Germline variants in the MBD4 gene are rare in patients with uveal melanoma

• Published in: Acta ophthalmologica (Oxford, England) Vol. 97; no. S263
• Main Authors: Repo, Pauliina, Jäntti, Johannes, Järvinen, Reetta‐Stiina, Täll, Martin, Raivio, Virpi, Kivelä, Tero, Turunen, Joni
• Format: Journal Article
• Language: English
• Published: Malden Wiley Subscription Services, Inc 01-12-2019
• Subjects: CpG islands; Gene frequency; Immune checkpoint inhibitors; Inhibitors; Mbd4 gene; Melanoma; Mutation; Phenotypes; Tumorigenesis; Tumors; Finland
• ISSN: 1755-375X; 1755-3768
• DOI: 10.1111/j.1755-3768.2019.5458

Purpose
The mutation profile of uveal melanoma (UM) is unusual as these tumors generally have very few somatic events. Eight genes are recognized as drivers of UM tumorigenesis, typically consisting of one mutually exclusive mutation in GNAQ, GNA11, PLCB4 or CYSLTR2 combined with one mutually exclusive mutation in EIF1AX, SF3B1, SRSF2 or BAP1. Germline variants predisposing to UM have so far been described only in BAP1. Recently, four patients with UM were found with germline loss of function (LOF) variants in the methyl‐CpG binding domain 4 (MBD4) gene that was suggested to be a UM predisposition gene. Loss of functional MBD4 induces a hypermutated profile, making the tumor more susceptible to immune checkpoint inhibitors. We investigated MBD4 variants in patients with UM to identify pathogenic variants and to estimate their clinical relevance.
Methods
Sanger sequencing of MBD4 in 440 Finnish patients with uveal melanoma diagnosed from 2010 to 2017.
Results
Eight rare (minor allele frequency in gnomAD Fin <0.5%) MBD4 missense variants were identified in 16 patients. One of them was likely pathogenic. The UM has not metastasized. The frequency of likely pathogenic MBD4 variants in Finnish patients with UM was 0.2% (95% CI, 0.01–1.3). No LOF variants were found. The frequency of LOF variants in the general population in Finland is 0.05%, according to the gnomAD database, suggesting one should occur by chance in every 2000 patients with UM.
Conclusions
MBD4 variants do not seem to predispose to UM in Finland. Somatic loss of MBD4 function might still modify the tumor phenotype through accumulating mutations and changing the response of the tumor to immune checkpoint inhibitors. However, the utility of germline MBD4 sequencing is low.