkan, additional, Palmer, Jane M., additional, Perić, Barbara, additional, Pjanova, Dace, additional, Pritchard, Antonia L., additional, Puig, Susana, additional, Schmid, Helen, additional, van der Stoep, Nienke, additional, Tucker, Margaret A., additional, Wadt, Karin A.W., additional, Yang, Xiaohong R., additional, Newton-Bishop, Julia A., additional, and Kanetsky, Peter A., additional

Published
2019
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41. NEK11 as a candidate high-penetrance melanoma susceptibility gene.

Author

Christodoulou, Eirini, van Doorn, Remco, Visser, Mijke, Teunisse, Amina, Versluis, Mieke, van der Velden, Pieter, Hayward, Nicholas K., Jochemsen, Aart, and Gruis, Nelleke

Abstract

Background A proportion of patients diagnosed with cutaneous melanoma reports a positive family history. Inherited variants in CDKN2A and several other genes have been shown to predispose to melanoma; however, the genetic basis of familial melanoma remains unknown in most cases. The objective of this study was to provide insight into the genetic basis of familial melanoma. Methods In order to identify novel melanoma susceptibility genes, whole exome sequencing (WES) analysis was applied in a Dutch family with melanoma. The causality of a candidate variant was characterised by performing cosegregation analysis in five affected family members using patient-derived tissues and digital droplet PCR analysis to accurately quantify mutant allele frequency. Functional in-vitro studies were performed to assess the pathogenicity of the candidate variant. Results Application of WES identified a rare, nonsense variant in the NEK11 gene (c.1120C>T, p.Arg374Ter), cosegregating in all five affected members of a Dutch family. NEK11 (NIMA-related Kinase 11) is involved in the DNA damage response, enforcing the G2/M cell cycle checkpoint. In a melanoma from a variant carrier, somatic loss of the wildtype allele of this putative tumour suppressor gene was demonstrated. Functional analyses showed that the NEK11 p.Arg374Ter mutation results in strongly reduced expression of the truncated protein caused by proteasomal degradation. Conclusion The NEK11 p.Arg374Ter variant identified in this family leads to loss-of-function through protein instability. Collectively, these findings support NEK11 as a melanoma susceptibility gene. [ABSTRACT FROM AUTHOR]

Published
2020
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42. High Growth Rate of Pancreatic Ductal Adenocarcinoma in CDKN2A-p16-Leiden Mutation Carriers

Author

Ibrahim, Isaura S., primary, Wasser, Martin N., additional, Wu, Yinghui, additional, Inderson, Akin, additional, de Vos tot Nederveen Cappel, Wouter H., additional, Morreau, Hans, additional, Hes, Frederik J., additional, Veenendaal, Roeland A., additional, Putter, Hein, additional, Feshtali, Shirin, additional, van Mil, Anneke M., additional, Gruis, Nelleke A., additional, Tollenaar, Rob A., additional, Bergman, Wilma, additional, Bonsing, Bert A., additional, and Vasen, Hans F.A., additional

Published
2018
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43. CM-Score: a validated scoring system to predict CDKN2A germline mutations in melanoma families from Northern Europe

Author

Potjer, Thomas P, primary, Helgadottir, Hildur, additional, Leenheer, Mirjam, additional, van der Stoep, Nienke, additional, Gruis, Nelleke A, additional, Höiom, Veronica, additional, Olsson, Håkan, additional, van Doorn, Remco, additional, Vasen, Hans F A, additional, van Asperen, Christi J, additional, Dekkers, Olaf M, additional, and Hes, Frederik J, additional

Published
2018
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44. Germline CDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma.

Author

UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/MEXP - Médecine expérimentale, Jouenne, Fanélie, Chauvot de Beauchene, Isaure, Bollaert, Emeline, Avril, Marie-Françoise, Caron, Olivier, Ingster, Olivier, Lecesne, Axel, Benusiglio, Patrick, Terrier, Philippe, Caumette, Vincent, Pissaloux, Daniel, de la Fouchardière, Arnaud, Cabaret, Odile, N'Diaye, Birama, Velghe, Amélie, Bougeard, Gaelle, Mann, Graham J, Koscielny, Serge, Barrett, Jennifer H, Harland, Mark, Newton-Bishop, Julia, Gruis, Nelleke, Van Doorn, Remco, Gauthier-Villars, Marion, Pierron, Gaelle, Stoppa-Lyonnet, Dominique, Coupier, Isabelle, Guimbaud, Rosine, Delnatte, Capucine, Scoazec, Jean-Yves, Eggermont, Alexander M, Feunteun, Jean, Tchertanov, Luba, Demoulin, Jean-Baptiste, Frebourg, Thierry, Bressac-de Paillerets, Brigitte, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/MEXP - Médecine expérimentale, Jouenne, Fanélie, Chauvot de Beauchene, Isaure, Bollaert, Emeline, Avril, Marie-Françoise, Caron, Olivier, Ingster, Olivier, Lecesne, Axel, Benusiglio, Patrick, Terrier, Philippe, Caumette, Vincent, Pissaloux, Daniel, de la Fouchardière, Arnaud, Cabaret, Odile, N'Diaye, Birama, Velghe, Amélie, Bougeard, Gaelle, Mann, Graham J, Koscielny, Serge, Barrett, Jennifer H, Harland, Mark, Newton-Bishop, Julia, Gruis, Nelleke, Van Doorn, Remco, Gauthier-Villars, Marion, Pierron, Gaelle, Stoppa-Lyonnet, Dominique, Coupier, Isabelle, Guimbaud, Rosine, Delnatte, Capucine, Scoazec, Jean-Yves, Eggermont, Alexander M, Feunteun, Jean, Tchertanov, Luba, Demoulin, Jean-Baptiste, Frebourg, Thierry, and Bressac-de Paillerets, Brigitte

Abstract

BACKGROUND: Sarcomas are rare mesenchymal malignancies whose pathogenesis is poorly understood; both environmental and genetic risk factors could contribute to their aetiology. METHODS AND RESULTS: We performed whole-exome sequencing (WES) in a familial aggregation of three individuals affected with soft-tissue sarcoma (STS) without TP53 mutation (Li-Fraumeni-like, LFL) and found a shared pathogenic mutation in CDKN2A tumour suppressor gene. We searched for individuals with sarcoma among 474 melanoma-prone families with a CDKN2A-/+ genotype and for CDKN2A mutations in 190 TP53-negative LFL families where the index case was a sarcoma. Including the initial family, eight independent sarcoma cases carried a germline mutation in the CDKN2A/p16INK4A gene. In five out of seven formalin-fixed paraffin-embedded sarcomas, heterozygosity was lost at germline CDKN2A mutations sites demonstrating complete loss of function. As sarcomas are rare in CDKN2A/p16INK4A carriers, we searched in constitutional WES of nine carriers for potential modifying rare variants and identified three in platelet-derived growth factor receptor (PDGFRA) gene. Molecular modelling showed that two never-described variants could impact the PDGFRA extracellular domain structure. CONCLUSION: Germline mutations in CDKN2A/P16INK4A, a gene known to predispose to hereditary melanoma, pancreatic cancer and tobacco-related cancers, account also for a subset of hereditary sarcoma. In addition, we identified PDGFRA as a candidate modifier gene.

Published
2017

45. Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families

Author

Taylor, Nicholas J, Mitra, Nandita, Goldstein, Alisa M, Tucker, Margaret A, Avril, Marie-Françoise, Azizi, Esther, Bergman, Wilma, Bishop, D Timothy, Bressac-de Paillerets, Brigitte, Bruno, William, Calista, Donato, Cannon-Albright, Lisa A, Cuellar, Francisco, Cust, Anne E, Demenais, Florence, Elder, David E, Gerdes, Anne-Marie, Ghiorzo, Paola, Grazziotin, Thais C, Hansson, Johan, Harland, Mark, Hayward, Nicholas K, Hocevar, Marko, Höiom, Veronica, Ingvar, Christian, Landi, Maria Teresa, Landman, Gilles, Larre-Borges, Alejandra, Leachman, Sancy A, Mann, Graham J, Nagore, Eduardo, Olsson, Håkan, Palmer, Jane M, Perić, Barbara, Pjanova, Dace, Pritchard, Antonia, Puig, Susana, van der Stoep, Nienke, Wadt, Karin A W, Whitaker, Linda, Yang, Xiaohong R, Newton Bishop, Julia A, Gruis, Nelleke A, Kanetsky, Peter A, Taylor, Nicholas J, Mitra, Nandita, Goldstein, Alisa M, Tucker, Margaret A, Avril, Marie-Françoise, Azizi, Esther, Bergman, Wilma, Bishop, D Timothy, Bressac-de Paillerets, Brigitte, Bruno, William, Calista, Donato, Cannon-Albright, Lisa A, Cuellar, Francisco, Cust, Anne E, Demenais, Florence, Elder, David E, Gerdes, Anne-Marie, Ghiorzo, Paola, Grazziotin, Thais C, Hansson, Johan, Harland, Mark, Hayward, Nicholas K, Hocevar, Marko, Höiom, Veronica, Ingvar, Christian, Landi, Maria Teresa, Landman, Gilles, Larre-Borges, Alejandra, Leachman, Sancy A, Mann, Graham J, Nagore, Eduardo, Olsson, Håkan, Palmer, Jane M, Perić, Barbara, Pjanova, Dace, Pritchard, Antonia, Puig, Susana, van der Stoep, Nienke, Wadt, Karin A W, Whitaker, Linda, Yang, Xiaohong R, Newton Bishop, Julia A, Gruis, Nelleke A, and Kanetsky, Peter A

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

46. GermlineCDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma

Author

Jouenne, Fanélie, primary, Chauvot de Beauchene, Isaure, additional, Bollaert, Emeline, additional, Avril, Marie-Françoise, additional, Caron, Olivier, additional, Ingster, Olivier, additional, Lecesne, Axel, additional, Benusiglio, Patrick, additional, Terrier, Philippe, additional, Caumette, Vincent, additional, Pissaloux, Daniel, additional, de la Fouchardière, Arnaud, additional, Cabaret, Odile, additional, N’Diaye, Birama, additional, Velghe, Amélie, additional, Bougeard, Gaelle, additional, Mann, Graham J, additional, Koscielny, Serge, additional, Barrett, Jennifer H, additional, Harland, Mark, additional, Newton-Bishop, Julia, additional, Gruis, Nelleke, additional, Van Doorn, Remco, additional, Gauthier-Villars, Marion, additional, Pierron, Gaelle, additional, Stoppa-Lyonnet, Dominique, additional, Coupier, Isabelle, additional, Guimbaud, Rosine, additional, Delnatte, Capucine, additional, Scoazec, Jean-Yves, additional, Eggermont, Alexander M, additional, Feunteun, Jean, additional, Tchertanov, Luba, additional, Demoulin, Jean-Baptiste, additional, Frebourg, Thierry, additional, and Bressac-de Paillerets, Brigitte, additional

Published
2017
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47. Genomic analysis and clinical management of adolescent cutaneous melanoma

Author

Rabbie, Roy, primary, Rashid, Mamunur, additional, Arance, Ana M., additional, Sánchez, Marcelo, additional, Tell-Marti, Gemma, additional, Potrony, Miriam, additional, Conill, Carles, additional, van Doorn, Remco, additional, Dentro, Stefan, additional, Gruis, Nelleke A., additional, Corrie, Pippa, additional, Iyer, Vivek, additional, Robles-Espinoza, Carla Daniela, additional, Puig-Butille, Joan A., additional, Puig, Susana, additional, and Adams, David J., additional

Published
2017
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48. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma

Author

Law, Matthew H. Bishop, D. Timothy Lee, Jeffrey E. Brossard, Myriam Martin, Nicholas G. Moses, Eric K. Song, Fengju and Barrett, Jennifer H. Kumar, Rajiv Easton, Douglas F. and Pharoah, Paul D. P. Swerdlow, Anthony J. Kypreou, Katerina P. and Taylor, John C. Harland, Mark Randerson-Moor, Juliette and Akslen, Lars A. Andresen, Per A. Avril, Marie-Franoise and Azizi, Esther Scarra, Giovanna Bianchi Brown, Kevin M. and Debniak, Tadeusz Duffy, David L. Elder, David E. Fang, Shenying Friedman, Eitan Galan, Pilar Ghiorzo, Paola and Gillanders, Elizabeth M. Goldstein, Alisa M. Gruis, Nelleke A. and Hansson, Johan Helsing, Per Hocevar, Marko Hoeiom, Veronica Ingvar, Christian Kanetsky, Peter A. Chen, Wei V. and Landi, Maria Teresa Lang, Julie Lathrop, G. Mark and Lubinski, Jan Mackie, Rona M. Mann, Graham J. Molven, Anders and Montgomery, Grant W. Novakovic, Srdjan Olsson, Hakan and Puig, Susana Puig-Butille, Joan Anton Qureshi, Abrar A. and Radford-Smith, Graham L. van der Stoep, Nienke van Doorn, Remco and Whiteman, David C. Craig, Jamie E. Schadendorf, Dirk and Simms, Lisa A. Burdon, Kathryn P. Nyholt, Dale R. Pooley, Karen A. Orr, Nick Stratigos, Alexander J. Cust, Anne E. and Ward, Sarah V. Hayward, Nicholas K. Han, Jiali Schulze, Hans-Joachim Dunning, Alison M. Bishop, Julia A. Newton and Demenais, Florence Amos, Christopher I. MacGregor, Stuart and Iles, Mark M. GenoMEL Consortium Essen-Heidelberg Investigators and SDH Study Grp Q-MEGA QTWIN Investigators AMFS Investigators and ATHENS Melanoma Study Grp

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 x 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.

Published
2015

49. The role of MC1Rgene variants and phenotypical features in predicting high nevus count

Author

van der Poel, Louise A.J., Bergman, Wilma, Gruis, Nelleke A., and Kukutsch, Nicole A.

Abstract

Variants in the Melanocortin 1 Receptor (MC1R) gene have been associated with an increased risk of melanoma, but the role in nevus count is unclear. We investigated if specific MC1Rgene variants or the number of MC1Rgene variants and phenotypical features were associated with nevus count. A total of 494 participants of the ‘Leiden skin cancer study’ were included and the MC1R gene coding sequence was analysed by single-strand conformation polymorphism analysis followed by sequencing of unknown variants. The association between MC1Rgene variants and nevus count and the association between age, gender and phenotypical features and nevus count were studied using the Chi-square test. Study of nine frequently occurring MC1Rgene variants in participants without skin cancer (n = 203) showed that the ‘r’ Val60Leu variant was significantly associated with high nevus count (>50 nevi) (P = 0.017). This association was very strong among women (P < 0.001), but not present among men. Having one or two MC1Rvariants in general did not show a significant difference in the nevus count. Hair colour, skin type, eye colour and age were not significantly associated with nevus count, whereas gender showed a significant association (P = 0.008), with the highest nevus counts in female. The Val60Leu variant of the MC1R gene could be a promising candidate as an independent predictor of high nevus count, particularly in women. This information about the genetic makeup could promote personalized follow-up strategies and might help to prevent skin cancer in the future.

Published
2020
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50. NEK11as a candidate high-penetrance melanoma susceptibility gene

Author

Christodoulou, Eirini, van Doorn, Remco, Visser, Mijke, Teunisse, Amina, Versluis, Mieke, van der Velden, Pieter, Hayward, Nicholas K, Jochemsen, Aart, and Gruis, Nelleke

Abstract

BackgroundA proportion of patients diagnosed with cutaneous melanoma reports a positive family history. Inherited variants in CDKN2Aand several other genes have been shown to predispose to melanoma; however, the genetic basis of familial melanoma remains unknown in most cases. The objective of this study was to provide insight into the genetic basis of familial melanoma.MethodsIn order to identify novel melanoma susceptibility genes, whole exome sequencing (WES) analysis was applied in a Dutch family with melanoma. The causality of a candidate variant was characterised by performing cosegregation analysis in five affected family members using patient-derived tissues and digital droplet PCR analysis to accurately quantify mutant allele frequency. Functional in-vitro studies were performed to assess the pathogenicity of the candidate variant.ResultsApplication of WES identified a rare, nonsense variant in the NEK11gene (c.1120C>T, p.Arg374Ter), cosegregating in all five affected members of a Dutch family. NEK11 (NIMA-related Kinase 11) is involved in the DNA damage response, enforcing the G2/M cell cycle checkpoint. In a melanoma from a variant carrier, somatic loss of the wildtype allele of this putative tumour suppressor gene was demonstrated. Functional analyses showed that the NEK11p.Arg374Ter mutation results in strongly reduced expression of the truncated protein caused by proteasomal degradation.ConclusionThe NEK11p.Arg374Ter variant identified in this family leads to loss-of-function through protein instability. Collectively, these findings support NEK11as a melanoma susceptibility gene.

Published
2020
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