Abstract
Expression of DNA repair genes was studied in uveal melanoma (UM) in order to identify genes that may play a role in metastases formation. We searched for genes that are differentially expressed between tumors with a favorable and unfavorable prognosis. Gene-expression profiling was performed on 64 primary UM from the Leiden University Medical Center (LUMC), Leiden, The Netherlands. The expression of 121 genes encoding proteins involved in DNA repair pathways was analyzed: a total of 44 genes differed between disomy 3 and monosomy 3 tumors. Results were validated in a cohort from Genoa and Paris and the The Cancer Genome Atlas (TCGA) cohort. Expression of the PRKDC, WDR48, XPC, and BAP1 genes was significantly associated with clinical outcome after validation. PRKDC was highly expressed in metastasizing UM (p < 0.001), whereas WDR48, XPC, and BAP1 were lowly expressed (p < 0.001, p = 0.006, p = 0.003, respectively). Low expression of WDR48 and XPC was related to a large tumor diameter (p = 0.01 and p = 0.004, respectively), and a mixed/epithelioid cell type (p = 0.007 and p = 0.03, respectively). We conclude that the expression of WDR48, XPC, and BAP1 is significantly lower in UM with an unfavorable prognosis, while these tumors have a significantly higher expression of PRKDC. Pharmacological inhibition of DNA-PKcs resulted in decreased survival of UM cells. PRKDC may be involved in proliferation, invasion and metastasis of UM cells. Unraveling the role of DNA repair genes may enhance our understanding of UM biology and result in the identification of new therapeutic targets.
Highlights
Uveal melanoma (UM) is an ocular malignancy that arises from melanocytes residing in the uveal tract, which consists of the iris, ciliary body and choroid
Accurate deubiquitination of the FANCD2 protein by the USP1/UAF1 complex is essential for an intact Fanconi Anemia pathway and proper DNA damage repair [60,61]. Because of this crucial role of the WDR48 gene, and the association that we found of a low expression of WDR48 with poor prognosis, a defective Fanconi Anemia repair pathway may play a role in the malignant transformation of UM
We show that several important DNA-repair molecules are differentially expressed between tumors with good and adverse prognosis
Summary
Uveal melanoma (UM) is an ocular malignancy that arises from melanocytes residing in the uveal tract, which consists of the iris, ciliary body and choroid. It is the second most common type of melanoma and the most common primary intraocular malignancy in adults, affecting approximately. Despite excellent regional tumor control, UM is still often lethal: up to 50% of patients will develop metastatic disease, for which no effective treatment exists [11]. Metastatic disease may develop at any time from the initial diagnosis of the primary tumor to several years after diagnosis [13]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
