05 | Revisiting cancer risk associated with the MITF p.e318k variant beyond melanoma

Debora Tonello¹, Beatrice Zennaro¹, Stefania Pellegrini¹, Monica Quaggio², Luisa Piccin³, Alessio Fabozzi⁴, Luigi Dall’Olmo^2|5, Saveria Tropea⁵, Maria Chiara Scaini¹, Chiara Menin¹ | ¹Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padova; ²Department of Surgery, Oncology and Gastroenterology, Section of Immunology and Oncology, AIDS Reference Center, University of Padova, Padova; ³Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova; ⁴Oncology Unit 3, Veneto Institute of Oncology - IOV-IRCCS, Padua; ⁵Soft-Tissue, Peritoneum, and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.

Background: The p.E318K variant of the Melanocyte Inducing Transcription Factor (MITF) has been implicated in genetic predisposition to melanoma as an intermediate penetrance allele. Epidemiological studies have shown a putative association between MITF p.E318K and renal cell carcinoma (RCC), but this evidence is still inconsistent. The aim of this study was to assess the broader cancer spectrum related to this variant, focusing on the correlation with RCC.

Methods: MITF p.E318K was evaluated in 894 melanoma patients with a non-informative genetic test for high penetrant melanoma genes (CDKN2A, CDK4, POT1, BAP1). Personal and family cancer history, including CNS/brain, breast, renal, pancreatic, gastrointestinal and hematologic cancer, was compared between carriers (MITF+) and non-carriers (MITF-). The occurrence of multiple primary melanomas (MPMs) was also considered. Fisher’s exact test was used to calculate odds ratios (OR) with 95% confidence intervals (CI), with false discovery rate (FDR) correction.

Results: According to previous studies, the overall prevalence of the MITF p.E318K variant was 3.4% (30/894) and MPMs were more common among MITF+ cases (63%). No significant associations occurred in the MITF+ group compared to the MITF- for breast cancer (30% vs 32%), gastrointestinal cancers (13% vs 25%), pancreatic cancer (27% vs 21%), brain tumors (17% vs 11%) or RCC (10% vs 7%). Moreover, none of the 26 patients with both melanoma and RCC was MITF carrier. Unexpectedly, a strong association was observed for hematologic tumors (33% MITF+ vs 9% MITF-, p=0,0003).

Conclusions: Our study confirms previous results on the association of MITF-E318K with an increased risk of melanoma, but not of RCC. Based on this evidence, specific surveillance for RCC in MITF p.E318K carriers does not appear to be currently warranted. Moreover, a novel association with hematologic tumors was observed. Further studies are needed to validate whether hematologic cancers are part of the MITF p.E318K-associated tumor spectrum.