Dermatologic surveillance in healthy carriers of CDKN2A and p.E318K MITF germline variants from melanoma-prone families: a 14 years hospital-based experience

Pathogenic variants in the CDKN2A gene are the most common genetic cause of hereditary melanoma, significantly increasing the risk of multiple melanomas at an early age and the incidence of noncutaneous tumors, particularly pancreatic cancer. Similarly, the MITF p.E318K variant is associated with an elevated risk of cutaneous melanoma, renal cell carcinoma, and pancreatic cancer. This study investigates the incidence of cutaneous and noncutaneous cancers among first- and second-degree relatives of patients with cutaneous melanoma who carry the same CDKN2A or MITF p.E318K germline variants as their corresponding index case. Among 62 relatives of patients with cutaneous melanoma, 48 (77.4%) carried CDKN2A variants, while 14 (22.6%) carried the MITF p.E318K variant. Of the 39 CDKN2A carriers with follow-up data (mean duration: 60.87 months), 31 were cancer-free at the time of genetic diagnosis, while eight had a prior cancer history, including seven with cutaneous melanoma. During follow-up, five carriers developed a new cancer. In CDKN2A families, additional cutaneous melanoma and pancreatic cancer cases were observed in 43.75 and 21.87% families, respectively. In the MITF cohort, none of the 12 cancer-free carriers developed cutaneous melanoma during a mean follow-up of 24.64 months, although two developed basal cell carcinoma. Among the three index cases, two had invasive cutaneous melanoma, and all three families had pancreatic cancer cases. This study highlights the heightened elevated cancer risk for CDKN2A and MITF p.E318K variant emphasizing the need for ongoing surveillance.