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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 3  |  Page : 570-573

The value of serum survivin level in early diagnosis of cancer


1 Department of Medical Oncology, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
2 Department of Biochemistry, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
3 Department of Internal Medicine, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
4 Department of Neurosurgery, Bakirkoy Prof. Dr. Mazhar Osman Psychiatry and Neurology Education and Research Hospital, Istanbul, Turkey
5 Department of Medical Oncology, Karadeniz Technical University Medical School, Trabzon, Turkey
6 Department of General Surgery, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey

Date of Web Publication12-Jun-2018

Correspondence Address:
Hakan Kocoglu
Department of Internal Medicine, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.171369

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 > Abstract 


Objective: Survivin is one of the apoptosis inhibitor proteins, and it plays a key role in tumor angiogenesis and cancer progression. This study was conducted to investigate the serum level of survivin to determine its diagnostic value in cancer patients.
Materials and Methods: Blood samples were taken from cancer patients (n = 67) prior to surgery or chemo/radiotherapy and age-matched healthy volunteers (n = 23). The serum levels of survivin were analyzed by enzyme-linked immunosorbent assays. The difference in serum levels between patients and control was evaluated by using statistical methods. Correlation between the serum levels of survivin and clinicopathological features of cancer patients were also evaluated.
Results: The diagnoses of patients were breast cancer (49.3%), colon cancer (25.4%), ovarian cancer (14.9%), and other cancers (10.4%). Serum survivin levels were significantly higher in cancer patients than healthy subjects (196.23 pg/ml vs. 117.73 pg/ml, respectively, P = 0.019). No significant relations were found between serum survivin level and demographic characteristics of cancer. The optimal cut-off value of serum survivin was determined at >120.8 pg/ml, and its serum levels above this cut-off value were associated with 4.198 times increased risk of cancer.
Conclusion: Our study results may suggest that high serum survivin levels can show 4 times increased risk of cancer in a subject with a high suspicion of cancer. Furthermore, survivin level was not influenced with demographic characteristics of breast, gastric, colorectal, prostate, ovarian cancer, and glioblastome multiforme.

Keywords: Cancer, diagnostic marker, malignancy, prognosis, risk indicator, survivin


How to cite this article:
Gunaldi M, Isiksacan N, Kocoglu H, Okuturlar Y, Gunaldi O, Topcu TO, Karabulut M. The value of serum survivin level in early diagnosis of cancer. J Can Res Ther 2018;14:570-3

How to cite this URL:
Gunaldi M, Isiksacan N, Kocoglu H, Okuturlar Y, Gunaldi O, Topcu TO, Karabulut M. The value of serum survivin level in early diagnosis of cancer. J Can Res Ther [serial online] 2018 [cited 2020 Jul 8];14:570-3. Available from: http://www.cancerjournal.net/text.asp?2018/14/3/570/171369




 > Introduction Top


Apoptosis is a strictly regulated process that includes complex intracellular signaling pathways and molecular cascades needed for the development of embryo and fetus where there are destruction and reconstitution of cellular structures.[1] Current evidence have shown that survivin has a role in the regulation of mitosis. Survivin inhibits apoptosis by interfering with the function of caspase-3, caspase-7, and caspase-9.[2] Surviving may also inhibit apoptosis by caspase-independent pathways.[2] Suppression of apoptosis may initiate carcinogenesis in several ways. Survivin, also known as baculoviral inhibitor of apoptosis repeat-containing 5, is a member of the inhibitor of apoptosis family and has both anti-apoptotic and mitotic regulatory functions.[1] Until recently, it was known that survivin is located in cytoplasm, mitochondria, and nucleus of the cell. However, recent studies showed that surviving also presents in exosomes which are released from cells to extracellular space by the exocytosis of multivesicular bodies.[3]

Increasing evidence supports a promising role of survivin as a tumor biomarker. Until now, serum surviving had been investigated in several studies (by different methods) to determine whether it can be used as a screening, follow-up, and early diagnostic test and its effect on prognosis.[1],[2],[3],[4],[5],[6],[7],[8] Survivin overexpression is associated with adverse outcomes in various cancers including breast, lung, colorectal, prostate, and ovarian cancer.[9] Promising results have been obtained on urine survivin as a diagnostic marker of bladder cancer.[10] Quantitative assays of survivin in malignant pleural effusion are additionally useful in lung cancer diagnosis.[11] The serum level of survivin that is measurable before surgical intervention may be useful as a biomarker. In this study, serum survivin levels of patients and controls were investigated by enzyme-linked ımmunosorbent assay (ELISA) technique with the purpose of whether it may be used as an early diagnostic marker in a subject with a high suspicion of cancer.


 > Materials and Methods Top


This clinical trial was conducted at the Department of Medical Oncology of our hospital. A total number of 90 subjects consisted of 67 patients with diagnosed cancer (pathological confirmed), and 23 age-matched healthy subjects were admitted to the study. Patients who had undergone surgery, chemo/radiotherapy and patients with underlying acute or chronic disease (acute infections, diabetes mellitus, hypertension, kidney diseases, cardiovascular disorders, rheumatological diseases, etc.) were excluded. The characteristics of the patients with respect to age, gender, diagnosis, performance status, smoking, comorbidity, family history, grade of tumor, metastasis status, liver metastasis status, blood parameters, and the last health records were recorded for analyses. The study was approved by our hospital's Local Ethical Committee and written informed consent was provided from all subjects prior to the assessment.

Blood sample collection

Blood samples of patients were drawn before initiating chemo (radio) therapy and/or surgical resection of tumor. Venous blood samples were collected in tubes from the antecubital vein, after an overnight fastening. The tubes were centrifuged at 2000 × g (10 min) to remove the plasma and serum. The plasma and serum samples were kept at −80°C until the analysis of HSP70 levels.

Measurement of survivin

Serum level of survivin was measured using ELISA assay based on biotin double antibody sandwich technique according to manufacturer's instructions (Shanghai Yehua Biological Technology, Shanghai, PRC). Reference values: 0.5 pg/ml–150 pg/ml.

Other variables

Complete blood count was determined in a Coulter LH 750 autoanalyzer (Beckman Coulter, CA, USA). Serum carcinoembriyogenic antigen (CEA) were determined by Beckman Coulter AU 5800 chemistry autoanalyzer and DXI 800 systems by using commercial kits (Beckman Coulter, CA, USA). Reference range: CEA: 0–3.3 U/ml.

Statistical analyses

Statistical analyses were done by Number Cruncher Statistical System 2007 and Power Analysis and Sample Size, 2008 Statistical Software (Utah, USA). During the evaluation of study variables, descriptive statistical methods (mean, standard error, median, rate, and ratio) were used. For a comparison of variables of normal distribution, the t-test for independent samples was used, and the Kruskal–Wallis test and the Mann–Whitney U-test were used for the comparison of variables with nonnormal distribution. Receiver operating characteristic (ROC) analysis was used to determine the cut-off value of survivin. Statistical significance was accepted as P < 0.05 in all tests.


 > Results Top


A total number of 90 subjects consisted of 67 patients newly diagnosed with cancer and 23 healthy subjects were included in the study. For types of cancers see [Table 1]. There was no significant difference in the mean age between patients and control subjects (62.57 ± 13.16 vs. 57.26 ± 10.93 years, respectively, P = 0.077). Serum survivin levels were significantly higher in patients than controls (196.23 pg/ml vs. 117.73 pg/ml, respectively, P = 0.019) [Table 1].
Table 1: Clinical features and serum survivin levels of cancer patients and healthy subjects

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It was determined that serum survivin level was not influenced with gender, performance status, comorbidity, smoking, family history of cancer, type of cancer, metastasis status, liver metastasis status, mortality, presence or absence of leukocytosis, anemia, thrombocytosis, and high tumor markers (P ≥ 0.05) [Table 2].
Table 2: Evaluation of serum survivin levels and clinic characteristics of patients

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The cut-off values of survivin levels for predicting cancer was determined by ROC analysis. The cut-off value of survivin in prediction of cancer was determined at ≥120.8 pg/ml. This cut-off value had a sensitivity at 59.70%, specificity at 73.91%, positive predictive value at 86.96%, and negative predictive value at 38.64% (area under the curve: 0.665 (95% confidence interval [95% CI]: 0.549–0.780), P = 0.019) [Figure 1]. The risk ratio for survivin ≥120.8 pg/ml to predict cancer was 4.198 (95% CI: 1.467–12.007) [Figure 2].
Figure 1: Receiver operating characteristic curves for serum survivin to discriminate between cancer patients and healthy group

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Figure 2: Distribution of serum survivin both cancer patients and control group

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 > Discussion Top


After the revealing of the fact that survivin is a protein that inhibits apoptosis and regulates mitosis, researchers has focused on survivin and they investigated its utilization as a biomarker in cancer screening and as an indicator in prediction of cancer prognosis. In recent years, significant studies have been made on several types of cancer in attempts to determine this matter and remarkable results have been yielded.[1],[2],[3],[4],[5],[6],[7],[8],[12],[13],[14],[15],[16] Furthermore, according to the results of these studies, it has been determined that cytoplasmic expression of survivin is a significant biomarker of prognosis; however, its expression in the nucleus is not a predictive biomarker for prognosis.[12],[17] It has been reported that breast cancer also exhibits overexpression of survivin and it has been associated with poor prognosis.[18],[19],[20],[21]

Studies, associated with the utilization of serum survivin as a diagnostic marker, have shown that patients with hepatocellular carcinoma (HCC), over carcinoma or acute lymphoblastic leukemia (ALL) have higher serum survivin levels than healthy subjects.[1],[4],[5] However in contrast with these studies, two studies performed on patients with lung cancer, have not shown statistically significant increase in serum survivin levels.[4],[8] Although patients with lung cancer are not included in our study population, it was observed that serum survivin levels of patients diagnosed with breast, gastric, colorectal, prostate, ovarian cancer or glioblastome multiforme were significantly higher when compared to control groups.

Among the studies, in which serum survivin levels were found significantly higher in patients with cancer compared to healthy controls; cut-off values were found as 13.7 pg/ml in HCC; 110 pg/ml in ovarian cancers; 15.18 pg/ml in ALL.[1],[5],[6] In our study, the cut-off value of serum survivin level in patients with cancer was found as 120.8 pg/ml and it was determined that subjects who had above levels of that cut-off value have 4.198 times higher risk of cancer.

When evaluating the relation between serum survivin levels and general clinicopathologic characteristics of cancer, such as tumor aggressiveness, grade, phase, and lymph node condition, some studies have found a significant relationship [3],[5],[22] while others not.[7],[20] In our study, no significant relation were found between serum survivin level and demographic characteristics of cancer (metastasis status, liver metastasis, and blood parameters characteristics).

In some studies performed on some types of cancer, it had been investigated the relationship between serum survivin level and prognosis. It has been shown that both histopathological expression and high serum levels of survivin were associated with poor prognosis in patients with prostate cancer, serous ovarian cancer, ALL, and breast cancer.[3],[4],[5],[6],[18],[19],[23] On the other hand, in studies carried out on patients with lung cancer, it has been claimed that serum survivin levels do not have any prognostic value.[4],[8] In our study, which does not include patients with lung cancer, a statistical significance was determined by serum survivin levels between patients and controls.

As a result, as the feature of survivin is being an intracellular anti-apoptotic protein, its diagnostic value had been investigated in several type of cancer studies by histopathological or serum level examinations. Regardless of, there are different results in the relation between survivin expression and clinicopathological features and prognosis of cancer, common result in almost all these studies is that survivin expression is significantly high. In our study, which comprises patients with different types of malignancies, as we have found serum survivin level significantly high at the time of diagnosis, we may claim that survivin may be used as a marker that imply malignancy or as a marker for differential diagnosis of malignancy and other benign diseases. More studies that involve a large number of patients with several types of malignancies instead of a single type of malignancy are required to determine the prognostic and clinical significance of survivin.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
El-Attar HA, Kandil MH, El-Kerm YM, El-Ghandour MK. Comparison of serum survivin and alpha fetoprotein in Egyptian patients with hepatocellular carcinoma associated with hepatitis C viral infection. Asian Pac J Cancer Prev 2010;11:897-903.  Back to cited text no. 1
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Wu YK, Chen KT, Kuo YB, Huang YS, Chan EC. Quantitative detection of survivin in malignant pleural effusion for the diagnosis and prognosis of lung cancer. Cancer Lett 2009;273:331-5.  Back to cited text no. 11
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Liu JL, Gao W, Kang QM, Zhang XJ, Yang SG. Prognostic value of survivin in patients with gastric cancer: A systematic review with meta-analysis. PLoS One 2013;8:e71930.  Back to cited text no. 12
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Groner B, Weiss A. Targeting survivin in cancer: Novel drug development approaches. BioDrugs 2014;28:27-39.  Back to cited text no. 13
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Mobahat M, Narendran A, Riabowol K. Survivin as a preferential target for cancer therapy. Int J Mol Sci 2014;15:2494-516.  Back to cited text no. 14
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Vandghanooni S, Eskandani M, Montazeri V, Halimi M, Babaei E, Feizi MA. Survivin-deltaEx3: A novel biomarker for diagnosis of papillary thyroid carcinoma. J Cancer Res Ther 2011;7:325-30.  Back to cited text no. 15
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Wu Y, Wang G, Wei J, Wen X. Survivin protein expression positively correlated with proliferative activity of cancer cells in bladder cancer. Indian J Med Sci 2005;59:235-42.  Back to cited text no. 16
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Tsai WC, Chu CH, Yu CP, Sheu LF, Chen A, Chiang H, et al. Matriptase and survivin expression associated with tumor progression and malignant potential in breast cancer of Chinese women: Tissue microarray analysis of immunostaining scores with clinicopathological parameters. Dis Markers 2008;24:89-99.  Back to cited text no. 18
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Izawa A, Kobayashi D, Nasu S, Saito K, Moriai R, Asanuma K, et al. Relevance of c-erbB2, PLU-1 and survivin mRNA expression to diagnostic assessment of breast cancer. Anticancer Res 2002;22:2965-9.  Back to cited text no. 21
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