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

Abstract

Background: 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. Methods: 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. Results: 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.

Keywords: bilateral uveal melanoma; candidate genes; genetic predisposition; incidence.

Figure 1

Imaging test results for the diagnosis of BUM in patient BUM1. (A) Ocular ultrasound showing the presence of the first choroidal mass in the patient’s left eye. (B) Histological slice of the UM, obtained after enucleation of the LE. (C) Fundus of the right eye, showing the UM diagnosed in the patient in 2016. (D) Ocular ultrasound scan of the patient’s right eye.

Figure 2

Imaging tests corresponding to the diagnosis of BUM in patient BUM2. (A) Fundus of the eye showing the UM detected in the patient’s left eye. (B) Ocular ultrasound scan carried out on the left eye showing the presence of UM located in the lower nasal quadrant. (C) Fundus of the patient’s right eye, showing a mass located below the fovea compatible with the diagnosis of a small melanoma. (D) Ocular ultrasound scan of the RE of the patient, showing a choroidal mass compatible with a melanoma.

Figure 3

Imaging tests performed on the LE of patient BUM3, compatible with a diagnosis of BUM. (A) Fundus of the LE of patient BUM3 showing a choroidal pigmented mass in the temporal periphery. (B) Ocular ultrasound of LE showing a choroidal mass compatible with a UM measuring 4.5 mm in height and 15.3 mm in base.

Figure 4

Imaging test results of the choroidal pigment mass under study in patient BUM4. (A) Eye fundus showing a mass with mixed pigmentation. (B) Ocular ultrasound of the LE displaying a choroidal mass compatible with uveal melanoma, measuring 3.6 mm in height and 14.3 mm in base.