DNA Replication Licensing Factors and Aurora Kinases are Linked to Aneuploidy and Clinical Outcome in Epithelial Ovarian Carcinoma

Abstract

Purpose: DNA replication licensing factors and Aurora kinases play critical roles in maintaining genomic integrity. We used multiparameter analyses of these cell cycle regulatory proteins to investigate their role in the progression of epithelial ovarian carcinoma (EOC). Experimental Design: In a cohort of 143 patients, we linked the protein expression profiles of the proliferation marker Ki67, the replication licensing factors Mcm2 and geminin, and the Aurora A and B kinases to tumor DNA ploidy status and clinical outcome. Results: Ki67, Mcm2, geminin, and Aurora A and B are significantly associated with tumor grade and ploidy status (P < 0.0001). Aurora A and its substrate H3S10ph are also significantly associated with Federation of International Obstetricians and Gynecologists tumor stage (P = 0.006 and P = 0.002, respectively). Aurora A and tumor ploidy status are predictive of disease-free survival in this cohort [hazard ratio (HR), 1.29; 95% confidence intervals (95% CI), 1.06-1.58, P = 0.01and HR, 1.80 (1.05-3.08), P = 0.03, respectively], with Aurora A of particular prognostic importance in early stage disease [HR, 1.72 (1.19-2.48), P = 0.004 for disease-free survival and HR, 1.81 (1.14-2.87), P = 0.01for overall survival]. Conclusions: Our data show that Ki67, Mcm2, geminin and Aurora A and B can be used as an adjunct to conventional prognostic indicators and as an aid to develop a tumor progression model for EOC. Dysregulation of Aurora A seems to be an early event in EOC with a key role in tumor progression. In view of present drug development programs for specific Aurora kinase inhibitors, our findings have important implications for the use of Aurora A as a biomarker and as a potential therapeutic target.

The cell cycle and cancer

“…Moreover, Mcm2-7 expression levels are powerful prognostic indicators in diverse tumour types, including cancers of the lung, breast, kidney, bladder, prostate and ovary [71][72][73][74][75][76][77]. This finding is consistent with large-scale meta-analysis of cancer microarray data, which identified up-regulation of the MCM2-6 genes as a component of poor prognostic signatures [78].…”

“…As discussed above, expression of the Mcm2-7 proteins allows tumour cells engaged in the cell division cycle to be clearly distinguished from cells residing in out-of-cycle states. Geminin, which prevents relicensing of replication origins after the initiation of DNA synthesis, is only present in cells progressing through S, G 2 and M phases, as are the mitotic engine kinases Plk1, Aurora A and Aurora B [74,107,108]. These three kinases control most mitotic events, including centrosome maturation and separation, chromosome orientation and segregation [8].…”

“…The disappointing intent-to-treat analyses of large, conventionally designed trials, such as TACT and tAnGo, suggests that further improvements in adjuvant treatment will require individualized therapeutic decisions [116,117]. Cell cycle phase analysis of breast and ovarian cancers has shown that it is tumours displaying the accelerated cell cycle phenotype that are most likely to show a clinically relevant response to S-or M-phase-directed agents (Table 1, Figure 3B) [3,74,110,111,118]. As non-proliferating cells are radiation-resistant, whereas cycling cells are most sensitive to radiation insult during transit through G 2 and M phase, tumours displaying the accelerated cell cycle phenotype may also represent those that are most radiation-sensitive.…”

Multiparameter analysis using cell cycle biomarkers for small-size lung adenocarcinoma: prognostic implications

“…After DNA replication is initiated during the cell cycle, Geminin inhibits re-uploading of the MCM proteins onto chromatin, thus preventing DNA re-replication in the same cell cycle (13). It has been confirmed that these proteins are useful biomakers that reflect the proliferative activity of the tumor cells and predict the survival of patients Multiparameter analysis using cell cycle biomarkers for small-size lung adenocarcinoma : Prognostic implications TOMOHIRO HARUKI 1,2 , KOHEI SHOMORI 1 , TATSUSHI SHIOMI 1 , YUJI TANIGUCHI 2 , HIROSHIGE NAKAMURA 2 and HISAO ITO 1 1 with various types of cancer (5)(6)(7)(8)(9)(10)(11)(14)(15)(16)(17)(18). Aurora A, known as a member of the serine/threonine kinase family, controls a subset of critical mitotic events including centrosome maturation and separation, as well as chromosome orientation and segregation (19).…”

“…However, these have not actually contributed to improving the prognosis of patients with early-stage NSCLC. Although almost all of these previous studies described the prognostic significance of a single biomarker, recent investigations have suggested that prognostic prediction is more reliable when multiparameter analysis with several biomarkers is performed than with analysis with a single one (9)(10)(11).…”