Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT - 27/07/19
Doi : 10.1016/j.jaad.2019.01.079
Nicholas J. Taylor, PhD a, Nandita Mitra, PhD b, Lu Qian, MS c, Marie-Françoise Avril, MD d, D. Timothy Bishop, PhD e, Brigitte Bressac-de Paillerets, PhD f, William Bruno, MD, PhD g, Donato Calista, MD h, Francisco Cuellar, MD i, Anne E. Cust, PhD j, k, Florence Demenais, MD l, David E. Elder, MD m, Anne-Marie Gerdes, PhD n, Paola Ghiorzo, PhD g, Alisa M. Goldstein, PhD o, Thais C. Grazziotin, MD p, Nelleke A. Gruis, PhD q, Johan Hansson, MD, PhD r, Mark Harland, PhD e, Nicholas K. Hayward, PhD s, Marko Hocevar, MD, PhD t, Veronica Höiom, PhD r, Elizabeth A. Holland, BSc k, u, Christian Ingvar, MD, PhD v, w, Maria Teresa Landi, MD, PhD o, Gilles Landman, MD, PhD x, Alejandra Larre-Borges, MD y, Graham J. Mann, PhD k, u, Eduardo Nagore, MD, PhD z, Håkan Olsson, MD, PhD v, w, Jane M. Palmer, RN s, Barbara Perić, MD, PhD t, Dace Pjanova, PhD aa, Antonia L. Pritchard, PhD s, Susana Puig, MD, PhD i, bb, Helen Schmid, MPH k, u, Nienke van der Stoep, PhD cc, Margaret A. Tucker, MD o, Karin A.W. Wadt, MD, PhD n, Xiaohong R. Yang, PhD o, Julia A. Newton-Bishop, MD e, Peter A. Kanetsky, PhD c, ⁎ 
on behalf of the
on behalf of the
GenoMEL Study Group
a Department of Epidemiology and Biostatistics, Texas A&M University, College Station, Texas
b Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania
c Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
d Assistance Publique-Hôpitaux de Paris, Hôpital Cochin et Université Paris Descartes, Paris, France
e Section of Epidemiology and Biostatistics, Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom
f Gustave Roussy, Université Paris-Saclay, Département de Biopathologie and Institut National de la Santé et de la Recherche Médicale U1186, Villejuif, France
g Department of Internal Medicine and Medical Specialties, University of Genoa and Istituto de Ricovero e Cura a Carattere Scientifico AOU San Martino-IST, Genoa, Italy
h Dermatology Unit, Maurizio Bufalini Hospital, Cesena, Italy
i Melanoma Unit, Dermatology Department, Hospital Clinic Barcelona, Institut de Investigacions Biomediques August Pi Sunyer, Universitat de Barcelona, Barcelona, Spain
j Sydney School of Public Health, The University of Sydney, Sydney, Australia
k Melanoma Institute Australia, The University of Sydney, Sydney, Australia
l Institut National de la Santé et de la Recherche Médicale UMR-946, Genetic Variation and Human Disease Unit, Université Paris Diderot, Paris, France
m Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
n Department of Clinical Genetics, University Hospital of Copenhagen, Copenhagen, Denmark
o Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
p Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil
q Department of Dermatology, Leiden University Medical Centre, Leiden, the Netherlands
r Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
s QIMR Berghofer Medical Research Institute, Herston, Australia
t Institute of Oncology Ljubljana, Zaloska, Ljubljana, Slovenia
u Westmead Institute for Medical Research, University of Sydney, Sydney, Australia
v Department of Clinical Sciences, Lund University Hospital Lund, Sweden
w Department of Surgery, Lund University Hospital, Lund, Sweden
x Department of Pathology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
y Unidad de Lesiones Pigmentadas, Cátedra de Dermatología, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay
z Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain
aa Latvian Biomedical Research and Study Centre, Riga, Latvia
bb Centro de Investigacion Biomedica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain
cc Department of Clinical Genetics, Leiden University Medical Center Leiden, the Netherlands
∗Reprint requests: Peter A. Kanetsky, PhD, MPH, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, MRC Bldg 213, Tampa, FL 33612.H. Lee Moffitt Cancer Center and Research Institute12902 Magnolia DrMRC Bldg 213TampaFL33612
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.
Il testo completo di questo articolo è disponibile in PDF.Key words : CDKN2A, familial melanoma, GenoMEL, GenoMELPREDICT, mutation prediction
Abbreviations used : AUC, CDKN2A, CI, ROC
Mappa
| Funding sources: Supported by the Cancer Research UK Programme Award (nos. C588/A4994 and C588/A10589); a Cancer Research UK project grant (C8216/A6129); the US National Institutes of Health (CA83115 to Drs Kanetsky, Bishop, and Elder; CA5558 to Dr Landi; Dr Taylor was supported by CA147832 to Dr Kanetsky); the Intramural Research Program of the National Institutions of Health, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics; the National Health and Medical Research Council of Australia (NHMRC107359, 402761, 633004, 566946, 211172); the Cancer Council New South Wales (project grants 77/00, 06/10); the Cancer Institute New South Wales (CINSW 05/TPG/1-01, 10/TPG/1-02); the Cancer Council Victoria and the Cancer Council Queensland (project grant 371); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior; Fundação de Amparo à Pesquisa do Estado de São Paulo (no. 2007/04313-2); the National Health and Medical Research Council of Australia and the NCI (CA88363); the Cancer Research Foundations of Radiumhemmet and the Swedish Cancer Society; the Paulsson Trust, Lund University; the Swedish Cancer Society and European Research Council Advanced Grant (ERC-2011-294576); the research at the Melanoma Unit in Barcelona is partially funded by Spanish Fondo de Investigaciones Sanitarias (grants PI15/00716 and PI15/00956); Centros de Investigación Biomédica en Red de Enfermedades Raras of the Instituto de Salud Carlos III, Spain, is co-financed by European Development Regional Fund “A way to achieve Europe”; the Agency for Management of University and Research Grants 2014_SGR_603 of the Catalan government, Spain; the European Commission under the 6th Framework Programme (contract no. LSHC-CT-2006-018702, GenoMEL) and the 7th Framework Programme, Diagnoptics; a grant from Fundació La Marató de TV3201331-30, Catalonia, Spain; a grant from Fundación Científica de la Asociación Española Contra el Cáncer, Spain (GCB15152978SOEN); Centres de Recerca de Catalunya Programme/Generalitat de Catalunya; the Italian Association for Cancer Research (to Dr Ghiorzo); the Italian Ministry of Health-Ricerca Finalizzata 2016 (to IRCCS San Martino-IST, Genoa); the Programme Hospitalier de Recherche Clinique (PHRC-AOM-07-195) awarded to Dr Avril and Dr Demenais; a grant from the Institut National du Cancer (to Dr Bressac de-Paillerets for coordination of Melanoma Oncogenetics in France); the Comisión Honoraria de Lucha Contra el Cáncer, Comisión Sectorial de Investigación Científica, Fundación Manuel Pérez, Montevideo, Uruguay; the Dutch Cancer Society (UL 2012-5489 to Dr Gruis); a scholarship awarded by Consejo Nacional de Ciencia y Tecnología, Mexico (152256/158706 to Dr Cuellar); and a Career Development Fellowship from the National Health and Medical Research Council (1147843) and Cancer Institute New South Wales (15/CDF/1-14) to Dr Cust. Part of the work was carried out at the Esther Koplowitz Center, Barcelona. |
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| Conflicts of interest: None disclosed. |
© 2019
American Academy of Dermatology, Inc. Tutti i diritti riservati.
Vol 81 - N° 2
P. 386-394 - agosto 2019 Ritorno al numero
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