MITF – Renal Cell Carcinoma

The microphthalmia-associated transcription factor gene MITF encodes a bHLH-Zip transcription factor critical for melanocyte and renal tubular cell homeostasis. A germline missense variant, c.952G>A (p.Glu318Lys), also known as p.E318K, has been implicated in predisposition to melanoma and renal cell carcinoma (PMID:26650189). Initial case–control data in 531 melanoma patients revealed a 2.6% carrier frequency in multiple primary melanoma cases and an overall odds ratio of 3.3 for melanoma risk; RCC risk was inferred and led to recommendations for renal surveillance (PMID:26650189).

In a Danish cohort of 48 early-onset or familial RCC patients, targeted sequencing of renal cancer susceptibility genes identified the MITF p.E318K variant in a single RCC-affected individual from a melanoma-prone family, with no additional segregation or family history of RCC (PMID:31034483).

A population-based Australian study of 1,029 RCC cases screened 21 known cancer predisposition genes and reported one carrier of MITF c.952G>A (p.Glu318Lys) among 18 participants with pathogenic or likely pathogenic germline variants in RCC genes, again without co-segregation data (PMID:39272843).

Inheritance of MITF p.E318K appears autosomal dominant with incomplete penetrance; no formal segregation analysis has been reported in RCC families. Affected relatives have not been documented beyond the index cases.

Functional characterization of p.E318K suggests altered SUMO-dependent regulation of MITF activity in melanocytes, but renal-specific assays are lacking. No in vitro or in vivo functional studies directly link p.E318K to renal tumorigenesis; mechanistic inference is based on its impact on transcriptional control in other cell types.

Overall, the association between MITF and Renal Cell Carcinoma is supported by a very small number of probands without segregation data and no direct functional validation in renal tissue. Additional familial studies and tumor-specific assays are needed. Key Take-home: MITF p.E318K testing for RCC predisposition remains investigational and should be considered only in the context of multi-cancer genetic evaluation.

References

• JAMA Dermatology • 2016 • Prevalence of MITF p.E318K in Patients With Melanoma Independent of the Presence of CDKN2A Causative Mutations. PMID:26650189
• PLOS One • 2019 • Exploring the hereditary background of renal cancer in Denmark. PMID:31034483
• Unspecified Journal • 2023 • Prevalence of clinically actionable germline variants in renal cell carcinoma predisposition genes in an Australian population-based cohort. PMID:39272843

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