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Background. For more than 25 years families with an increased susceptibility to melanoma have been under surveillance at our institution. Objective: We sought to investigate the effectiveness of surveillance for CDKN2A-mutated families and causes for failure of the program in patients with more advanced tumors. Methods: In a retrospective case-control study, Breslow thickness of melanomas diagnosed in relatives enrolled in the surveillance program were compared with melanomas of unscreened index patients. We investigated the influence of mode of detection and length of surveillance interval on outcome. Results: Surveillance melanomas (n = 226, median thickness: 0.50 mm) had a significantly lower Breslow thickness (multiplication factor: 0.61 [95% confidence interval 0.47-0.80], P < .001) than index melanomas (n = 40, median thickness: 0.98 mm). Index melanomas were more likely diagnosed with a Breslow thickness greater than 1.0 mm (odds ratio: 3.1 [95% confidence interval 1.2-8.1], P = .022). In all, 53% of. surveillance melanomas were diagnosed during regular screens, 7% during patients' first screen, 20% between regular screens, and 20% in patients who were noncompliant with the surveillance schedule. The majority of surveillance melanomas (58%) were detected within 6 months after the last screen. There was no correlation between tumor thickness and the length of the screening interval for tumors diagnosed within 24 months since the last screen. Limitations: The study is retrospective. Conclusions: Surveillance was associated with earlier detection of melanomas. Noncompliance was an important cause for failing surveillance. Shortening surveillance intervals may advance detection of tumors, but may paradoxically have little impact on prognosis. (J Am Acad Dermatol 2011;65:289-96.)

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 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. (J Am Acad Dermatol 2011;65:281-8.)

Background Atypical nevi (AN), present in either a familial or a sporadic setting, are strong indicators of increased melanoma risk. Objective To estimate the extent of this risk and the extent of reclassification of sporadic to familial cases during follow-up. Methods We studied 167 sporadic patients with AN (≥5). At the end of follow-up we updated the family history regarding melanoma and performed germline mutation analysis of the known melanoma susceptibility genes. Results We found a relative risk for melanoma of 46.1 (95% confidence interval 21.0-87.5). Six of 167 patients were carriers of a CDKN2A mutation. At the end of follow-up, 10 of 136 patients with sporadic AN reported being a member of a melanoma family. Limitations This study was conducted in an area with a founder mutation in many of its melanoma families; therefore the results may not be applicable to other populations. Conclusion We report a high relative risk of 46.1 of melanoma development in patients with sporadic AN. A significant proportion of this Dutch cohort reported additional cases in their families over time.

This review aims to provide an up-to-date view on our understanding of the molecular genetics of melanoma development. It gives an overview of genes (and loci) currently known to be substantially involved in melanoma predisposition and progression. Broadly, the review falls into 3 sections: genes/loci involved in melanoma susceptibility through germline mutation, tumor suppressor genes somatically mutated or deleted in melanoma, and oncogenes mutated somatically in melanoma. The main cellular pathways in which these genes are involved are summarized and discussed. From this it is evident that abberations of cell cycle regulation, DNA repair and receptor-mediated signal transduction are important for melanocytic neoplasia.

Approximately 5% to 10% of melanoma may be hereditary in nature, and about 2% of melanoma can be specifically attributed to pathogenic germline mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A). To appropriately identify the small proportion of patients who benefit most from referral to a genetics specialist for consideration of genetic testing for CDKN2A, we have reviewed available published studies of CDKN2A mutation analysis in cohorts with invasive, cutaneous melanoma and found variability in the rate of CDKN2A mutations based on geography, ethnicity, and the type of study and eligibility criteria used. Except in regions of high melanoma incidence, such as Australia, we found higher rates of CDKN2A positivity in individuals with 3 or more primary invasive melanomas and/or families with at least one invasive melanoma and two or more other diagnoses of invasive melanoma and/or pancreatic cancer among first- or second-degree relatives on the same side of the family. The work summarized in this review should help identify individuals who are appropriate candidates for referral for genetic consultation and possible testing.