A systematic review of cancer risks associated with MITF variants

The MITF E318K variant has been associated with melanoma risk, while risk associated with other variants or of other cancers remains uncertain. We performed a systematic review with meta-analysis of 11 retrospective case-control studies to evaluate cancer risks associated with germline MITF variants. Across 8,606 melanoma patients and 17,953 controls, the E318K variant was detected in 2.1% and 0.8% of individuals, respectively, corresponding to a significantly increased melanoma risk (OR 2.55, 95% CI 1.90-3.43). The association was stronger in patients with multiple primary melanomas, with carrier frequencies up to 2.6% compared to 1.0% in single melanoma cases and ORs reaching 4.45 in individual studies. Phenotypic analyses showed enrichment of high nevus burden (> 200 nevi), with ORs up to 12.4 in multiple melanoma cohorts. No consistent association with age at onset or pigmentary traits was observed. Evidence for non-melanoma cancers was limited and heterogeneous: a single study reported increased renal cancer risk (OR 7.64), whereas larger cohorts failed to replicate this finding; an association with pheochromocytoma/paraganglioma was observed (OR 3.19) but lacks confirmation. No other MITF variants demonstrated significant cancer risk. These findings support MITF E318K as a moderate-penetrance melanoma susceptibility allele, particularly associated with multiple primary melanomas.