Jasper I van der Rhee1, Pieta Krijnen2, Nelleke A Gruis3, Femke A de Snoo4, Hans F A Vasen5, Hein Putter6, Nicole A Kukutsch3, Wilma Bergman3. 1. Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: j.i.van_der_rhee@lumc.nl. 2. Leiden Cancer Registry, Comprehensive Cancer Center West, Leiden, The Netherlands. 3. Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands. 4. Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands; Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. 5. The Netherlands Foundation for the Detection of Hereditary Tumors, Leiden, The Netherlands. 6. Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands.
Abstract
BACKGROUND: About 10% of cutaneous malignant melanomas (CMM) occur in individuals with a family history of melanoma. In 20% to 40% of melanoma families germline mutations in CDKN2A are detected. Knowledge of the clinicohistologic characteristics of melanomas and patients from these families is important for optimization of management strategies, and may shed more light on the complex interplay of genetic and environmental factors in the pathogenesis of melanoma. OBJECTIVE: We sought to investigate the clinical and histologic characteristics of CMM in CDKN2A-mutated families. METHODS: Clinical and histologic characteristics of 182 patients with 429 CMM from families with a founder mutation in CDKN2A (p16-Leiden mutation) were compared with 7512 patients with 7842 CMM from a population-based cancer registry. RESULTS: Patients with p16-Leiden had their first melanoma 15.3 years younger than control patients. The 5-year cumulative incidence of second primary CMM was 23.4% for patients with p16-Leiden compared with 2.3% for control patients. The risk of a second melanoma was twice as high for patients with p16-Leiden who had their first melanoma before age 40 years, compared with older patients with p16-Leiden. Unlike control patients, there was no body site concordance of the first and second melanoma in patients with p16-Leiden and multiple primary melanomas. Patients with p16-Leiden had significantly more superficial spreading, and less nodular and lentiginous melanomas. LIMITATIONS: Ascertainment of patients with p16-Leiden was family based. The study was performed in families with a founder mutation, the p16-Leiden mutation. CONCLUSION: Our findings are consistent with a pathogenic pathway of melanoma development from nevi, starting early and ongoing throughout life, and not related to chronic sun exposure.
BACKGROUND: About 10% of cutaneous malignant melanomas (CMM) occur in individuals with a family history of melanoma. In 20% to 40% of melanoma families germline mutations in CDKN2A are detected. Knowledge of the clinicohistologic characteristics of melanomas and patients from these families is important for optimization of management strategies, and may shed more light on the complex interplay of genetic and environmental factors in the pathogenesis of melanoma. OBJECTIVE: We sought to investigate the clinical and histologic characteristics of CMM in CDKN2A-mutated families. METHODS: Clinical and histologic characteristics of 182 patients with 429 CMM from families with a founder mutation in CDKN2A (p16-Leiden mutation) were compared with 7512 patients with 7842 CMM from a population-based cancer registry. RESULTS:Patients with p16-Leiden had their first melanoma 15.3 years younger than control patients. The 5-year cumulative incidence of second primary CMM was 23.4% for patients with p16-Leiden compared with 2.3% for control patients. The risk of a second melanoma was twice as high for patients with p16-Leiden who had their first melanoma before age 40 years, compared with older patients with p16-Leiden. Unlike control patients, there was no body site concordance of the first and second melanoma in patients with p16-Leiden and multiple primary melanomas. Patients with p16-Leiden had significantly more superficial spreading, and less nodular and lentiginous melanomas. LIMITATIONS: Ascertainment of patients with p16-Leiden was family based. The study was performed in families with a founder mutation, the p16-Leiden mutation. CONCLUSION: Our findings are consistent with a pathogenic pathway of melanoma development from nevi, starting early and ongoing throughout life, and not related to chronic sun exposure.
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Authors: Hanne Eknes Puntervoll; Xiaohong R Yang; Hildegunn Høberg Vetti; Ingeborg M Bachmann; Marie Françoise Avril; Meriem Benfodda; Caterina Catricalà; Stéphane Dalle; Anne B Duval-Modeste; Paola Ghiorzo; Paola Grammatico; Mark Harland; Nicholas K Hayward; Hui-Han Hu; Thomas Jouary; Tanguy Martin-Denavit; Aija Ozola; Jane M Palmer; Lorenza Pastorino; Dace Pjanova; Nadem Soufir; Solrun J Steine; Alexander J Stratigos; Luc Thomas; Julie Tinat; Hensin Tsao; Ruta Veinalde; Margaret A Tucker; Brigitte Bressac-de Paillerets; Julia A Newton-Bishop; Alisa M Goldstein; Lars A Akslen; Anders Molven Journal: J Med Genet Date: 2013-02-05 Impact factor: 6.318