TY - JOUR
T1 - Differential expression of DNA repair genes in prognostically-favorable versus unfavorable uveal melanoma
AU - Dogrusöz, Mehmet
AU - Trasel, Andrea Ruschel
AU - Cao, Jinfeng
AU - Ҫolak, Selҫuk
AU - van Pelt, Sake I.
AU - Kroes, Wilma G.M.
AU - Teunisse, Amina F.A.S.
AU - Alsafadi, Samar
AU - van Duinen, Sjoerd G.
AU - Luyten, Gregorius P.M.
AU - van der Velden, Pieter A.
AU - Amaro, Adriana
AU - Pfeffer, Ulrich
AU - Jochemsen, Aart G.
AU - Jager, Martine J.
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
KW - BAP1
KW - DNA repair
KW - DNA-PK
KW - Oncology
KW - PRKDC
KW - Prognosis
KW - Uveal melanoma
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U2 - 10.3390/cancers11081104
DO - 10.3390/cancers11081104
M3 - Article
AN - SCOPUS:85070737505
VL - 11
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 8
M1 - 1104
ER -