Dualistic Role of MITF in Uveal Melanoma: Defining Two Distinct Cellular Subpopulations With Prognostic and...

Microphthalmia-associated transcription factor (MITF) regulates melanocyte differentiation, proliferation, and survival, intersecting with oncogenic and tumor-suppressive pathways. However, its prognostic significance in uveal melanoma (UM) remains unexplored in large cohorts. This study examines MITF's prognostic value and its correlation with key molecular markers-BAP1, preferentially expressed antigen in melanoma (PRAME), deoxythymidylate kinase (dTYMK), and poly(ADP-ribose) polymerase 1 (PARP1).

Immunostaining for MITF, BAP1, dTYMK, PARP1, and PRAME was performed on tissue microarrays from 154 UM cases with no prior therapy. We correlated MITF level with detailed clinicopathologic variables and patient outcomes. Scoring of MITF immunostainings was done using the H-score with further dichotomization into two subgroups with low (H-score < 15) and high level (H-score ≥ 15) using the Contal-O'Quinley method.

Patients with low MITF level were characterized by shorter cancer-specific overall (P = 0.019) and disease-free survival (P = 0.0038). Low MITF level was significantly correlated with the presence of distant metastases (P = 0.005), BAP1-negative tumors (P = 0.023), higher largest basal diameter (P < 0.001), and tumor-associated macrophages immune response (P < 0.001). On the other hand, high MITF level was correlated with a higher mitotic index (P = 0.033) and enhanced replicating potential of tumoral cells significantly correlated with dTYMK and PARP1 level (P < 0.001).

MITF delineates two UM subpopulations: (1) MITF-low tumors-slow proliferators with high invasive potential and inflammatory phenotype, and (2) MITF-high tumors-rapidly dividing cells with lower invasiveness and immunosuppressive properties. These findings suggest potential therapeutic strategies, including MITF re-induction for MITF-low tumors and dTYMK/PARP1 inhibitors for MITF-high UM.