Dataset Information

Elevated tumor tissue protein expression levels of kallikrein-related peptidases KLK10 and KLK11 are associated with a better prognosis in advanced high-grade serous ovarian cancer patients.

ABSTRACT: Several members of the KLK family have been proposed to modulate various tumor-relevant processes. Previously, we have shown that in advanced high-grade serous ovarian cancer tissue high KLK11 mRNA levels were significantly associated with prolonged overall and progression-free patients' survival. Furthermore, KLK11 mRNA expression positively correlated with KLK10 mRNA. In the present study, we examined the prognostic value for both KLK10 and KLK11 on the protein expression level by immunohistochemistry (IHC). A cohort encompassing 159 patient tumor samples afflicted with advanced high-grade (FIGO III/IV) serous ovarian cancer, present on tissue microarrays (TMA), was analyzed. For estimation of KLK10 and KLK11 immunoreactivity, an automated digital IHC image analysis algorithm was selected to quantify the antibody staining intensity in the tissues via an immunoreactive score (IRS). In line with the results obtained by mRNA analysis, KLK10 protein expression values were significantly and positively correlated with KLK11 protein expression values. In Kaplan-Meier analyses, both elevated KLK10, KLK11, and the combination of KLK10 and KLK11 protein levels were significantly linked with prolonged overall survival (OS). The addition of KLK10, KLK11 or the KLK10+KLK11 combination IRS to the base model in multivariate Cox analysis demonstrated that high KLK11 and KLK10+KLK11 protein expression levels, apart from clinical parameters, remained favorable independent predictive markers for OS. In conclusion, in the present study, we have validated the coordinate expression of KLK10 and KLK11 in advanced high-grade serous ovarian cancer. Furthermore, both increased KLK10 and KLK11 protein expression is associated with favorable prognosis in this major ovarian cancer subtype. The combined KLK10+KLK11 marker performed even stronger than KLK10 or KLK11 alone.

SUBMITTER: Geng X

PROVIDER: S-EPMC6176182 | biostudies-other | 2018

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Elevated tumor tissue protein expression levels of kallikrein-related peptidases KLK10 and KLK11 are associated with a better prognosis in advanced high-grade serous ovarian cancer patients.

Geng Xiaocong X Liu Yueyang Y Dreyer Tobias T Bronger Holger H Drecoll Enken E Magdolen Viktor V Dorn Julia J

American journal of cancer research 20180901 9

Several members of the KLK family have been proposed to modulate various tumor-relevant processes. Previously, we have shown that in advanced high-grade serous ovarian cancer tissue high KLK11 mRNA levels were significantly associated with prolonged overall and progression-free patients' survival. Furthermore, KLK11 mRNA expression positively correlated with KLK10 mRNA. In the present study, we examined the prognostic value for both KLK10 and KLK11 on the protein expression level by immunohistoc ...[more]

PMID: 30323977

Similar Datasets

Project description:BackgroundHigh-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of ovarian cancer. A growing body of evidence suggests tumor-supporting roles of several members of the kallikrein-related peptidase (KLK) family, including KLK5 and KLK7, in this cancer subtype. In normal physiology, KLK5 and KLK7 are the major proteases involved in skin desquamation. Moreover, in several cancer types KLK5 and KLK7 co-expression has been observed. Recently, we have shown that elevated KLK5 mRNA levels are associated with an unfavorable prognosis in HGSOC. Therefore, the aim of this study was to investigate the clinical significance of KLK7 mRNA expression and to explore its relation to KLK5 levels in HGSOC.MethodsmRNA expression levels of KLK7 were quantified by qPCR in a well-characterized patient cohort afflicted with advanced high-grade serous ovarian cancer (FIGO III/IV, n = 139). Previously determined KLK5 mRNA as well as KLK5 and KLK7 antigen concentrations were used to evaluate the relationship between the expression patterns of both factors on the mRNA as well as protein level in tumor tissue of HGSOC patients.ResultsThere were strong, significant positive correlations between KLK5 and KLK7 both at the mRNA and the protein level, suggesting coordinate expression of these proteases in HGSOC. In univariate analyses, elevated KLK7 levels as well as the combination of KLK5 + KLK7 (high and/or high versus low/low) were significantly associated with worse progression-free survival (PFS). High mRNA expression levels of KLK7 and the combination of KLK5 and KLK7 showed a trend towards significance for overall survival (OS). In multivariate analyses, KLK7 mRNA expression represented an unfavorable, statistically significant independent predictor for PFS and OS.ConclusionsThe findings imply that both increased KLK5 and KLK7 mRNA expression levels represent unfavorable prognostic biomarkers in advanced high-grade serous ovarian cancer, whereby multivariate analyses indicate that KLK7 mRNA exhibits a stronger predictive value as compared to KLK5 mRNA and the combination of KLK5 and KLK7.

Project description:BackgroundPrimary or acquired chemoresistance is a key link in the high mortality rate of ovarian cancer. There is no reliable method to predict chemoresistance in ovarian cancer. We hypothesized that specific methylation characteristics could distinguish chemoresistant and chemosensitive ovarian cancer patients.MethodsIn this study, we used 450 K Infinium Methylation BeadChip to detect the different methylation CpGs between ovarian cancer patients. The differential methylation genes were analyzed by GO and KEGG Pathway bioinformatics analysis. The candidate CpGs were confirmed by pyrosequencing. The expression of abnormal methylation gene was identified by QRT-PCR and IHC. ROC analysis confirmed the ability to predict chemotherapy outcomes. Prognosis was evaluated using Kaplan-Meier.ResultsIn advanced high-grade serous ovarian cancer, 8 CpGs (ITGB6:cg21105318, cg07896068, cg18437633; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934, cg13270625) remained hypermethylated in chemoresistant patients. The sensitivity, specificity and AUC of 8 CpGs (ITGB6:cg21105318, cg07896068, cg18437633; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934, cg13270625) methylation to predict chemotherapy sensitivity were 63.60-97.00%, 46.40-89.30% and 0.774-0.846. PFS of 6 candidate genes (ITGB6:cg21105318, cg07896068; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934) hypermethylation patients was significantly shorter. The expression of NCALD and LAMA3 in chemoresistant patients was lower than that of chemosensitive patients. Spearman analysis showed that NCALD and LAMA3 methylations were negatively correlated with their expression.ConclusionsAs a new biomarker of chemotherapy sensitivity, hypermethylation of NCALD and LAMA3 is associated with poor PFS in advanced high-grade serous ovarian cancer. In the future, further research on NCALD and LAMA3 will be needed to provide guidance for clinical stratification of demethylation therapy.

Project description:Purpose of reviewEpithelial ovarian cancer is a disease that encompasses a number of histologically and molecularly distinct entities; the most prevalent subtype being high-grade serous (HGS) carcinoma. Standard first-line treatment of advanced HGS carcinoma includes cytoreductive surgery plus intravenous paclitaxel/platinum-based chemotherapy. Despite excellent responses to initial treatment, the majority of patients develop recurrent disease within 3 years. The introduction of the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, and poly(ADP-ribose) polymerase (PARP) inhibitors into first-line management has changed the outlook for this lethal disease. In this review, we summarise the most recent clinical trials that determine current primary therapy of advanced HGS carcinoma and the ongoing trials that aim to change management in the future.Recent findingsRecent phase III clinical trials have shown that delayed primary surgery after completing neo-adjuvant chemotherapy is non-inferior to immediate primary surgery, but could provide a survival benefit in FIGO (International Federation of Gynecology and Obstetrics) stage IV disease. The use of weekly intravenous chemotherapy regimens has not been proven to be more effective than standard 3-weekly regimens in Western patient populations, and the use of intraperitoneal chemotherapy remains controversial in the first-line setting. In contrast, newer systemic anti-cancer therapies targeting angiogenesis and/or HR-deficient tumours have been successfully incorporated into front-line therapeutic regimens to treat HGS carcinoma. Recent results from randomised trials investigating the use of PARP inhibitors as monotherapy and in combination with the anti-angiogenic agent, bevacizumab, have demonstrated highly impressive efficacy when combined with traditional first-line multi-modality therapy. Management of HGS carcinoma is evolving, but further work is still required to optimise and integrate tumour and plasma biomarkers to exploit the potential of these highly efficacious targeted agents.

Project description:BackgroundThe most common subtype of ovarian cancer (OC) showing immunogenic potential is represented by the high-grade serous ovarian cancer (HGSOC), which is characterized by the presence of tumor-infiltrating immune cells able to modulate immune response. Because several studies showed a close correlation between OC patient's clinical outcome and expression of programmed cell death protein-1 or its ligand (PD-1/PD-L1), the aim of our study was to investigate if plasma levels of immunomodulatory proteins may predict prognosis of advanced HGSOC women.Patients and methodsThrough specific ELISA tests, we analyzed plasma concentrations of PD-L1, PD-1, butyrophilin sub-family 3A/CD277 receptor (BTN3A1), pan-BTN3As, butyrophilin sub-family 2 member A1 (BTN2A1), and B- and T-lymphocyte attenuator (BTLA) in one hundred patients affected by advanced HGSOC, before surgery and therapy. The Kaplan-Meier method was used to generate the survival curves, while univariate and multivariate analysis were performed using Cox proportional hazard regression models.ResultsFor each analyzed circulating biomarker, advanced HGSOC women were discriminated based on long (≥ 30 months) versus short progression-free survival (PFS < 30 months). The concentration cut-offs, obtained by receiver operating characteristic (ROC) analysis, allowed to observe that poor clinical outcome and median PFS ranging between 6 and 16 months were associated with higher baseline levels of PD-L1 (> 0.42 ng/mL), PD-1 (> 2.48 ng/mL), BTN3A1 (> 4.75 ng/mL), pan-BTN3As (> 13.06 ng/mL), BTN2A1 (> 5.59 ng/mL) and BTLA (> 2.78 ng/mL). Furthermore, a lower median PFS was associated with peritoneal carcinomatosis, age at diagnosis > 60 years or Body Mass Index (BMI) > 25. A multivariate analysis also suggested that plasma concentrations of PD-L1 ≤ 0.42 ng/mL (HR: 2.23; 95% CI: 1.34 to 3.73; p = 0.002), age at diagnosis ≤ 60 years (HR: 1.70; 95% CI: 1.07 to 2.70; p = 0.024) and absence of peritoneal carcinomatosis (HR: 1.87; 95% CI: 1.23 to 2.85; p = 0.003) were significant prognostic marker for a longer PFS in advanced HGSOC patients.ConclusionsThe identification of high-risk HGSOC women could be improved through determination of the plasma PD-L1, PD-1, BTN3A1, pan-BTN3As, BTN2A1 and BTLA levels.

Dataset Information

Elevated tumor tissue protein expression levels of kallikrein-related peptidases KLK10 and KLK11 are associated with a better prognosis in advanced high-grade serous ovarian cancer patients.

Publications

Elevated tumor tissue protein expression levels of kallikrein-related peptidases KLK10 and KLK11 are associated with a better prognosis in advanced high-grade serous ovarian cancer patients.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets