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Title: Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT.
Authors: Taylor NJ,  Mitra N,  Qian L,  Avril MF,  Bishop DT,  Bressac-de Paillerets B,  Bruno W,  Calista D,  Cuellar F,  Cust AE,  Demenais F,  Elder DE,  Gerdes AM,  Ghiorzo P,  Goldstein AM,  Grazziotin TC,  Gruis NA,  Hansson J,  Harland M,  Hayward NK,  Hocevar M,  Höiom V,  Holland EA,  Ingvar C,  Landi MT,  Landman G,  Larre-Borges A,  Mann GJ,  Nagore E,  Olsson H,  Palmer JM,  Perić B,  Pjanova D,  Pritchard AL,  Puig S,  Schmid H,  van der Stoep N,  Tucker MA,  Wadt KAW,  Yang XR,  Newton-Bishop JA,  Kanetsky PA,  GenoMEL Study Group
Journal: J Am Acad Dermatol
Date: 2019 Aug
Branches: CGB, ITEB, TDRP
PubMed ID: 30731170
PMC ID: PMC6634996
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.