Surveillance, <i>CDKN2A</i> and survival of familial melanoma

Abstract

Dermatological surveillance for patients with familial melanoma has become standard clinical practice. The benefit of surveillance has mainly been concluded from the diagnosis of melanoma at an earlier stage, before metastatic dissemination has occurred, in patients undergoing periodic skin examination.1, 2 The outcome measure preferably used to assess the impact of surveillance of patients at increased risk of cancer is survival, but this requires long-term studies on large patient cohorts. In the study by Pissa, Lapins, Sköldmark and Helgadottir published in this issue of JEADV, evidence is presented on the impact of dermatological surveillance on melanoma-specific survival for patients with familial melanoma, distinguished by the genetic cause of melanoma susceptibility.3 By combining data from a nation-wide prevention program, cancer registry and cause of death registry in Sweden, melanoma-specific survival and tumour stage were studied in a cohort of familial melanoma patients before and after introduction of a dermatological surveillance program. In the study, a distinction was made between patients whose melanoma predisposition was caused by a pathogenic variant of the CDKN2A gene (CDKN2A-mutant) and patients in whom no pathogenic CDKN2A gene variant was found (CDKN2A-wildtype). Inactivating variants of the CDKN2A gene, encoding the p16 and p14 tumour suppressor proteins, are the most common cause of familial melanoma, accounting for at least a third of all cases. Carriers of CDKN2A gene variants are at increased risk of melanoma, pancreatic cancer and other tumour types, a condition sometimes referred to as Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome.4 Comparison of clinical features and disease outcome of the four subsets of patients, pre/post surveillance and CDKN2A mutant/wildtype, allowed the authors to separately study the impact of surveillance and of CDKN2A mutation on melanoma-specific survival. The most significant difference in melanoma-specific survival was found between CDKN2A-mutant and CDKN2A-wildtype patients who were not included in the dermatological surveillance program. CDKN2A-mutant familial melanoma had a significantly worse melanoma-specific survival than CDKN2A-wildtype patients prior to introduction of the surveillance program, also after adjusting for stage and clinical prognostic factors. However, in patients under dermatological surveillance a difference in melanoma-specific survival between CDKN2A-mutant patients and CDKN2A-wildtype patients was not observed. Following introduction of the surveillance program, the tumour stage of melanomas diagnosed in the CDKN2A-mutant subset of patients was also lower than in such patients before surveillance was initiated. By contrast, introduction of the dermatological surveillance program did not appear to result in a similar beneficial impact on melanoma-specific survival and tumour stage in the CDKN2A-wildtype familial melanoma patients. It should be noted that some of the observed differences in melanoma-specific survival between patient subsets did not reach statistical significance, probably related to the relatively small number of melanomas diagnosed. Notwithstanding the intrinsic limitations of a retrospective study on cohorts with diverse clinical characteristics, the apparent differences in the impact of surveillance on the CDKN2A-mutant and CDKN2A-wildtype familial melanoma patient subsets are noteworthy. The clinical and biological determinants underlying these observations are not entirely clear. A possible biological explanation might be provided by differences in growth rate and metastatic capacity of melanomas that develop in CDKN2A-mutant and CDKN2A-wildtype patients. Once progressed to a higher stage before diagnosis, as more often occurs in the absence of dermatological surveillance, melanoma in CDKN2A-mutant patients might have a higher propensity to metastasize than in CDKN2A-wildtype patients.5 From this study, it can be concluded that dermatological surveillance is especially beneficial for patients with familial melanoma due to pathogenic CDKN2A germline variants, associated with a higher melanoma-specific survival rate and lower proportion of cases diagnosed with advanced tumours. In addition, the results help to explain discordant findings on the association between pathogenic CDKN2A gene variants and melanoma survival from previous studies performed in Sweden, Italy and the Netherlands.6-8 The present study provides support for surveillance of patients with familial melanoma and for the identification of patients carrying pathogenic CDKN2A gene variants who might benefit most from periodic skin examinations. None. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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