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Diamine oxidase is a Cu-containing enzyme which intracellularly participates in the regulation of the levels of putrescine, spermidine and spermine and in this process produces growth inhibitory amino aldehydes and hydrogen peroxide. Extracellularly, the enzyme participates in the inactivation of biogenic amines, notably histamine. Here we present evidence that in the presence of polyamines, diamine oxidase has the ability to bind DNA and to oxidise DNA-bound polyamines. The enzyme associates with chromosomal DNA since it can be released from human placental DNA by treatment with DNase I and it may be involved in the degradation of DNA. Thus, diamine oxidase may belong to a new class of DNA-binding proteins.

The purpose of the study was to determine the expression of BCl-2 in epithelial ovarian tumors and to correlate expression levels with selected clinicopathologic parameters, time to progression and prognosis of the disease. Using tissue arrays (TA), we analyzed BCl-2 expression in tissues from 191 women diagnosed with low malignant potential ovarian tumors (LMP) and from 582 patients diagnosed with ovarian cancer (OC). Using 30% as cutoff level for BCl-2 overexpression, 5% of LMPs were positive with a higher proportion of serous ovarian tumor of LMP, compared to mucinous ovarian tumor of LMP (p = 0.02). Women with a BCl-2-positive LMP tumor were older than women with a BCl-2 negative tumor (p = 0.02). Ten percent of OCs were positive for BCl-2 expression (or=30%). No significant association was found between BCl-2 expression levels and histologic type of tumors (serous vs mucinous, p = 0.19). A 30% cutoff value or a percentage scale showed that BCl-2 expression had no prognostic value, both in univariate and in multivariate survival analyses. No difference in time to progression was observed between patients with BCl-2-positive and negative tumors. These data suggest that BCl-2 expression may not be of important clinical value in the treatment of Danish OC patients.

Estrogen and progesterone are important hormones secreted by the ovary acting through specific receptors. Tumor tissue expression profiles of these have demonstrated prognostic value in malignancies such as breast, uterine and prostate cancer. In this study, including tissue samples from 773 Danish patients with an ovarian tumor, we evaluated whether estrogen receptor (ER) and progesterone receptor (PR) expression correlated with clinico-pathological parameters, and a possible prognostic impact on ovarian cancer (OC) patients was investigated. Using tissue array and immunohistochemistry, we analyzed the ER and PR expression levels in tissues from 582 women with OC and 191 women with low malignancy potential (LMP) ovarian tumors. Our results demonstrated that ER was expressed in 30 of the 191 LMP tumors (16%) and in 207 of the 582 OC (36%). PR was expressed in 38 LMP tumors (20%) and in 115 OC (20%). For both tumor types an excess of positive tumors was found in the serous compared to the mucinous subtype (por =0.00001). The frequency of ER expression-positive OC increased with increasing FIGO stage (p=0.0003), and the frequency of PR-positive tumors increased with increasing histological grade (p=0.0006). In a Cox survival analysis, a tissue ER and PR expression 10% or higher was found to imply an independent significant advantageous course of patient disease-specific survival (ER: hazard ratio (HR), 0.80; 95% confidence interval (CI), 0.63-0.99; PR: HR, 0.69; 95% CI, 0.51-0.94) together with FIGO stage, residual tumor after primary surgery, age at diagnosis and other histological types vs. serous adenocarcinoma. The histological grade of tumor was found to have no independent prognostic value. The prognostic value of ER and PR was found additive with a HR for patients with high ER and PR expression of 0.48 (95% CI, 0.31-0.74) compared to patients with10% expression for both receptors. In conclusion, our results predict that an elevated expression of ER and PR, alone and in combination, point to a favorable outcome for patients with OC.

To determine the CA125 tissue expression levels in borderline and invasive epithelial ovarian tumor tissues. Secondly, to evaluate whether CA125 tissue expression levels correlate with clinico-pathological parameters and serum CA125 levels and finally to investigate the prognostic value of tissue CA125 expression levels in ovarian cancer (OC) patients.We designed tissue arrays (TA) and analyzed the CA125 expression in tissues from 778 Danish women with an ovarian tumor. Furthermore, corresponding preoperative blood samples obtained before surgery were collected from 382 women with OC.Significantly more CA125 expression positive tumors (no expression vs. expression) were found in the serous subtype compared to the percentage of positive tumors in mucinous, endometroid and other subtypes for patients both with borderline ovarian tumors and with OC (p0.00001, p0.00001). Similarly, a positive significant correlation was found between elevated serum CA125 levels and elevated levels of CA125 tissue expression (N=382 stage I-IV OC, Spearman rho=0.31, p0.0001) (N=206 stage III OC, Spearman rho=0.30, p0.0001). We found a significantly shorter survival for stage III/IV OC patients with no CA125 tissue expression compared to stage III/IV OC patients with positive CA125 tissue expression (p=0.0003).Our finding that tissue CA125 expression was lacking in late stage primary OC tumor of Danish women with poor survival may be of value in selecting patients as eligible candidates for individually based treatments.

The p53 gene, a tumor suppressor gene located on the short arm of chromosome 17 (17p13), has been found mutated in 30-80% of epithelial ovarian cancers (OC), with the most frequently detected mutations in the conserved regions of the gene. A small number of studies investigated the survival of patients with p53 mutations in OC, but their conclusions are not in agreement.We analyzed the frequency of p53 mutations in 124 Danish women with OC, using Single-Stranded Conformation Polymorphism analysis in addition with DNA sequencing and evaluated if mutations correlated with clinicopathological parameters and with patient survival.Thirty-five (28%) ovarian tumors were found to contain one or more p53 variations, two of which were considered polymorphisms. Twenty-seven (82%) mutations were single nucleotide substitutions of which 23 (85%) were missense mutations and therefore led to amino acid substitutions. Significantly shorter survival was found for stage III/IV patients with a p53 missense mutation compared to stage III/IV OC patients with wild type p53 (P = 0.0018). Multivariate Cox regression analysis restricted to 107 OC patients with a p53 missense mutation or p53 wild type in the tumor tissue and with information on radicality of primary surgery showed that missense p53 mutation (HR = 2.5, 95% CI: 1.21-4.98), radicality after primary surgery (HR = 1.7, 95% CI: 1.04-2.88), tetranectin (mg/l: HR = 0.78, 95% CI: 0.67-0.91) and stage (I vs. III: HR = 0.30, 95% CI: 0.10-0.92, II vs. III: HR = 0.24, 95% CI: 0.05-1.05, IV vs. III: HR = 2.70, 95% CI: 1.22-5.98) were independent prognostic factors.Missense mutations in the conserved regions of p53 may be of prognostic value in Danish OC patients.

The level of the urokinase plasminogen activator receptor (uPAR) is elevated in tumor tissue from several forms of cancer. uPAR is shed from the cell surface and the soluble form, soluble urokinase plasminogen activator receptor (suPAR), has been detected in several body fluids. High plasma levels of suPAR in patients with colorectal cancer and high serum levels of suPAR in patients with recurrent metastatic breast cancer have been associated with poor prognosis. In patients with ovarian cancer (OC) it has been shown that the level of suPAR is very high in ascites and cystic fluid and that high serum levels of suPAR were associated with shorter survival of the patients. We evaluated suPAR preoperatively in plasma from primary OC stage III patients and tested for association with prognosis. The prognostic significance of suPAR was also compared to two biochemical markers; cancer antigen 125 (CA125) and tetranectin (TN). No significant differences were found between patients who died of OC compared to patients still alive regarding median plasma suPAR levels (p=0.62) and median serum CA125 levels (p=0.26). In contrast, a significant difference was found between dead and alive OC patients for the median serum TN level (p0.0001). Dividing the patients into two groups, corresponding to preoperative plasma suPAR levels below or equal to 2.0 ng/ml and higher than 2.0 ng/ml, no significant difference in survival was found between the two groups (p=0.49). When different cut-off levels of plasma suPAR were considered (2.74 ng/ml, 3.25 ng/ml and 4.18 ng/ml), no significant differences in survival could be detected (p=0.58, p=0.68 and p=0.05). Multivariate Cox regression analysis showed that the only independent prognostic factors were radicality after primary surgery (RH=5.34; 95% CI, 2.34-12.20; p0.0001) and preoperative serum TN (RH=0.69, 95% CI, 0.57-0.82; p0.0001), whereas plasma suPAR (4.18 ng/ml), age, histological type of tumour and serum CA 125 had no independent prognostic value. In conclusion, preoperative plasma suPAR level was of no prognostic value in this cohort of Danish stage III OC patients.

Activation of ras oncogenes has been demonstrated in ovarian tumours. All the reported studies are based on a relatively small number of patients and the results therefore remain a subject of debate.In this study, we analyzed the presence of mutations at codons 12 and 13 of the K-ras gene in 165 Danish women with ovarian tumours, including 138 invasive ovarian cancers and 27 borderline ovarian tumours, using a restriction fragment length polymorphism-polymerase chain reaction technique and evaluated whether such alterations were associated with the clinicopathological parameters of the patients and survival.K-ras codon 12 gene mutations were found in 8.7% of ovarian cancer patients and in 14.8% of the borderline ovarian tumour patients. A K-ras codon 13 gene mutation was found in 1.5% of ovarian cancer patients. K-ras mutations were found with a significantly higher frequency in mucinous tumours compared to serous tumours (P = 0.011).Mutation frequency was correlated with the histological type of tumour, but not with stage, radicality of operation, and age. Furthermore, no significant difference in survival was demonstrated between patients with or without K-ras mutation, neither in the univariate nor in the multivariate survival analyses.

YKL-40, a member of family 18 glycosyl hydrolases, is secreted by cancer cells. The function of YKL-40 in cancer diseases is unknown, but it is a growth factor of connective tissue cells and probably has a role in inflammation and remodeling of the extracellular matrix, a process also involved in metastatic malignant diseases. High serum YKL-40 has been associated with poor prognosis for patients with colorectal and recurrent breast cancer.The purpose of the present study was to examine the prognostic value of plasma YKL-40 in patients presenting with recurring ovarian cancer.YKL-40 was determined by ELISA in plasma samples from 73 patients with relapse of ovarian cancer shortly before start of second-line chemotherapy. The endpoint used was death because of ovarian cancer.Plasma YKL-40 was increased in ovarian cancer patients (median 94 micro g/L, range 20-1970 micro g/L) compared with age-matched controls (33 micro g/L, range 20-130 micro g/L) (p0.001). Fifty-five per cent of the patients had a plasma YKL-40 level above the upper normal 95th percentile of controls. Patients with high plasma YKL-40 (i.e.130 micro g/L or160 micro g/L) at the time of relapse had significantly shorter survival than patients with normal levels (respectively p = 0.007 and p = 0.004). Plasma YKL-40 proved to be an independent prognostic factor in a multivariate Cox analysis (YKL-40160 micro g/L; HR = 2.27) (p = 0.006), including serum CA-125 and clinical/histological parameters.High plasma YKL-40 is related to short survival in patients with recurrent ovarian cancer.

The p53 gene is frequently mutated in various human tumours. In addition, single nucleotide polymorphisms are often observed in exons and introns of the p53 gene in normal tissues and tumours.The prevalence of a polymorphism involving codon 72 of exon 4 in the p53 gene was studied in peripheral white blood cells and tumour tissues from Danish ovarian tumour patients and in peripheral white blood cells from controls. The analyses were performed by Polymerase Chain Reaction (PCR), Restriction Fragment Length Polymorphism (RFLP) and DNA sequencing. The amino acid residue at this position is either arginine (p53-Arg) or proline (p53-Pro).There was no correlation between the frequency of the three genotypes (Pro/Pro, Arg/Arg and Arg/Pro) and age, stage or histological type of the tumour. A significant difference in survival was observed between ovarian cancer stage III patients with a shift from one genotype in the blood to another genotype in the tissue and patients with no shift (p=0.0216).Kaplan-Meier survival analyses and multivariate Cox regression analysis stratified to stage III ovarian cancer patients showed that a shift from one genotype in the blood to another genotype in the tissue is a prognostic factor in Danish ovarian cancer patients.