Short Report: The Variants in CHEK2 in Metastatic Uveal Melanoma

TL;DR

This study reports a small percentage of metastatic uveal melanoma patients with CHEK2 gene variants and suggests potential benefits from DNA repair-targeted therapies.

Contribution

The study is the first to report the incidence of CHEK2 variants in metastatic uveal melanoma patients.

Findings

CHEK2 variants were found in 1.4% of metastatic uveal melanoma patients.

Four primary uveal melanoma patients had germline CHEK2 mutations.

Patients with CHEK2 variants may benefit from DNA repair-targeted therapies.

Abstract

Background: Uveal melanoma (UM) is a rare subtype of melanoma with distinct clinical and molecular features compared to other melanoma subtypes. UM tumors are frequently detected with mutations in GNA11, GNAQ, EIF1AX, BAP1, and SF3B1 instead of the typical mutations associated with cutaneous melanoma. Although hereditary UM is rare, germline BAP1 loss predisposes patients to UM and various other cancers. The CHEK2 (Checkpoint kinase 2) gene that encodes the protein CHK2, a serine-threonine kinase, is a cell cycle checkpoint regulator that acts as a tumor suppressor. CHK2 is involved in DNA repair, cell cycle arrest, or apoptosis in response to DNA damage. CHEK2 mutations have been linked to various cancers. While there is no strong evidence that CHEK2 mutations increase the risk of melanoma, two cases of germline CHEK2 mutations in UM patients have been reported. However, the incidence of CHEK2 variants in metastatic UM (MUM) has not been investigated. Thus, we conducted a retrospective analysis of patients with MUM and CHEK2 variants to understand this link better. Methods: We collected MUM cases from 2016 to 2024 from institutional databases. Tissues underwent analyses of molecular and genomic features, including tumor mutational burden, and were performed by a Clinically Certified Laboratory. Next-generation sequencing and variant calling were conducted to identify CHEK2 variants. Results: In this study, we reported ten patients with CHEK2 variants among 740 metastatic UM patients (1.4%) and four primary UM patients with CHEK2 germline mutations. Conclusions: Although rare, UM patients with an abnormal ATM–CHEK2 axis might receive clinical benefits from medications that target DNA repair mechanisms.

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