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2. Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia

Author

Dalmasso, B. Pastorino, L. Nathan, V Shah, N. N. Palmer, J. M. Howlie, M. Johansson, P. A. Freedman, N. D. and Carter, B. D. Beane-Freeman, L. Hicks, B. Molven, A. and Helgadottir, H. Sankar, A. Tsao, H. Stratigos, A. J. and Helsing, P. Van Doorn, R. Gruis, N. A. Visser, M. Wadt, K. A. W. Mann, G. Holland, E. A. Nagore, E. Potrony, M. and Puig, S. Menin, C. Peris, K. Fargnoli, M. C. and Calista, D. Soufir, N. Harland, M. Bishop, T. Kanetsky, P. A. Elder, D. E. Andreotti, V Vanni, I Bruno, W. and Hoiom, V Tucker, M. A. Yang, X. R. Andresen, P. A. and Adams, D. J. Landi, M. T. Hayward, N. K. Goldstein, A. M. and Ghiorzo, P. GenoMEL MelaNostrum Consortia

Abstract

Purpose Ataxia-Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. Methods From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. Results LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56-4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6-5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case-control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018). Conclusion This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.

Published
2021

3. Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia

Author

Dalmasso, B., Pastorino, L., Nathan, V., Shah, N. N., Palmer, J. M., Howlie, M., Johansson, P. A., Freedman, N. D., Carter, B. D., Beane-Freeman, L., Hicks, B., Molven, A., Helgadottir, H., Sankar, A., Tsao, H., Stratigos, A. J., Helsing, P., Van Doorn, R., Gruis, N. A., Visser, M., Wadt, K. A. W., Mann, G., Holland, E. A., Nagore, E., Potrony, M., Puig, S., Menin, C., Peris, Ketty, Fargnoli, Maria Concetta, Calista, D., Soufir, N., Harland, M., Bishop, T., Kanetsky, P. A., Elder, D. E., Andreotti, V., Vanni, I., Bruno, W., Hoiom, V., Tucker, M. A., Yang, X. R., Andresen, P. A., Adams, D. J., Landi, M. T., Hayward, N. K., Goldstein, A. M., Ghiorzo, P., Peris K. (ORCID:0000-0002-5237-0463), Fargnoli M. C., Dalmasso, B., Pastorino, L., Nathan, V., Shah, N. N., Palmer, J. M., Howlie, M., Johansson, P. A., Freedman, N. D., Carter, B. D., Beane-Freeman, L., Hicks, B., Molven, A., Helgadottir, H., Sankar, A., Tsao, H., Stratigos, A. J., Helsing, P., Van Doorn, R., Gruis, N. A., Visser, M., Wadt, K. A. W., Mann, G., Holland, E. A., Nagore, E., Potrony, M., Puig, S., Menin, C., Peris, Ketty, Fargnoli, Maria Concetta, Calista, D., Soufir, N., Harland, M., Bishop, T., Kanetsky, P. A., Elder, D. E., Andreotti, V., Vanni, I., Bruno, W., Hoiom, V., Tucker, M. A., Yang, X. R., Andresen, P. A., Adams, D. J., Landi, M. T., Hayward, N. K., Goldstein, A. M., Ghiorzo, P., Peris K. (ORCID:0000-0002-5237-0463), and Fargnoli M. C.

Abstract

Purpose: Ataxia–Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. Methods: From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. Results: LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56–4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6–5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case–control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018). Conclusion: This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.

Published
2021

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

Author

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, Raimondi, S, Tagliabue E., Gandini S., Bellocco R., Maisonneuve P., Newton-Bishop J., Polsky D., Lazovich D., Kanetsky P. A., Ghiorzo P., Gruis N. A., Landi M. T., Menin C., Fargnoli M. C., Garcia-Borron J. C., Han J., Little J., Sera F., Raimondi S., 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, Raimondi, S, Tagliabue E., Gandini S., Bellocco R., Maisonneuve P., Newton-Bishop J., Polsky D., Lazovich D., Kanetsky P. A., Ghiorzo P., Gruis N. A., Landi M. T., Menin C., Fargnoli M. C., Garcia-Borron J. C., Han J., Little J., Sera F., and Raimondi S.

Abstract

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.

Published
2018

5. Genome‐wide characterization of 5‐hydoxymethylcytosine in melanoma reveals major differences with nevus

Author

Salgado, C., Oosting, J., Janssen, B., Kumar, R., Gruis, N., and Doorn, R. van

Abstract

Melanoma demonstrates altered patterns of DNA methylation that are associated with genetic instability and transcriptional repression of numerous genes. Active DNA demethylation is mediated by TET enzymes that catalyze conversion of 5-methylcytosine (mC) to 5-hydroxymethylcytosine (hmC). Loss of hmC occurs in melanoma and correlates with disease progression. Here we analysed the genomic distribution of hmC along with mC in nevus and melanoma using oxidative bisulfite chemistry combined with high-density arrays. HmC was enriched relative to mC at enhancers, 5’UTR regions and CpG shores in nevus and melanoma samples, pointing to specific TET enzyme activity. The proportion of interrogated CpG sites with high hmC levels was lower in melanoma (0.54%) than in nevus (2.0%). Depletion of hmC in melanoma was evident across all chromosomes and intragenic regions, being more pronounced in metastatic than in non-metastatic tumours. The patterns of hmC distribution in melanoma samples differed significantly from those in nevus samples, exceeding differences in mC patterns. We identified specific CpG sites and regions with significantly lower hmC levels in melanoma than in nevus that might serve as diagnostic markers. Differentially hydroxymethylated regions localized to cancer-related genes, including the PTEN gene promoter, suggesting that deregulated DNA hydroxymethylation may contribute to melanoma pathogenesis.

Published
2020

6. 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

7. 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

9. 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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10. 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

12. 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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13. 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

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

Author

Pasquali, E, García Borrón, J, Fargnoli, M, Gandini, S, Maisonneuve, P, Bagnardi, V, Specchia, C, Liu, F, Kayser, M, Nijsten, T, Nagore, E, Kumar, R, Hansson, J, Kanetsky, P, Ghiorzo, P, Debniak, T, Branicki, W, Gruis, N, Han, J, Dwyer, T, Blizzard, L, Landi, M, Palmieri, G, Ribas, G, Stratigos, A, Council, M, Autier, P, Little, J, Newton Bishop, J, Sera, F, Raimondi, S, Caini, S, Hofman, A, Uitterlinden, A, Scherer, D, Hoiom, V, Pastorino, L, Cochrane, J, Fernandez De Misa, R, Morling, N, Johansen, P, Pfeiffer, R, Kypreou, K, Bowcock, A, Cornelius, L, Motokawa, T, Anno, S, Helsing, P, Andresen, P, Wong, T, Wong, T., BAGNARDI, VINCENZO, Pasquali, E, García Borrón, J, Fargnoli, M, Gandini, S, Maisonneuve, P, Bagnardi, V, Specchia, C, Liu, F, Kayser, M, Nijsten, T, Nagore, E, Kumar, R, Hansson, J, Kanetsky, P, Ghiorzo, P, Debniak, T, Branicki, W, Gruis, N, Han, J, Dwyer, T, Blizzard, L, Landi, M, Palmieri, G, Ribas, G, Stratigos, A, Council, M, Autier, P, Little, J, Newton Bishop, J, Sera, F, Raimondi, S, Caini, S, Hofman, A, Uitterlinden, A, Scherer, D, Hoiom, V, Pastorino, L, Cochrane, J, Fernandez De Misa, R, Morling, N, Johansen, P, Pfeiffer, R, Kypreou, K, Bowcock, A, Cornelius, L, Motokawa, T, Anno, S, Helsing, P, Andresen, P, Wong, T, Wong, T., and BAGNARDI, VINCENZO

Abstract

The MC1R gene is a key regulator of skin pigmentation. We aimed to evaluate the association between MC1R variants and the risk of sporadic cutaneous melanoma (CM) within the M-SKIP project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. Data included 5,160 cases and 12,119 controls from 17 studies. We calculated a summary odds ratio (SOR) for the association of each of the nine most studied MC1R variants and of variants combined with CM by using random-effects models. Stratified analysis by phenotypic characteristics were also performed. Melanoma risk increased with presence of any of the main MC1R variants: the SOR for each variant ranged from 1.47 (95%CI: 1.17-1.84) for V60L to 2.74 (1.53-4.89) for D84E. Carriers of any MC1R variant had a 66% higher risk of developing melanoma compared with wildtype subjects (SOR; 95%CI: 1.66; 1.41-1.96) and the risk attributable to MC1R variants was 28%. When taking into account phenotypic characteristics, we found that MC1R-associated melanoma risk increased only for darker-pigmented Caucasians: SOR (95%CI) was 3.14 (2.06-4.80) for subjects with no freckles, no red hair and skin Type III/IV. Our study documents the important role of all the main MC1R variants in sporadic CM and suggests that they have a direct effect on melanoma risk, independently on the phenotypic characteristics of carriers. This is of particular importance for assessing preventive strategies, which may be directed to darker-pigmented Caucasians with MC1R variants as well as to lightly pigmented, fairskinned subjects.

Published
2015

18. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma

Author

Law, M., Bishop, D., Lee, J., Brossard, M., Martin, N., Moses, Eric, Song, F., Barrett, J., Kumar, R., Easton, D., Pharoah, P., Swerdlow, A., Kypreou, K., Taylor, J., Harland, M., Randerson-Moor, J., Akslen, L., Andresen, P., Avril, M., Azizi, E., Scarrà, G., Brown, K., Debniak, T., Duffy, D., Elder, D., Fang, S., Friedman, E., Galan, P., Ghiorzo, P., Gillanders, E., Goldstein, A., Gruis, N., Hansson, J., Helsing, P., Hocevar, M., Höiom, V., Ingvar, C., Kanetsky, P., Chen, W., Landi, M., Lang, J., Lathrop, G., Lubinski, J., MacKie, R., Mann, G., Molven, A., Montgomery, G., Novakovic, S., Olsson, H., Puig, S., Puig-Butille, J., Qureshi, A., Radford-Smith, G., Van Der Stoep, N., Van Doorn, R., Whiteman, D., Craig, J., Schadendorf, D., Simms, L., Burdon, K., Nyholt, D., Pooley, K., Orr, N., Stratigos, A., Cust, A., Ward, S., Hayward, N., Han, J., Schulze, H., Dunning, A., Bishop, J., Demenais, F., Amos, C., MacGregor, S., Iles, M., Law, M., Bishop, D., Lee, J., Brossard, M., Martin, N., Moses, Eric, Song, F., Barrett, J., Kumar, R., Easton, D., Pharoah, P., Swerdlow, A., Kypreou, K., Taylor, J., Harland, M., Randerson-Moor, J., Akslen, L., Andresen, P., Avril, M., Azizi, E., Scarrà, G., Brown, K., Debniak, T., Duffy, D., Elder, D., Fang, S., Friedman, E., Galan, P., Ghiorzo, P., Gillanders, E., Goldstein, A., Gruis, N., Hansson, J., Helsing, P., Hocevar, M., Höiom, V., Ingvar, C., Kanetsky, P., Chen, W., Landi, M., Lang, J., Lathrop, G., Lubinski, J., MacKie, R., Mann, G., Molven, A., Montgomery, G., Novakovic, S., Olsson, H., Puig, S., Puig-Butille, J., Qureshi, A., Radford-Smith, G., Van Der Stoep, N., Van Doorn, R., Whiteman, D., Craig, J., Schadendorf, D., Simms, L., Burdon, K., Nyholt, D., Pooley, K., Orr, N., Stratigos, A., Cust, A., Ward, S., Hayward, N., Han, J., Schulze, H., Dunning, A., Bishop, J., Demenais, F., Amos, C., MacGregor, S., and Iles, M.

Abstract

Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10−8), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.

Published
2015

21. The effect on melanoma risk of genes previously associated with telomere length

Author

Iles, M., Bishop, D., Taylor, J., Hayward, N., Brossard, M., Cust, A., Dunning, A., Lee, J., Moses, Eric, Akslen, L., Andresen, P., Avril, M., Azizi, E., Scarra, G., Brown, K., Debniak, T., Elder, D., Friedman, E., Ghiorzo, P., Gillanders, E., Goldstein, A., Gruis, N., Hansson, J., Harland, M., Helsing, P., Hoçevar, M., Hoiom, V., Ingvar, C., Kanetsky, P., Landi, M., Lang, J., Lathrop, G., Lubinski, J., Mackie, R., Martin, N., Molven, A., Montgomery, G., Novakovi, S., Olsson, H., Puig, S., Puig-Butille, J., Radford-Smith, G., Randerson-Moor, J., Van Der Stoep, N., Van Doorn, R., Whiteman, D., Macgregor, S., Pooley, K., Ward, S., Mann, G., Amos, C., Pharoah, P., Demenais, F., Law, M., Bishop, J., Barrett, J., Iles, M., Bishop, D., Taylor, J., Hayward, N., Brossard, M., Cust, A., Dunning, A., Lee, J., Moses, Eric, Akslen, L., Andresen, P., Avril, M., Azizi, E., Scarra, G., Brown, K., Debniak, T., Elder, D., Friedman, E., Ghiorzo, P., Gillanders, E., Goldstein, A., Gruis, N., Hansson, J., Harland, M., Helsing, P., Hoçevar, M., Hoiom, V., Ingvar, C., Kanetsky, P., Landi, M., Lang, J., Lathrop, G., Lubinski, J., Mackie, R., Martin, N., Molven, A., Montgomery, G., Novakovi, S., Olsson, H., Puig, S., Puig-Butille, J., Radford-Smith, G., Randerson-Moor, J., Van Der Stoep, N., Van Doorn, R., Whiteman, D., Macgregor, S., Pooley, K., Ward, S., Mann, G., Amos, C., Pharoah, P., Demenais, F., Law, M., Bishop, J., and Barrett, J.

Abstract

Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10-9, two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.

Published
2014

22. A comparison of CDKN2A mutation detection within the Melanoma Genetics Consortium (GenoMEL)

Author

Harland, M, Goldstein, Am, Kukalizch, K, Taylor, C, Hogg, D, Puig, S, Badenas, C, Gruis, N, TER HUURNE, J, Bergman, W, Hayward, Nk, Stark, M, Tsao, H, Tucker, Ma, Landi, Mt, Bianchi, Giovanna, Ghiorzo, Paola, Kanetsky, Pa, Elder, D, Mann, Gj, Holland, Ea, Bishop, Dt, NEWTON BISHOP, J, Malvehy, J., Badenas, C., Cervera, R., Francisco, Cuellar, Rosa, Marti, JOAN BRUNET VIDAL, Guang, Yang, Nicholas, Martin, David, Whiteman, Adele, Green, Joanne, Aitken, Paola, Minghetti, Michela, Mantelli, Pastorino, Lorenza, Nasti, Sabina, Gargiulo, Sara, Sara, Gliori, Sushila, Mistry, JULIETTE RERSON MOOR, Wilma, Bergman, TER HUURNE, JEANET A. C., CLASINE VAN DER DRIFT, LENY VAN MOURIK, COBY OUT LUITING, FRANS VAN NIEUWPOORT, Valerie, Chaudru, Agnes, Chompret, Caroline, Kanengiesser, Michel, J. L., Grange, F., Sassolas, B., Limacher, J. M., Couillet, D., Truchetet, F., Cesarini, J. P., Boitier, F., CHEVRANT BRETON, J., Lasset, C., Longy, M., Joly, P., BASSET SEGUIN, N., Lesimple, T., Dugast, C., Michael, Ming, PATRICIA VAN BELLE, Anton, Platz, Suzanne, Egyhazi, Rainer, Tuominen, Diana, Linden, Helen, Schmid, Alon, Scope, Felix, Pavlotsky, Eitan, Friedman, and Mark, Eliason

Subjects
Genetics, Cancer Research, Polymorphism, Genetic, Skin Neoplasms, Genes, p16, Melanoma, Cancer, Biology, medicine.disease, Article, Denaturing high performance liquid chromatography, Germline mutation, Oncology, CDKN2A, Genotype, medicine, Humans, Genetic Predisposition to Disease, Genetic variability, Gene, Chromatography, High Pressure Liquid, Germ-Line Mutation
Abstract

CDKN2A is the major melanoma susceptibility gene so far identified, but only 40% of three or more case families have identified mutations. A comparison of mutation detection rates was carried out by "blind" exchange of samples across GenoMEL, the Melanoma Genetics Consortium, to establish the false negative detection rates. Denaturing high performance liquid chromatography (DHPLC) screening results from 451 samples were compared to screening data from nine research groups in which the initial mutation screen had been done predominantly by sequencing. Three samples with mutations identified at the local centres were not detected by the DHPLC screen. No additional mutations were detected by DHPLC. Mutation detection across groups within GenoMEL is carried out to a consistently high standard. The relatively low rate of CDKN2A mutation detection is not due to failure to detect mutations and implies the existence of other high penetrance melanoma susceptibility genes.

Published
2008

23. Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma‐prone families from three continents

Author

Goldstein, A. M., Chan, M., Harland, M., Hayward, N. K., Demenais, F., Bishop, D. T., Azizi, E., Bergman, W., Bianchi, Giovanna, Bruno, William, Calista, D., CANNON ALBRIGHT, L. A., Chaudru, V., Chompret, A., Cuellar, F., Elder, D. E., Ghiorzo, Paola, Gillanders, E. M., Gruis, N. A., Jhansson, Dhogg, Holland, E. A., Kanetsky, PETER A., Kefford, R. F., Landi, Mt, Lang, Ju, Leachman, S. A., Mackie, R. M., Magnusson, V., Mann, G. J., NEWTON BISHOP, J., Palmer, J. M., Spuig, PUIG BUTILLE, J. A., Stark, M., Tsao, H., Tucker, M. A., Whitaker, L., Yakobson, E., Malvehy, J., Badenas, C., Cervera, R., Francisco, Cuellar, Rosa, Marti´, JOAN BRUNET VIDAL, Guang, Yang, Nicholas, Martin, David, Whiteman, Adele, Green, Joanne, Aitken, Paola, Minghetti, Mantelli, Michela, Pastorino, Lorenza, Nasti, Sabina, Gargiulo, Sara, Sara, Gliori, Sushila, Mistry, JULIETTE RANDERSON MOOR, Wilma, Bergman, TER HUURNE, JEANET A. C., CLASINE VAN DER DRIFT, LENY VAN MOURIK, COBY OUT LUITING, FRANS VAN NIEUWPOORT, Valerie, Chaudru, Agnes, Chompret, Caroline, Kanengiesser, Michel, J. L., Grange, F., Sassolas, B., Limacher, J. M., Couillet, D., Truchetet, F., Cesarini, J. P., Boitier, F., CHEVRANT BRETON, J., Lasset, C., Longy, M., Joly, P., BASSET SEGUIN, N., Lesimple, T., Dugast, C., Arupa, Ganguly, Michael, Ming, PATRICIA VAN BELLE, Anton, Platz, Suzanne, Egyhazi, Rainer, Tuominen, Diana, Linden, Helen, Schmid, Alon, Scope, Felix, Pavlotsky, Eitan, Friedman, and Mark, Eliason

Subjects
Male, medicine.medical_specialty, Skin Neoplasms, Biology, medicine.disease_cause, Germline mutation, CDKN2A, Genetic variation, Genetics, medicine, Humans, Hereditary Melanoma, neoplasms, Melanoma, Genetics (clinical), Cyclin-Dependent Kinase Inhibitor p16, Germ-Line Mutation, Mutation, Incidence (epidemiology), Incidence, Australia, Genetic Variation, medicine.disease, Europe, North America, Medical genetics, Original Article, Female, Demography
Abstract

BACKGROUND: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer. METHODS: These four features were examined in 385 families with > or =3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents. RESULTS: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, > or =2 patients with MPM, median age at melanoma diagnosis or =6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only > or =1 patient with MPM and age at diagnosis < or =40 years simultaneously predicted the mutation risk. CONCLUSIONS: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer-CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.

Published
2006

24. Melanocortin-1 receptor, skin cancer and phenotypic characteristics (M-SKIP) project: study design and methods for pooling results of genetic epidemiological studies

Author

Raimondi, S, Gandini, S, Fargnoli, M, Bagnardi, V, Maisonneuve, P, Specchia, C, Kumar, R, Nagore, E, Han, J, Hansson, J, Kanetsky, P, Ghiorzo, P, Gruis, N, Dwyer, T, Blizzard, L, Fernandez de Misa, R, Branicki, W, Debniak, T, Morling, N, Landi, M, Palmieri, G, Ribas, G, Stratigos, A, Cornelius, L, Motokawa, T, Anno, S, Helsing, P, Wong, T, Autier, P, García Borrón, J, Little, J, Newton Bishop, J, Sera, F, Liu, F, Kayser, M, Nijsten, T, Study Group, G, BAGNARDI, VINCENZO, Study Group, G., Raimondi, S, Gandini, S, Fargnoli, M, Bagnardi, V, Maisonneuve, P, Specchia, C, Kumar, R, Nagore, E, Han, J, Hansson, J, Kanetsky, P, Ghiorzo, P, Gruis, N, Dwyer, T, Blizzard, L, Fernandez de Misa, R, Branicki, W, Debniak, T, Morling, N, Landi, M, Palmieri, G, Ribas, G, Stratigos, A, Cornelius, L, Motokawa, T, Anno, S, Helsing, P, Wong, T, Autier, P, García Borrón, J, Little, J, Newton Bishop, J, Sera, F, Liu, F, Kayser, M, Nijsten, T, Study Group, G, BAGNARDI, VINCENZO, and Study Group, G.

Abstract

BACKGROUND: For complex diseases like cancer, pooled-analysis of individual data represents a powerful tool to investigate the joint contribution of genetic, phenotypic and environmental factors to the development of a disease. Pooled-analysis of epidemiological studies has many advantages over meta-analysis, and preliminary results may be obtained faster and with lower costs than with prospective consortia. Design and methods Based on our experience with the study design of the Melanocortin-1 receptor (MC1R) gene, SKin cancer and Phenotypic characteristics (M-SKIP) project, we describe the most important steps in planning and conducting a pooled-analysis of genetic epidemiological studies. We then present the statistical analysis plan that we are going to apply, giving particular attention to methods of analysis recently proposed to account for between-study heterogeneity and to explore the joint contribution of genetic, phenotypic and environmental factors in the development of a disease. Within the M-SKIP project, data on 10,959 skin cancer cases and 14,785 controls from 31 international investigators were checked for quality and recoded for standardization. We first proposed to fit the aggregated data with randomeffects logistic regression models. However, for the M-SKIP project, a two-stage analysis will be preferred to overcome the problem regarding the availability of different study covariates. The joint contribution of MC1R variants and phenotypic characteristics to skin cancer development will be studied via logic regression modeling. DISCUSSION: Methodological guidelines to correctly design and conduct pooled-analyses are needed to facilitate application of such methods, thus providing a better summary of the actual findings on specific fields.

Published
2012

26. A cell cycle regulator potentially involved in genesis of many tumor types

Author

Kamb, A., Gruis, N., Weaver-Feldhaus, J., Liu, Q., Harshman, K., Tavtigian, S., Stockert, E., Day, R., Johnson, B., and Skolnick, M.

Abstract

A putative tumor suppressor locus on the short arm of human chromosome 9 has been localized to a region of less than 40 kilobases by means of homozygous deletions in melanoma cell lines. This region contained a gene, Multiple Tumor Suppressor 1 (MTS1), that encodes a previously identified inhibitor (p16) of cyclin-dependent kinase 4. MTS1 was homozygously deleted at high frequency in cell lines derived from tumors of lung, breast, brain, bone, skin, bladder, kidney, ovary, and lymphocyte. Melanoma cell lines that carried at least one copy of MTS1 frequently carried nonsense, missense, or frameshift mutations in the gene. These findings suggest that MTS1 mutations are involved in tumor formation in a wide range of tissues.

Published
1994

28. Sun exposure and melanoma risk at different latitudes: a pooled analysis of 5700 cases and 7216 controls

Author

Chang, Y.-m., primary, Barrett, J. H., additional, Bishop, D. T., additional, Armstrong, B. K., additional, Bataille, V., additional, Bergman, W., additional, Berwick, M., additional, Bracci, P. M., additional, Elwood, J. M., additional, Ernstoff, M. S., additional, Gallagher, R. P., additional, Green, A. C., additional, Gruis, N. A., additional, Holly, E. A., additional, Ingvar, C., additional, Kanetsky, P. A., additional, Karagas, M. R., additional, Lee, T. K., additional, Le Marchand, L., additional, Mackie, R. M., additional, Olsson, H., additional, Osterlind, A., additional, Rebbeck, T. R., additional, Sasieni, P., additional, Siskind, V., additional, Swerdlow, A. J., additional, Titus-Ernstoff, L., additional, Zens, M. S., additional, and Newton-Bishop, J. A., additional

Published
2009
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30. MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project.

Author

Tagliabue, E, Fargnoli, M C, Gandini, S, Maisonneuve, P, Liu, F, Kayser, M, Nijsten, T, Han, J, Kumar, R, Gruis, N A, Ferrucci, L, Branicki, W, Dwyer, T, Blizzard, L, Helsing, P, Autier, P, García-Borrón, J C, Kanetsky, P A, Landi, M T, and Little, J

Subjects
RISK factors of skin cancer, MELANOCORTIN receptors, GENETIC polymorphisms, ODDS ratio, RANDOM effects model, BASAL cell carcinoma
Abstract

Background:The melanocortin-1-receptor (MC1R) gene regulates human pigmentation and is highly polymorphic in populations of European origins. The aims of this study were to evaluate the association between MC1R variants and the risk of non-melanoma skin cancer (NMSC), and to investigate whether risk estimates differed by phenotypic characteristics.Methods:Data on 3527 NMSC cases and 9391 controls were gathered through the M-SKIP Project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. We calculated summary odds ratios (SOR) with random-effect models, and performed stratified analyses.Results:Subjects carrying at least one MC1R variant had an increased risk of NMSC overall, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC): SOR (95%CI) were 1.48 (1.24-1.76), 1.39 (1.15-1.69) and 1.61 (1.35-1.91), respectively. All of the investigated variants showed positive associations with NMSC, with consistent significant results obtained for V60L, D84E, V92M, R151C, R160W, R163Q and D294H: SOR (95%CI) ranged from 1.42 (1.19-1.70) for V60L to 2.66 (1.06-6.65) for D84E variant. In stratified analysis, there was no consistent pattern of association between MC1R and NMSC by skin type, but we consistently observed higher SORs for subjects without red hair.Conclusions:Our pooled-analysis highlighted a role of MC1R variants in NMSC development and suggested an effect modification by red hair colour phenotype. [ABSTRACT FROM AUTHOR]

Published
2015
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33. IL-17 Genetics of the FAMMM Syndrome

Author

Velden, P. A., primary, Nieuwpoort, F. A., additional, Out-Luiting, C., additional, Smit, N. P., additional, Pavel, S., additional, Snoo, F. A., additional, Bergman, W., additional, Tensen, C. P., additional, Frants, R. R., additional, Willemze, R., additional, and Gruis, N. A., additional

Published
2003
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35. Multiple agminate Spitz naevi

Author

Hulshof, M. M., primary, van Haeringen, A., additional, Gruis, N. A., additional, Snels, D. C. G. T. M., additional, and Bergman, W., additional

Published
1998
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36. Germline Mutations of the CDKN2 Gene in UK Melanoma Families

Author

Harland, M., primary, Meloni, R., additional, Gruis, N., additional, Pinney, E., additional, Brookes, S., additional, Spurr, N. K., additional, Frischauf, A.-M., additional, Bataille, V., additional, Peters, G., additional, Cuzick, J., additional, Selby, P., additional, Bishop, D. T., additional, and Bishop, J. N., additional

Published
1997
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44. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus

Author

Kamb, A., primary, Shattuck-Eidens, D., additional, Eeles, R., additional, Liu, Q., additional, Gruis, N. A., additional, Ding, W., additional, Hussey, C., additional, Tran, T., additional, Miki, Y., additional, Weaver-Feldhaus, J., additional, McClure, M., additional, Aitken, J. F., additional, Anderson, D. E., additional, Bergman, W., additional, Frants, R., additional, Goldgar, D. E., additional, Green, A., additional, MacLennan, R., additional, Martin, N. G., additional, Meyer, L. J., additional, Youl, P., additional, Zone, J. J., additional, Skolnick, M. H., additional, and Cannon-Albright, L. A., additional

Published
1994
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47. A locus linked to p16 modifies melanoma risk in Dutch familial atypical multiple mole melanoma (FAMMM) syndrome families.

Author

van der Velden, P A, Sandkuijl, L A, Bergman, W, Hille, E T, Frants, R R, and Gruis, N A

Abstract

The CDKN2A gene that encodes the cell cycle inhibitor p16 shows mutations in many but not all 9p21-linked melanoma families. Most Dutch melanoma families segregate for a unique founder mutation (p16-Leiden), encoding a truncated nonfunctional p16 protein. The highly variable risk for p16-Leiden carriers to develop melanoma suggests a role for other genetic and/or environmental factors. We hypothesized that a 9p21 gene other than CDKN2A may be relevant in the remaining 9p21-linked melanoma families without p16 mutations but may also act as a risk modifier in p16-Leiden carriers. Haplotype analysis for 9p21 was performed using microsatellite markers in six p16-Leiden families originating from a founder population. p16-Leiden carriers in two families shared an unexpectedly large founder haplotype ( approximately 20-cM) around CDKN2A, mostly in proximal direction. Melanoma-positive p16-Leiden carriers from these families showed this extensive proximal haplotype compared with melanoma-negative p16-Leiden carriers from the same families. Additional p16-Leiden families less heavily affected with melanoma showed shorter haplotypes sharing, excluding the region proximally of CDKN2A. The presence of a gene involved in melanoma susceptibility proximal of CDKN2A is corroborated by somatic deletions of 9p in tumors, which frequently do not include CDKN2A but a more proximal chromosomal area instead. Our results provide a candidate region for further gene mapping in p16-negative 9p21-linked melanoma families and guide the search for risk modifiers in melanoma development.

Published
1999

48. The effect on melanoma risk of genes previously associated with telomere length

Author

Iles, M. M., Bishop, D. T., Taylor, J. C., Hayward, N. K., Brossard, M., Cust, A. E., Dunning, A. M., Lee, J. E., Moses, E. K., Akslen, L. A., Amfs, Investigators, Andresen, P. A., Avril, M. F., Azizi, E., Scarrà, G. B., Brown, K. M., Debniak, T., Elder, D. E., Friedman, E., Ghiorzo, P., Gillanders, E. M., Goldstein, A. M., Gruis, N. A., Hansson, J., Harland, M., Helsing, P., Hočevar, M., Höiom, V., Ibd, Investigators, Ingvar, C., Kanetsky, P. A., Landi, M. T., Lang, J., Lathrop, G. M., Lubiński, J., Mackie, R. M., Nicholas Martin, Molven, A., Montgomery, G. W., Novaković, S., Olsson, H., Puig, S., Puig-Butille, J. A., Qmega Qtwin, And Investigators, Radford-Smith, G. L., Randerson-Moor, J., Sdh, Study Group, Stoep, N., Doorn, R., Whiteman, D. C., Macgregor, S., Pooley, K. A., Ward, S. V., Mann, G. J., Amos, C. I., Pharoah, P. D., Demenais, F., Law, M. H., Newton Bishop, J. A., Barrett, J. H., GenoMEL Consortium, Dunning, Alison [0000-0001-6651-7166], Pooley, Karen [0000-0002-1274-9460], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository

Subjects
Skin Neoplasms, Telomere-Binding Proteins, Australia, DNA Helicases, Confounding Factors, Epidemiologic, Zinc Fingers, Telomere, Polymorphism, Single Nucleotide, United States, Europe, Ribonucleoproteins, Predictive Value of Tests, Research Design, Humans, RNA, Israel, Melanoma, Telomerase, Germ-Line Mutation
Abstract

Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10(-9), two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.

50. A comparison of CDKN2A mutation detection within the Melanoma Genetics Consortium (GenoMEL)

Author

Harland M, Goldstein AM, Kukalizch K, Taylor C, Hogg D, Puig S, Badenas C, Gruis N, ter Huurne J, Bergman W, Hayward NK, Stark M, Tsao H, Tucker MA, Landi MT, Scarra GB, Ghiorzo P, Kanetsky PA, Elder D, and Mann GJ

Abstract

CDKN2A is the major melanoma susceptibility gene so far identified, but only 40% of three or more case families have identified mutations. A comparison of mutation detection rates was carried out by 'blind' exchange of samples across GenoMEL, the Melanoma Genetics Consortium, to establish the false negative detection rates. Denaturing high performance liquid chromatography (DHPLC) screening results from 451 samples were compared to screening data from nine research groups in which the initial mutation screen had been done predominantly by sequencing. Three samples with mutations identified at the local centres were not detected by the DHPLC screen. No additional mutations were detected by DHPLC. Mutation detection across groups within GenoMEL is carried out to a consistently high standard. The relatively low rate of CDKN2A mutation detection is not due to failure to detect mutations and implies the existence of other high penetrance melanoma susceptibility genes. [ABSTRACT FROM AUTHOR]

Published
2008
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