The Microphthalmia-Associated Transcription Factor p.E318K Mutation Does Not Play a Major Role in Sporadic Renal Cell Tumors from Caucasian Patients

Abstract

Objective: The transcription factor MITF (microphthalmia-associated transcription factor) is known to induce expression of hypoxia-inducible factor (HIF1-α), which is involved in renal carcinogenesis. The MITF p.E318K mutation leads to deficient SUMOylation of MITF, resulting in enhanced activation of its target genes. A case-control study on melanoma patients who coincidentally were affected by renal cell carcinoma (RCC) has revealed an elevated risk for mutation carriers to be affected by one or both of these malignancies, suggesting a possible role for MITF p.E318K in renal carcinogenesis. The same study described an MITF mutation frequency of 1.5% in a small cohort of sporadic RCC, but comprehensive data on sporadic renal cell tumors are missing. We therefore tested a large cohort of sporadic renal tumors for MITF p.E318K mutation status. Methods: Genomic DNA was extracted from 426 formalin-fixed, paraffin-embedded sporadic renal tumors that had been graded according to the 2004 WHO classification of renal tumors and staged according to the 2002 TNM classification. The tumor cohort was enriched with papillary and chromophobe RCC, and also contained benign oncocytomas. DNA was tested for MITF p.E318K by pyrosequencing. Results: Of 403 analyzable tumors, 402 renal tumors were wild-type ones, and only 1 case showed the MITF p.E318K mutation. This tumor was a clear-cell RCC (pT3b N0 M0 G3 according to the TNM classification 2002). The affected patient was male, 61 years old, and had no known coexisting malignancies. Conclusion: The MITF p.E318K mutation does not appear to play a major role in sporadic RCC carcinogenesis, but is possibly restricted to a rare subpopulation of inherited RCC.

Clinical, pathological and dermoscopic phenotype of MITF p.E318K carrier cutaneous melanoma patients

“…Concerning the role of the p.E318K variant in the predisposition to tumors other than melanoma, we confirm the association with renal cell carcinoma (RCC) previously described [6,7,[13][14][15]. The association with pancreatic cancer we previously observed in a smaller series of patients [13] was not confirmed here, and therefore remains to be further explored.…”

“…Due to the above-mentioned links with melanoma and kidney cancer susceptibility, current research is focusing on the relationship between p.E318K and the clinicophenotypic features of individuals carrying this variant [9,[11][12][13][14][15][16]. However, current literature on dermoscopic features of nevi and melanomas in these patients is still limited, and predisposition to non-melanoma cancers according to MITF germline status needs to be further investigated [11,14,16].…”

Cancer risks associated with the germline MITF(E318K) variant

“…Bertolotto et al identified over a fivefold increased risk for carriers to develop RCC, melanoma, or both cancers in 829 patients (OR 5.55; 95% CI 2.59-12.91; p = 1.2E−6) and identified a fivefold risk of developing RCC only in 164 "genetically-enriched" patients who were wild-type for RCC-predisposing genes (OR 5.19; 95% CI 1.37-16.87; p = 0.008) 2 . In contrast, other studies did not find an association with sporadic RCC 5,12,13 . Ghiorzo et al identified a 31-fold increased risk of melanoma in carriers with a personal or family history of pancreatic cancer (OR 30.85; 95% CI 6.85-138.9; p = 0.0005), but did not find significant enrichment of the variant in sporadic pancreatic cancer patients (0/210 patients had the variant) 4 11 .…”

“…Thus, MITF(E318K) may play a role in driving cancer formation in a subset of "genetically-enriched" RCC patients by a still undisclosed biological mechanism. Of note, several other researchers have also failed to identify an association of sporadic RCC with MITF(E318K) 5,12,13 . This may also explain Ghiorzo et al 's findings, as their association was only noted in melanoma patients with a personal or family of pancreatic cancer, and not in patients with sporadic pancreatic cancer.…”

“…A rare functional variant of MITF(E318K) has been shown to disrupt a conserved SUMOylation site and to confer a two-to fourfold risk for cutaneous melanoma 1,2 . Moreover, there have been small studies suggesting that this variant is also associated with other cancers such as renal cell carcinoma (RCC) [1][2][3][4][5][6][7][8][9][10][11][12][13] . However, since epidemiologic observations have documented an association between cutaneous melanoma and many other malignancies, including RCC, it is possible that MITF(E318K) represents a germline "passenger" mutation in these other cancers without directly impacting the risk of these other cancers such as RCC.…”