KLK6 and KLK13 predict tumor recurrence in epithelial ovarian carcinoma

Abstract

Background: The human kallikrein-related peptidase family consists of 15 genes. Twelve of these genes are overexpressed in ovarian cancer and may represent potential markers for diagnosis, prognosis, and/or response to treatment. The aim of this study was to determine the prognostic significance of kallikrein-related peptidase 6 (KLK6) and kallikrein-related peptidase 13 (KLK13) in epithelial ovarian cancer by quantifying gene expression levels with tumour pathology and patient survival data.

Methods: Total RNA was isolated from 106 patients diagnosed with primary ovarian cancer, as well as 8 normal ovary controls. Samples were analysed by quantitative real-time PCR for KLK6 and KLK13 expression. Correlation between kallikrein gene expression and clinical characteristics was evaluated with the chi(2)-test. Survival analysis was performed using Kaplan-Meier and Cox proportional hazards regression models.

Results: Expression levels of both KLK6 and KLK13 mRNA were significantly increased in invasive cancers relative to normal ovaries (P=0.002 and 0.039 respectively). High KLK6 and KLK13 expression was an indicator of poor prognosis, with patients having a shorter recurrence-free survival (P=0.002 and 0.027 respectively). High KLK6 expression was also significantly associated with lower overall survival (P=0.011). When subjected to multivariate analysis, patients with either high KLK6 or KLK13 were 3- and 2.2-fold, respectively, more likely to have a recurrence than patients with low kallikrein expression.

Conclusion: These data show increased mRNA expression of KLK6 and KLK13 in ovarian cancer compared to normal ovarian tissues. High KLK6 or KLK13 expression in primary ovarian tumours can significantly predict prognosis in terms of recurrence-free survival and overall survival. In all, this study shows KLK6 and KLK13 as potential biomarkers and may be therapeutic targets for treatment of ovarian cancer.

Figure 1

KLK6 and KLK13 expression in normal ovarian surface epithelium (OSE) and epithelial ovarian cancer. The normal OSE stains positive for both KLK6 (A) and KLK13 (B). Serous epithelial cancers express KLK6 (C) and KLK13 (D) in the cytoplasm. In a mucinous ovarian tumour, KLK6 shows strong expression (E). KLK13 is positively expressed in a clear cell ovarian tumour (F). All photomicrographs were taken at × 40 magnification.

Figure 2

Kaplan–Meier survival curves showing the proportion of patients who are recurrence free (A) and alive (B) at the given time after diagnosis. Patients are stratified based on KLK6 expression and compared by the log-rank test. Patients whose tumours are KLK6 low are represented with the broken line, whereas patients whose tumours are KLK6 high are represented by the solid line. n, number of patients.

Figure 3

Kaplan–Meier survival curves showing the proportion of patients who are recurrence free (A) and alive (B) at the given time following diagnosis. Patients are stratified based on KLK13 expression and compared by the log-rank test. Patients whose tumours are KLK13 low are represented with the broken line, whereas patients whose tumours are KLK13 high are represented by the solid line. n, number of patients.