Bilateral Uveal Melanoma: An Insight into Genetic Predisposition in Four New Unrelated Patients and Review of Published Cases

Primary bilateral uveal melanoma (BUM) is an exceptionally rare form of uveal melanoma (UM). This study aimed to explore the potential existence of a genetic predisposition towards the development of BUM.

Our findings suggest the presence of yet-to-be-discovered genes that may contribute to UM predisposition, as evidenced by the absence of pathogenic variants in known UM predisposition genes among the four BUM patients studied. The TERF2IP and BAX genes emerge as noteworthy candidates for further investigation regarding their role in genetic predisposition to UM. Specifically, the potential role of UM as a candidate cancer within the spectrum of cancers linked to pathogenic variants in the TERF2IP gene and other genes associated with the shelterin complex warrants further examination. Additional functional studies are necessary to support or challenge this hypothesis.

We employed an exome sequencing approach on germline DNA from four unrelated patients diagnosed with BUM, seeking pathogenic or likely pathogenic variants indicative of a genetic predisposition to UM.

None of the patients exhibited pathogenic variants in the BAP1 gene. However, loss-of-function (LoF) variants in the TERF2IP and BAX genes were identified in two of the BUM patients. For patients BUM1 and BUM2, no pathogenic/likely pathogenic variants of significant clinical relevance to BUM were found to warrant inclusion in this report. Conclusions: Our findings suggest the presence of yet-to-be-discovered genes that may contribute to UM predisposition, as evidenced by the absence of pathogenic variants in known UM predisposition genes among the four BUM patients studied. The TERF2IP and BAX genes emerge as noteworthy candidates for further investigation regarding their role in genetic predisposition to UM. Specifically, the potential role of UM as a candidate cancer within the spectrum of cancers linked to pathogenic variants in the TERF2IP gene and other genes associated with the shelterin complex warrants further examination. Additional functional studies are necessary to support or challenge this hypothesis.