Genetic Determinants of Radiotherapy Resistance in Uveal Melanoma

Abstract

Radiotherapy remains the cornerstone of local treatment for uveal melanoma (UM), achieving high rates of primary tumor control. Nevertheless, a substantial proportion of patients experience disease progression and metastatic relapse, underscoring a fundamental biological limitation of radiotherapy efficacy in this malignancy. Accumulating evidence indicates that radioresistance in UM is not driven by high mutational burden, but rather by a distinctive genetic architecture dominated by chromosomal alterations and adaptive DNA damage response programs. High-risk cytogenetic states in UM, particularly those defined by large-scale chromosomal imbalance, have emerged as key biological contexts shaping radiotherapy tolerance. Rather than acting as passive prognostic markers, these configurations appear to remodel genome maintenance capacity by selectively dampening tumor-suppressive safeguards while favoring DNA damage tolerance and survival-oriented repair responses. In parallel, early oncogenic events that drive tumor initiation indirectly reinforce radioresistance by sustaining pro-survival signaling programs, transcriptional adaptability, and stress resilience. Together, these features establish a cellular state in which radiation-induced damage is accommodated rather than eliminated, permitting clonogenic persistence despite adequate local dose delivery. This review integrates genomic, cytogenetic, and radiobiological evidence to propose a unifying framework in which UM radioresistance arises from coordinated genetic reprogramming of DNA repair and survival pathways. Understanding these determinants is essential for the rational development of radiosensitization strategies and for improving long-term disease control in UM.