Differential Expression of DNA Repair Genes in Prognostically-Favorable versus Unfavorable Uveal Melanoma

Cancers

AminaF. A. S. Teunisse¹  WilmaG. M. Kroes¹  AartG. Jochemsen²  Selҫuk Ҫolak²  MartineJ. Jager³  Andrea Ruschel Trasel³  PieterA. van der Velden³  SakeI. van Pelt³  GregoriusP. M. Luyten³  Jinfeng Cao³  Mehmet Dogrusöz³  SjoerdG. van Duinen⁴  Samar Alsafadi⁵  Ulrich Pfeffer⁶  Adriana Amaro⁶ 

[1] Department of Clinical Genetics, Leiden University Medical Center, 2333 AZ Leiden, The Netherlands;Department of Molecular Cell Biology, Leiden University Medical Center, 2333 AZ Leiden, The Netherlands;Department of Ophthalmology, Leiden University Medical Center, 2333 AZ Leiden, The Netherlands;Department of Pathology, Leiden University Medical Center, 2333 AZ Leiden, The Netherlands;Department of Translational Research, PSL Research University, Institute Curie, 75248 Paris, France;Laboratory of Tumor Epigenetics, Department of Integrated Oncology Therapies, IRCCS Ospedale Policlinico San Martino, 16133 Genoa, Italy;

关键词: uveal melanoma;    oncology;    DNA repair;    DNA-PK;    PRKDC;    BAP1;    prognosis;   

DOI  :  10.3390/cancers11081104

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown