|Year : 2017 | Volume
| Issue : 2 | Page : 55-59
To find the role of DNA damage marker 8-hydroxy 2-deoxy guanosine in patients of prostate cancer, benign prostatic hyperplasia and its association to other prognostic factors of prostate cancer
Lalit Kumar1, Sriniwas Kumar2, Sakshi Agarwal3
1 Department of Urology, S P Medical College, Bikaner, Rajasthan, India
2 Department of General Surgery, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India
3 Department of Obstetrics and Gynaecology, S P Medical College, Bikaner, Rajasthan, India
|Date of Web Publication||20-Jun-2017|
Department of Urology, S P Medical College, Bikaner, Rajasthan
Source of Support: None, Conflict of Interest: None
Purpose: The aim of the study was to identify correlation between DNA damage marker 8-hydroxy 2-deoxy guanosine (8-OHdG) and other prognostic factors such as Gleason's score, serum prostate-specific antigen (PSA), and stage in carcinoma prostate and to assess a probability-correlation between DNA damage and benign prostatic hyperplasia (BPH) and control. Materials and Methods: A study has been carried out prospectively. Forty patients of carcinoma prostate, 34 BPH, and 14 healthy controls were included in the study between the period of July 2010 to July 2012. Serum 8-OHdG level was measured in all subjects as a marker of DNA damage. Results: Serum 8-OHdG level was significantly raised in patient with prostate cancer (313.39 ± 69.48 ng/mL) as compared with BPH patients (204.42 ± 40.97 ng/mL) and control group (198.94 ± 15.74 ng/mL) with P< 0.001. Serum 8-OHdG level in BPH patients was higher than the controls, but the mean difference was statistically insignificant (P = 1.000). The patients with serum PSA >20 ng/mL, Gleason's score >6 had higher mean 8-OHdG levels as compared to serum PSA ≤20 and Gleason score ≤6, as P< 0.05. There was also direct association found between prostate volume and stage of the tumor though it was not significant. Conclusions: These findings suggest that oxidative stress level was significantly raised in prostate cancer patients. It was also observed that a significant direct association exists between oxidative stress and certain clinicopathologic factors, including serum PSA, Gleason score, and metastasis which show that with progression of disease, there was increase in oxidative stress level.
Keywords: 8-hydroxy 2-deoxy guanosine, benign prostatic hyperplasia, cancer, DNA, prostate
|How to cite this article:|
Kumar L, Kumar S, Agarwal S. To find the role of DNA damage marker 8-hydroxy 2-deoxy guanosine in patients of prostate cancer, benign prostatic hyperplasia and its association to other prognostic factors of prostate cancer. J Integr Nephrol Androl 2017;4:55-9
|How to cite this URL:|
Kumar L, Kumar S, Agarwal S. To find the role of DNA damage marker 8-hydroxy 2-deoxy guanosine in patients of prostate cancer, benign prostatic hyperplasia and its association to other prognostic factors of prostate cancer. J Integr Nephrol Androl [serial online] 2017 [cited 2023 May 31];4:55-9. Available from: http://www.journal-ina.com/text.asp?2017/4/2/55/208581
| Introduction|| |
Prostate cancer is the most commonly diagnosed cancer among men in the United States. As the population ages, so will the number of diagnosed prostate cancer cases. Until recently, prostate cancer had been considered to be a major health problem in Western countries; however, it is now reported as an emerging threat to the health of aging men in Asia. In addition to aging, other factors such as genetic, epigenetic, and environmental risk factors also increase the probability of developing prostate cancer.
Although little is known regarding etiology and factors that influence the clinical outcome “elevated oxidative stress” in the cellular microenvironment is a common denominator in prostate cancer and aging. Oxidative stress causes damage to multiple cellular components such as DNA, proteins, and lipids and is clearly implicated in prostate cancer. Furthermore, human prostate tissue has been shown to be particularly vulnerable to oxidative DNA damage due to more rapid cell turnover, fewer DNA repair enzymes, and chronic inflammation of prostate epithelial cells., However, data remain limited regarding the effects of oxidative stress on the initiation and progression of prostate cancer.
The assessment of oxidative DNA damage products in various biological matrices, such as serum and/or urinary 8-hydroxy 2-deoxy guanosine (8-OHdG) or 8-nitroguanine, could be important to understanding the role of oxidative stress in cancer development and disease intervention. Accurate and reliable measurement of oxidative damage to lipid, protein, and DNA are important in the evaluation of the extent and distribution of reactive oxygen species (ROS)-induced damage in the disease processes. In fact, several recent studies demonstrated the usefulness of urinary 8-OHdG excretion as a biomarker of DNA oxidation using clinical specimens.,
The present study was undertaken to observe and find the role of ROS in inducing DNA damage in patients of prostate cancer. We planned to estimate the levels 8-OHdG in serum of these patients and to look for any clinicopathologic correlations in patients with prostate cancer, benign prostatic hyperplasia (BPH), and control subjects.
| Materials And Methods|| |
The present study has been carried out prospectively and was approved by the Ethical Committee of our Institute. This study was conducted during July 2010–July 2012.
Selection of cases
Forty cases of carcinoma prostate who were admitted in urology, ward, respectively were included in the study. A detailed history, clinical examination, and routine investigations of the patients were done. Diagnosis and staging of carcinoma prostate were done by ultrasonography abdomen with postvoidal residual urine, serum prostate-specific antigen (PSA), histopathological biopsy, Gleason score, computed tomography/magnetic resonance imaging pelvis, and bone scan.
Selection of controls
Age-matched 34 BPH patients and 14 healthy controls were included in group after informed consent. Blood was collected from all the control group peoples as done in patients.
Estimation of 8-hydroxy-2-deoxy guanosine
Blood samples were collected, especially from the antecubital vein of the above-stated subjects. Venous blood sample about 5 mL was collected in clean and dry plain vials without any anticoagulant. The blood was allowed to clot at room temperature at 2000 r/min in a clinical centrifuge for 10–15 min. The sera, thus removed, were stored at −20°C in a sterile plain glass vial until analyzed. Serum was used to pipette out at the time of analysis after thawing. Cayman enzyme immunoassay 8-OHDG kit with reagents was used for analysis. Results were read by enzyme-linked immunosorbent assay (ELISA) reader for the determination of 8-OHDG values in the serum.
The statistical analysis was done using SPSS for windows version 16.0 software (SPSS Inc., Chicago, USA). For noncontinuous data, Chi-square test was used. The mean and standard deviation of the parameters studied during observation period were calculated for multiple groups was compared using ANOVA test and in two continuous variables, Z-test was used. The critical value of “P” indicating the probability of significant difference was taken as <0.05 for comparisons.
| Results|| |
Following observations were made.
The mean age for all cases was 68.38 ± 8.89 years (range: 50–80 years). Maximum numbers of cases 16 (40%) were in between 61 and 70 years age group. In comparison, the mean age for controls was 65.22 ± 5.47 years. There was no statistically significant age difference among cases and controls.
On digital rectal examination, maximum 62.5% cases had nodularity/induration/hardness. The mean prostate volume was 54.62 ± 16.02 mm 3 (range: 20.8–108.82 mm 3). 21/40 (52.5%) cases had of prostatic volume >40 mm 3. The mean PSA for all cases was 70.78 ± 90.47 ng/mL (range: 10.2–418 ng/mL). Majority of cases 31/40 (77.17%) had serum PSA value >20 ng/mL [Figure 1]. In 28/40 (70%) cases, Gleason score was >6. Two cases (5%) were of stage T1, eight cases (20%) were of stage T2, 14 cases (35%) were of stage T3, and 16 cases (40%) were of stage T4 [Figure 2]. Sixteen cases (40%) presented with metastasis (M1).
|Figure 1: Distribution of patients according to prostate-specific antigen, prostate volume, and digital rectal examination findings. PSA: prostate.specific antigen|
Click here to view
The mean values of serum 8-OHdG were increasing with the increase in the serum PSA level, and the cases with serum PSA level >20 have significantly (P < 0.027) higher serum 8-OHdG level then the patient with serum PSA ≤20. Similarly, patients with Gleason score >6, prostate volume >40 mm 3, and presence of metastatic disease were found to have higher mean serum 8-OHdG level [Table 1].
|Table 1: Serum 8-hydroxy-2'-deoxyguanosine level according to serum prostate specific antigen, prostate volume and Gleason score and metastatic status|
Click here to view
On comparing the relationship between tumor stage and serum 8-OHdG values, we found that serum 8-OHdG values increased as the tumor stage advances, and the mean difference was statistically insignificant [Table 2].
|Table 2: Relationship between tumor stage and serum 8-hydroxy-2'-deoxyguanosine|
Click here to view
In the present study, it was seen that serum 8-OHdG level was significantly raised in patient with prostate cancer as compared BPH patients and healthy control group (P < 0.001). Serum 8-OHdG level in BPH patients was higher than the healthy controls, but the mean difference was statistically insignificant (P = 1.000) [Table 3].
|Table 3: Correlation between serum 8-hydroxy-2'-deoxyguanosine level in carcinoma prostate, benign prostatic hyperplasia and controls|
Click here to view
| Discussion|| |
Prostate cancer is primarily a disease of the elderly with more than three-quarter of the cases occurring in men above 65 years of age. This disease has become a major health problem globally during the last few decades. Studies have shown that prostate cancer is the second most frequently diagnosed cancer in men worldwide and the fifth most common cancer overall. Approximately, one in six men will be diagnosed with prostate cancer during his lifetime, and about one in 36 men will die because of this problem. In India, it is one of the five leading sites of cancers among males.
In the present study, we studied prognostic factors including serum PSA, Gleason score, tumor stage, and identified a correlation with DNA damage marker which is an important element in the pathogenesis of carcinoma prostate. One of the common features associated with cancer cells is increased ROS generation which are known to be mutagenic and therefore playing an important role in cancer formation. The mutagenic capacity of free radicals is due to the direct interactions of hydroxyl radicals with DNA.
Over the last decade, association between prostate cancer risk and oxidative stress has been recognized, and epidemiological, experimental, and clinical studies have unequivocally proven a role for oxidative stress in the development and progression of this disease. Differences in prostate cancer incidence among various races as environment, diet, lifestyle, genetic constitution, and hormone of an individual/community are some of the contributing risk factors for occurrence of prostate cancer. Although recent studies have indicated that oxidative stress is higher in the epithelium of prostate cancer patients than men without the disease, the association of ROS-mediated oxidative stress and prostate cancer risk remains to be elucidated.
The oxidative hydroxylation of guanine in the eight-position is the most frequent and most mutagenic lesion in nuclear DNA. Oxidative damage to DNA, reflected in the formation of 8-OHdG, is important in mutagenesis and carcinogenesis. Recently, increasing evidence have shown that malignant cells contain high concentrations of oxidized DNA lesion. Tumor also tends to generate large amounts of hydrogen peroxide. Increased 8-OHdG also has been detected in various tumors. In uterine myomas, the concentration of 8-OHdG was found to increase with the size of tumor. In breast cancer, higher concentrations of 8-OHdG and 5-hydroxymethyl-2V-deoxyuridine in DNA were detected in both cancer tissues and blood cells.,
In the present study, we estimated the serum level of 8-OHdG in forty cases of carcinoma prostate to assess its potential role as a tumor marker. The mean serum 8-OHdG level in study group was 313.39 ± 69.48 ng/mL, while in control group, the level of 8-OHdG was found to be 198.94 ± 15.74 ng/mL. Statistically, analysis revealed that the value of 8-OHdG in study group was not only higher than control group but also statistically significant too with a P< 0.001 [Table 3].
Also in the present study, we have correlated both the serum levels of 8-OHdG and several parameters related to prostate cancer, such as serum PSA, prostate volume, clinical stage, histological grade, and metastasis. When serum 8-OHdG level was compared with serum PSA, patient with serum PSA ≤20 ng/mL had mean 8-OHdG level 266.30 ± 45.52 ng/mL, and the patient with serum PSA >20 ng/mL had mean 8-OHdG level 317.17 ± 61.60 ng/mL, the difference of which was found to be statistically significant [Table 1]. This suggests that 8-OHdG is elevated in patients with disseminated disease since a cutoff PSA level of 20 ng/mL has been described as a marker for disseminated disease.
When serum 8-OHdG level was compared with prostate volume, patients with prostate volume >40 mm 3 had higher serum 8-OHdG, but P value came to be 0.271 suggesting only tendency of positive correlation. While comparing serum 8-OHdG level with Gleason score, patients with Gleason score ≤6 had a mean 8-OHdG level of 267.24 ± 46.39 ng/mL, while patients with Gleason score >6 had a mean 8-OHdG level of 326.32 ± 69.53 ng/mL, and this clearly shows that not only does the 8-OHdG level increase with increase in Gleason score but also their mean difference was statistically significant (P = 0.010) [Table 1]. Similar findings were observed by Pande et al., who found that with increase in Gleason score >6, the 8-OHdG level raised significantly.
Similar to findings in previous study by Pande et al., in the present study, when serum 8-OHdG level was compared with the stage of the tumor, 8-OHdG level increased with tumor progression and in the presence of metastasis as previously found, but difference was significant in the presence of metastasis but not with increase in tumor stage only [Table 1] and [Table 2].
Similar to the results regarding prostate cancer in the present study, Chiou et al. found an increase in 8-OHdG and its analogs in patients with prostate cancer (58.8 + 43.4 ng/mg creatinine, n = 16) when compared with that of healthy individuals (36.1 + 24.5 ng/mg creatinine, n = 24) (P = 0.021). They concluded that the competitive ELISA for 8-OHdG and its analogs appears to be a simple method for quantifying the extent of oxidative stress and may have potential for identifying cancer risk.
Miyake et al. evaluated the significance of oxidative DNA damage in patients with prostate cancer based on the measurement of urinary 8-OHdG. The ratio of urinary 8-OHdG-to-Cr (8-OHdG/Cr) in patients with prostate cancer was significantly higher than in age-matched healthy controls just like observed in the present study. In contradiction to our study, they found only age was significantly associated with 8-OHdG/Cr in prostate cancer cases among several clinicopathological factors, including serum PSA, metastasis, and Gleason score. They concluded that oxidative stress may be involved in an early event in prostate cancer development.
| Conclusions|| |
The present study showed that oxidative stress level was significantly raised in prostate cancer patients. It was also observed that a significant association exists between oxidative stress and certain clinicopathologic factors including serum PSA, Gleason score, and metastasis which shows that with progression of disease, there was increase in oxidative stress level.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Zhang L, Yang BX, Zhang HT, Wang JG, Wang HL, Zhao XJ. Prostate cancer: An emerging threat to the health of aging men in Asia. Asian J Androl 2011;13:574-8.
Baker AM, Oberley LW, Cohen MB. Expression of antioxidant enzymes in human prostatic adenocarcinoma. Prostate 1997;32:229-33.
Bostwick DG, Alexander EE, Singh R, Shan A, Qian J, Santella RM, et al.
Antioxidant enzyme expression and reactive oxygen species damage in prostatic intraepithelial neoplasia and cancer. Cancer 2000;89:123-34.
Erhola M, Toyokuni S, Okada K, Tanaka T, Hiai H, Ochi H, et al.
Biomarker evidence of DNA oxidation in lung cancer patients: Association of urinary 8-hydroxy-2'-deoxyguanosine excretion with radiotherapy, chemotherapy, and response to treatment. FEBS Lett 1997;409:287-91.
Tsuboi H, Kouda K, Takeuchi H, Takigawa M, Masamoto Y, Takeuchi M, et al.
8-hydroxydeoxyguanosine in urine as an index of oxidative damage to DNA in the evaluation of atopic dermatitis. Br J Dermatol 1998;138:1033-5.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al
. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer 2014. doi:10.1002/ijc.29210.
Ganesh B, Saoba SL, Sarade MN, Pinjari SV. Risk factors for prostate cancer: An hospital-based case-control study from Mumbai, India. Indian J Urol 2011;27:345-50.
] [Full text]
Fleshner NE, Klotz LH. Diet, androgens, oxidative stress and prostate cancer susceptibility. Cancer Metastasis Rev 1998-1999;17:325-30.
Klungland A, Rosewell I, Hollenbach S, Larsen E, Daly G, Epe B, et al.
Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage. Proc Natl Acad Sci U S A 1999;96:13300-5.
Toyokuni S, Okamoto K, Yodoi J, Hiai H. Persistent oxidative stress in cancer. FEBS Lett 1995;358:1-3.
Szatrowski TP, Nathan CF. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res 1991;51:794-8.
Foksinski M, Kotzbach R, Szymanski W, Olinski R. The concentration of typical biomarker of oxidative stress 8-hydroxy-2V-deoxyguanosine is higher in uterine myomas than in control tissues and correlates with the size of the tumor. Free Radic Biol Med 2000;29:597-601.
Matsui A, Ikeda T, Enomoto K, Hosoda K, Nakashima H, Omae K, et al.
Increased formation of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, in human breast cancer tissue and its relationship to GSTP1 and COMT genotypes. Cancer Lett 2000;151:87-95.
Djuric Z, Heibrun LK, Simon MS, Smith D, Luongo DA, LoRusso PMet al
. Concentrations of 5-hydroxymethyl-2V-deoxyuridine in DNA from blood as a marker of breast cancer. Cancer 1996;77:691-6.
Pande D, Negi R, Karki K, Dwivedi US, Khanna RS, Khanna HD. Simultaneous progression of oxidative stress, angiogenesis, and cell proliferation in prostate carcinoma. Urol Oncol 2013;31:1561-6.
Chiou CC, Chang PY, Chan EC, Wu TL, Tsao KC, Wu JT. Urinary 8-hydroxydeoxyguanosine and its analogs as DNA marker of oxidative stress: Development of an ELISA and measurement in both bladder and prostate cancers. Clin Chim Acta 2003;334:87-94.
Miyake H, Hara I, Kamidono S, Eto H. Oxidative DNA damage in patients with prostate cancer and its response to treatment. J Urol 2004;171:1533-6.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
|This article has been cited by|
||Effect of chocolate on older patients with cancer in palliative care: a randomised controlled study
| ||Josiane C. Vettori, Luanda G. da-Silva, Karina Pfrimer, Alceu A. Jordăo, Paulo Louzada-Junior, Júlio C. Moriguti, Eduardo Ferriolli, Nereida K. C. Lima |
| ||BMC Palliative Care. 2022; 21(1) |
|[Pubmed] | [DOI]|
||Neuroinflammatory Triangle Presenting Novel Pharmacological Targets for Ischemic Brain Injury
| ||Zaib A. Shaheryar,Mahtab A. Khan,Ch. Sherjeel Adnan,Awais Ali Zaidi,Daniel Hänggi,Sajjad Muhammad |
| ||Frontiers in Immunology. 2021; 12 |
|[Pubmed] | [DOI]|
||Potential contribution of ELISA and LFI Assays to assessment of the oxidative stress condition based on 8-oxodG biomarker
| ||Lucilene Dornelles Mello |
| ||Analytical Biochemistry. 2021; : 114215 |
|[Pubmed] | [DOI]|
||Sensors for diagnosis of prostate cancer: Looking beyond the prostate specific antigen
| ||Corinne Dejous,Uma Maheswari Krishnan |
| ||Biosensors and Bioelectronics. 2020; : 112790 |
|[Pubmed] | [DOI]|