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

Author(s):Show less -

Taylor, Nicholas J. ^[1] ; Mitra, Nandita ^[2] ; Qian, Lu ^[3] ; Avril, Marie-Francoise ^{[4, 5]} ; Bishop, D. Timothy ^[6] ; Bressac-de Paillerets, Brigitte ^{[7, 8]} ; Bruno, William ^{[9, 10]} ; Calista, Donato ^[11] ; Cuellar, Francisco ^[12] ; Cust, Anne E. ^{[13, 14]} ; Demenais, Florence ^[15] ; Elder, David E. ^[16] ; Gerdes, Anne-Marie ^[17] ; Ghiorzo, Paola ^{[9, 10]} ; Goldstein, Alisa M. ^[18] ; Grazziotin, Thais C. ^[19] ; Gruis, Nelleke A. ^[20] ; Hansson, Johan ^[21] ; Harland, Mark ^[6] ; Hayward, Nicholas K. ^[22] ; Hocevar, Marko ^[23] ; Hoiom, Veronica ^[21] ; Holland, Elizabeth A. ^{[14, 24]} ; Ingvar, Christian ^{[25, 26]} ; Landi, Maria Teresa ^[18] ; Landman, Gilles ^[27] ; Larre-Borges, Alejandra ^[28] ; Mann, Graham J. ^{[14, 24]} ; Nagore, Eduardo ^[29] ; Olsson, Hakan ^{[25, 26]} ; Palmer, Jane M. ^[22] ; Peric, Barbara ^[23] ; Pjanova, Dace ^[30] ; Pritchard, Antonia L. ^[22] ; Puig, Susana ^{[12, 31]} ; Schmid, Helen ^{[14, 24]} ; van der Stoep, Nienke ^[32] ; Tucker, Margaret A. ^[18] ; Wadt, Karin A. W. ^[17] ; Yang, Xiaohong R. ^[18] ; Newton-Bishop, Julia A. ^[6] ; Kanetsky, Peter A. ^[3] ; Grp, GenoMEL Study

Affiliation:Show less -

^[1] Texas A&M Univ, Dept Epidemiol & Biostat, College Stn, TX - USA

^[2] Univ Penn, Dept Biostat Epidemiol & Informat, Philadelphia, PA 19104 - USA

^[3] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL 33612 - USA

^[4] Univ Paris 05, Paris - France

^[5] Hop Cochin, AP HP, Paris - France

^[6] Univ Leeds, Leeds Inst Med Res St James, Sect Epidemiol & Biostat, Leeds, W Yorkshire - England

^[7] Univ Paris Saclay, Gustave Roussy, Dept Biopathol, Villejuif - France

^[8] INSERM, U1186, Villejuif - France

^[9] Univ Genoa, Dept Internal Med & Med Specialties, Genoa - Italy

^[10] Ist Ricovero & Cura Carattere Sci AOU San Martino, Genoa - Italy

^[11] Maurizio Bufalini Hosp, Dermatol Unit, Cesena - Italy

^[12] Univ Barcelona, Inst Invest Biomed August Pi Sunyer, Hosp Clin Barcelona, Dermatol Dept, Melanoma Unit, Barcelona - Spain

^[13] Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW - Australia

^[14] Univ Sydney, Melanoma Inst Australia, Sydney, NSW - Australia

^[15] Univ Paris Diderot, INSERM, UMR 946, Genet Variat & Human Dis Unit, Paris - France

^[16] Hosp Univ Penn, Dept Pathol & Lab Med, 3400 Spruce St, Philadelphia, PA 19104 - USA

^[17] Univ Hosp Copenhagen, Dept Clin Genet, Copenhagen - Denmark

^[18] NCI, Human Genet Program, Div Canc Epidemiol & Genet, Bethesda, MD 20892 - USA

^[19] Pontificia Univ Catolica Rio Grande do Sul, Porto Alegre, RS - Brazil

^[20] Leiden Univ, Med Ctr, Dept Dermatol, Leiden - Netherlands

^[21] Karolinska Inst, Dept Oncol Pathol, Stockholm - Sweden

^[22] QIMR Berghofer Med Res Inst, Herston, Qld - Australia

^[23] Inst Oncol Ljubljana, Zaloska - Slovenia

^[24] Univ Sydney, Westmead Inst Med Res, Sydney, NSW - Australia

^[25] Lund Univ Hosp, Dept Clin Sci, Lund - Sweden

^[26] Lund Univ Hosp, Dept Surg, Lund - Sweden

^[27] Univ Fed Sao Paulo, Escola Paulista Med, Dept Pathol, Sao Paulo, SP - Brazil

^[28] Univ Republica, Hosp Clin, Catedra Dermatol, Unidad Les Pigmentadas, Montevideo - Uruguay

^[29] Inst Valenciano Oncol, Dept Dermatol, Valencia - Spain

^[30] Latvian Biomed Res & Study Ctr, Riga - Latvia

^[31] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras, Barcelona - Spain

^[32] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden - Netherlands

• Document type: Journal article
• Source: JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY; v. 81, n. 2, p. 386-394, AUG 2019.
• Web of Science Citations: 1

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. (AU)

• FAPESP's process: 07/04313-2 - Genetic and environmental risk factors to the development of melanoma in Latin America
• Grantee: Gilles Landman
• Support Opportunities: Regular Research Grants