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. 2020 Sep;33(5):756-762.
doi: 10.1111/pcmr.12892. Epub 2020 Jun 1.

Germline loss-of-function variants in MBD4 are rare in Finnish patients with uveal melanoma

Pauliina Repo  1   2 , Johannes E Jäntti  1 , Reetta-Stiina Järvinen  1   2 , Elina S Rantala  2 , Martin Täll  2 , Virpi Raivio  2 , Tero T Kivelä  2 , Joni A Turunen  1   2
Affiliations

Germline loss-of-function variants in MBD4 are rare in Finnish patients with uveal melanoma

Pauliina Repo et al. Pigment Cell Melanoma Res. 2020 Sep.

Abstract

Uveal melanoma (UM) is a rare intraocular cancer with the highest incidence in northern latitudes. Metastases develop in approximately 50% of patients, whereafter the median survival is 13 months. Generally, the mutation burden of these tumors is low. Germline variants predisposing to UM have been previously described in BRCA1-associated protein 1 (BAP1). Recently, germline and somatic loss-of-function (LOF) variants in the methyl-CpG-binding domain 4 (MBD4) gene have been found to cause a hypermutated UM, and MBD4 also has been put forward as a gene predisposing to UM. We sequenced for MBD4 germline variants in 440 Finnish patients with UM and identified seven rare exonic missense variants in 16 (3.6%) patients, of which one likely alters MBD4 function. The frequency of likely pathogenic variants in our cohort is 0.23% (1/432; 95% CI, 0.01-1.28). We identified no LOF variants though their frequency in the Finnish population is 0.052%. Thus, our data do not support the suggestion that MBD4 germline variants predispose to UM. Somatic loss of MBD4 might modify the mutational burden in UM and change its response to immune checkpoint inhibitors.

Keywords: BRCA1-associated protein 1; familial cancer; hypermutated phenotype; immune checkpoint inhibitors; methyl-CpG-binding domain 4; uveal melanoma.

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