The MITF, p.E318K variant, as a risk factor for pheochromocytoma and paraganglioma

Abstract

Context: The microphthalmia-associated transcription factor (MITF) regulates the survival, proliferation, and differentiation of neural crest-derived lineages. Recent studies reported an increased risk ofmelanomain individuals carrying the rare variant MITF, p.E318K (rs149617956).Whetherthis variant plays a role in other neural crest-derived tumors is unknown. Objective: In the present study, we aimed at determining the prevalence of the MITF, p.E318K variant, in a well-characterized French cohort of pheochromocytomas/paragangliomas (PCC/PGL). Design and Methods: Genomic DNA from 555 unrelated patients with PCC/PGL was genotyped for the p.E318K variant in MITF using Sanger sequencing. MainOutcomeMeasure: The prevalence of the mutation in the PCC/PGL cohort was compared with a population-based sample of 2348 ethnically matched controls. Results: We identified seven carriers (five patients with sporadic PCCs, two with PGLs). The prevalence of the MITF, p.E318K variant, was higher in the PCC/PGL cohort than in controls, and appears to be a significant risk factor (odds ratio, 3.19; 95% confidence interval, 1.34-7.59; P = .005). Noteworthy, two patients were homozygous for the p.E318K risk allele, a patient with metastatic PCC and an SDHB-mutated patient with PGL. Conclusion: Our results indicate that the germline variant MITF, p.E318K is associated with an increased risk of other neural crest-derived tumors such as PCC/PGL.