Excluding skin cancers, colorectal cancer (CRC) is the third most commonly diagnosed cancer after breast and lung cancer and the second leading cause of death in both sexes [
Previous studies have reported that there is a strong relationship between increased fibrin/fibrinogen degradation product (FDP) levels and the presence of cancer [
The DR-70 ELISA is the first
In this study, we investigated the relationship between serum DR-70 levels and the presence of dysplastic polyps, that is, premalignant lesions in the adenoma-carcinoma sequence of CRC. We assessed the ability of DR-70 to predict the presence of premalignant lesions before they become intramucosal adenocarcinomas, that is, an early stage of colon cancer.
This study included 130 patients with adenomatous polyps as detected by colonoscopies at the Gastroenterology Clinic of the Haydarpaşa Numune Training and Research Hospital and 50 healthy blood donors who composed the control group following confirmation of lack of any colon polyps on colonoscopy. Subjects were excluded from the study if they had CRC, impaired hepatic or renal function, diabetes mellitus, an uncontrolled infection, familial adenomatous polyposis, or conditions that could affect fibrinolysis and/or thrombosis (e.g., deep vein thrombosis, pulmonary embolism, or anticoagulant use). Accordingly, patients with false positive results for DR-70 including 3 patients with Crohn’s disease, 2 patients with autoimmune hepatitis, 2 patients with infection, and in the sera of 4 patients with incompletely clotted blood during serum preparation were excluded from the present analysis.
The demographic and clinical characteristics of the subjects, including age, gender, and colonoscopy findings at the time of diagnosis, were recorded via a questionnaire form. The study protocol was approved by the hospital’s ethics committee and all study subjects provided written informed consent.
Carcinomas restricted to the epithelial layer without invasion into the lamina propria were classified as noninvasive high grade neoplasia.
A 5 mL sample of peripheral blood was obtained from each subject (i.e., both the patients with the adenomatous polyps and the healthy control subjects). The serum CEA and DR-70 levels and the hemogram for each participant were analyzed in the biochemistry laboratory of Haydarpaşa Numune Training and Research Hospital. The serum DR-70 concentration was measured following the manufacturer’s protocol for the AMDL-ELISA DR-70 kit (AMDL Inc., Tustin, CA, USA).
The Statistical Package for Social Sciences (SPSS) for Windows, v. 16.0, was used for all statistical analyses. The normal distribution of the continuous variables was analyzed using the one-sample Kolmogorov-Smirnov test. In addition to descriptive statistical methods, a one-way analysis of variance (ANOVA) was used to compare normally distributed parameters in more than two independent groups, whereas the Kruskal-Wallis test was used for parameters that did not show a normal distribution. If the results of the one-way ANOVA were significant, pairwise post hoc tests were performed using Tukey’s honestly significant difference (HSD) test. For parameters that did not show a normal distribution, the Mann-Whitney
We evaluated 130 patients (i.e., 72 males and 58 females) with a mean age of
Among the patient group, the median number of individual polyps found in the colonoscopy was five, and the median polyp size was 5.5 mm. The polyps were most abundant in the rectum and least abundant in the cecum. Fecal occult blood was detected in 25% of the patients. The median DR-70 concentration was 0.80
Comparisons of demographic characteristics and clinical parameters in the control, low grade dysplasia, and high grade dysplasia groups.
Controls ( |
Patients | ||||
---|---|---|---|---|---|
Low grade dysplasia ( |
High grade dysplasia ( |
Total ( |
|
||
Mean (SD) | |||||
Age (years) | 58.0 (6.2) | 60.1 (13.2) | 60.1 (11.5) | 60.1 (12.4) | 0.53a |
| |||||
Gender |
|
||||
Male | 22 (44.0) | 37 (51.4) | 35 (60.3) | 72 (55.4) | 0.23b |
Female | 28 (56.0) | 35 (58.6) | 23 (39.7) | 58 (44.6) | |
FOB positivity | — | 18 (25) | 13 (22.4) | 31 (23.8) | 0.73 |
| |||||
Median (min–max) | |||||
Number of polyps | — | 5 (1–6) | 5 (1–6) | 5 (1–6) | 0.50c |
Polyp size (mm) | — | 5 (0–20) | 6.0 (0–60) | 5.5 (0–60) | 0.02c |
DR-70 ( |
0.5 (0.2–0.8) | 0.6 (0.3–1.4) | 1.1 (0.3–4.3) | 0.8 (0.3–4.3) | <0.001d |
| |||||
Mean (SD) | |||||
CEA (ng/mL) | 1.0 (0.7) | 2.1 (0.7) | 2.2 (1.0) | 2.2 (0.8) | <0.001a |
When the control, low grade, and high grade groups were compared, significant differences were observed in the CEA levels (
A significant positive correlation was observed between the CEA and DR-70 concentrations (
Correlation between CEA, DR-70, and clinical parameters.
CEA (ng/mL) | DR-70 ( | |||
---|---|---|---|---|
|
|
|
| |
Polyp location | −0.008a | 0.93 | 0.108a | 0.22 |
Polyp size | −0.029a | 0.74 | 0.501a | <0.001 |
DR-70 ( |
0.230a | 0.002 | — | — |
CEA (ng/mL) | — | — | 0.230a | 0.002 |
Age | 0.026b | 0.73 | 0.098a | 0.19 |
Number of polyps | 0.148a | 0.09 | −0.058a | 0.51 |
To determine the independent factors that can predict high grade dysplastic polyps, the blood CEA levels, the blood DR-70 levels, the polyp sizes, and the ages of the participants were entered into a multiple logistic regression analysis (Table
Factors predicting high grade dysplastic polyps. Results of multiple logistic regression analysis.
|
OR | %95 CI | ||
---|---|---|---|---|
Lower bound | Upper bound | |||
CEA | 0.891 | 0.948 | 0.446 | 2.015 |
DR-70 |
|
104.816 | 16.476 | 666.832 |
Polyp size | 0.069 | 0.897 | 0.797 | 1.009 |
Age | 0.629 | 0.990 | 0.950 | 1.031 |
OR: odds ratio, CI: confidence interval.
When the receiver operating characteristic (ROC) curve was drawn to investigate the diagnostic ability of DR-70 and CEA to distinguish the presence of dysplasia from the healthy control group, the most suitable cutoff value for DR-70 was 0.7
Receiver operating characteristic (ROC) curve for the diagnostic ability of (a) DR-70, (b) CEA, and (c) DR-70 versus CEA to differentiate the presence of dysplasia from the healthy control.
When the receiver operating characteristic (ROC) curve was drawn to investigate the diagnostic ability of DR-70 and CEA in differentiation of low grade versus high grade dysplasia, the most suitable cutoff value for DR-70 was 0.9
Receiver operating characteristic (ROC) curve for the diagnostic ability of (a) DR-70, (b) CEA, and (c) DR-70 versus CEA to differentiate low grade dysplasia from high grade dysplasia.
Intramucosal adenocarcinomas do not invade beyond the mucosa or muscularis mucosae. Any cancerous invasion beyond the muscularis mucosae to the submucosal area is considered invasive [
The 5-year survival rate of patients with early stage colorectal carcinomas is around 90%. Many screening programs have been developed in order to detect these tumors as early as possible [
In a study in Germany of 85 patients with gastrointestinal cancers and 100 healthy individuals, the serum DR-70 concentration was found to be significantly higher in patients with advanced stage cancer as compared to that of those with early stage cancer. Since only 30 of these patients had CRC, this marker could not be shown to be organ-specific. In the current study, we excluded patients who had developed true CRC because our primary objective was to evaluate the ability of this marker to screen for early stage tumors [
Evaluation of DR-70 concentrations in various tumor types has shown that its highest sensitivity is in patients with stomach cancer (i.e., 92.6%) and the lowest sensitivity is in patients with rectal cancer (i.e., 66.7%). Serum DR-70 concentrations were significantly higher in patients with advanced adenomas as compared to healthy individuals without any polyps. Polyp location was not associated with DR-70 concentration [
In a study in the USA in which 75 serum samples were obtained from 39 healthy controls and 36 patients with recurrent CRC, the researchers found that the combined use of DR-70 and CEA had a sensitivity of 75% and a specificity of 58.97%. The optimal cutoff points for DR-70 and CEA were 3
This study does have several limitations. For example, we did not include CRC patients in the sample population. Moreover, we could not include serrated adenomas because only five of our patients presented with this condition. Lastly, the patient sample size, that is, 130 cases, may not be sufficiently large to determine the cutoff level between dysplastic lesions and healthy controls.
Indeed, higher levels of DR-70 were also reported in patients with malignancies of the lung, nasopharynx, tongue, gastrointestinal tract, breast, ovary, and prostate gland [
Cancers are characterized by irregularities at the cellular level. As these tumors progress, irregularities occur at the system level including the coagulation system. In cancer patients, the coagulation system can be affected by the inappropriate activation of either or both the coagulation and/or fibrinolytic pathways. Dysregulation of the coagulation system has major negative effects on cancer patients because of the involvement of this system in homeostasis and immunity [
To our knowledge, this study is the first to evaluate DR-70 as a marker in patients with advanced adenomatous polyps, that is, precursors of CRC. The diagnosis of early stage CRC using serum markers without the need for invasive interventions, like colonoscopies, will offer simpler and more cost-effective approaches. Further, prospective randomized studies involving more patients are needed to determine whether DR-70 ELISA can serve as a marker for early stage CRC.
The authors declare that there is no conflict of interests regarding the publication of this paper.