Leiden University Scholarly Publications

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Taylor, N.J.; Mitra, N.; Qian, L.; Avril, M.F.; Bishop, D.T.; Bressac-de Paillerets, B.; ... ; GenoMEL Study Grp (2019)

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

Article / Letter to editor
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 < ...Show moreBackground: 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.Show less
CDKN2A
familial melanoma
GenoMEL
GenoMELPREDICT
mutation prediction
All authors
Taylor, N.J.; Mitra, N.; Qian, L.; Avril, M.F.; Bishop, D.T.; Bressac-de Paillerets, B.; Bruno, W.; Calista, D.; Cuellar, F.; Cust, A.E.; Demenais, F.; Elder, D.E.; Gerdes, A.M.; Ghiorzo, P.; Goldstein, A.M.; Grazziotin, T.C.; Gruis, N.A.; Hansson, J.; Harland, M.; Hayward, N.K.; Hocevar, M.; Hoiom, V.; Holland, E.A.; Ingvar, C.; Landi, M.T.; Landman, G.; Larre-Borges, A.; Mann, G.J.; Nagore, E.; Olsson, H.; Palmer, J.M.; Peric, B.; Pjanova, D.; Pritchard, A.L.; Puig, S.; Schmid, H.; Stoep, N. van der; Tucker, M.A.; Wadt, K.A.W.; Yang, X.R.; Newton-Bishop, J.A.; Kanetsky, P.A.; GenoMEL Study Grp
Date
2019-08-01
Journal
Journal of The American Academy of Dermatology
Volume
81
Issue
2
Pages
386 - 394
DOI
doi:10.1016/j.jaad.2019.01.079