Short Report: The Variants in CHEK2 in Metastatic Uveal Melanoma

<b>Background:</b> 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 <i>GNA11</i>, <i>GNAQ</i>, <i>EIF1AX</i>, <i>BAP1</i>, and <i>SF3B1</i> instead of the typical mutations associated with cutaneous melanoma. Although hereditary UM is rare, germline <i>BAP1</i> loss predisposes patients to UM and various other cancers. The <i>CHEK2</i> (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. <i>CHEK2</i> mutations have been linked to various cancers. While there is no strong evidence that <i>CHEK2</i> mutations increase the risk of melanoma, two cases of germline <i>CHEK2</i> mutations in UM patients have been reported. However, the incidence of <i>CHEK2</i> variants in metastatic UM (MUM) has not been investigated. Thus, we conducted a retrospective analysis of patients with MUM and <i>CHEK2</i> variants to understand this link better. <b>Methods:</b> 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 <i>CHEK2</i> variants. <b>Results:</b> In this study, we reported ten patients with <i>CHEK2</i> variants among 740 metastatic UM patients (1.4%) and four primary UM patients with <i>CHEK2</i> germline mutations. <b>Conclusions:</b> Although rare, UM patients with an abnormal ATM-CHEK2 axis might receive clinical benefits from medications that target DNA repair mechanisms.