Familial atypical multiple mole melanoma (FAMMM) syndrome is a hereditary syndrome characterized by multiple dysplastic nevi and melanoma. Patients with FAMMM may have a heterozygous, inactivating, pathogenic germline variant in the CDKN2A gene, especially the NM_000077.4: c.225_243del19 (p.p75fs) variant, also known as p16-Leiden variant. Patients with this variant are at high risk for developing melanomas and pancreatic cancer due to somatic inactivation of the wild-type CDKN2A allele. The combination of an inactivating germline CDKN2A mutation and somatic inactivation of the wild-type CDKN2A allele in the same cell results in tumor formation. It has been suggested that carriers of a germline CDKN2A mutation are also at increased risk for several other cancer types, including esophageal cancer. Here, we describe two unrelated patients with the p16-Leiden variant who developed esophageal squamous cell cancer. Evidence of loss of the wild-type CDKN2A allele was obtained in the tumor tissue of both patients indicating biallelic inactivation of p16 in the tumor cells. These results suggest that these patients developed esophageal squamous cell cancer in the context of FAMMM syndrome.

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Keywords CDKN2A mutation, Esophageal cancer, Esophageal squamous cell carcinoma, FAMMM syndrome, p16-Leiden mutation
Persistent URL dx.doi.org/10.1016/j.ejmg.2020.103840, hdl.handle.net/1765/123804
Journal European Journal of Medical Genetics
van der Wilk, B.J. (Berend J.), Noordman, B.J, Atmodimedjo, P.N, Dinjens, W.N.M, Laheij, C, Wagner, A. (Anja), … van Lanschot, J.J.B. (2020). Development of esophageal squamous cell cancer in patients with FAMMM syndrome: Two clinical reports. European Journal of Medical Genetics. doi:10.1016/j.ejmg.2020.103840