Cancer Biomarkers - Volume 15, issue 5

Authors: Zhang, Jun | Yu, Xiao-Ling | Zheng, Guo-Feng | Zhao, Fei

Article Type: Research Article

Abstract: OBJECTIVE: This meta-analysis investigated the correlation between the promoter methylation of death-associated protein kinase (DAPK ) and the clinicopathological features in patients with non-small cell lung cancer (NSCLC). METHOD: Scientific literature databases were exhaustively searched to retrieve published studies relevant to DAPK methylation and NSCLC. Retrieved studies published in English and Chinese languages were screened according to the stringent predefined inclusion and exclusion criteria, and high quality studies were selected for meta-analysis. All statistical analyses were performed utilizing STATA software (Version 12.0, Stata Corporation, College Station, TX, USA). RESULTS: A total of 14 …published studies (5 in English and 9 in Chinese) were enrolled in the present meta-analysis, and contained 1238 patients with NSCLC. The results indicated that NSCLC patients with metastatic phenotype were strongly associated with significantly higher methylation rate of DAPK compared to NSCLC patients without metastasis. Additionally, in NSCLC patients carrying tumors with DAPK methylation, the 5-year survival rate was remarkedly lower than NSCLC patients without DAPK methylation. However, we did not find significant correlation between DAPK methylation and histological stage or tumor node metastasis (TNM) stage in NSCLC patients. CONCLUSION: Our meta-analysis results reveal that DAPK promoter methylation might be associated with tumor metastasis and poor prognosis in NSCLC patients, although no correlation with histological types and TNM stage in NSCLC patients were found. Show more

Keywords: Death-associated protein kinase (DAPK), non-small cell lung cancer, clinicopathological features, prognosis, meta-analysis

DOI: 10.3233/CBM-150501

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 609-617, 2015

Authors: Danish, Qazi | Mokhdomi, Taseem A. | Bukhari, Shoiab | Ahmad, Raies

Article Type: Research Article

Abstract: Lung cancer is the major cause of cancer-related mortality worldwide owing to its late-stage detection and aggressive behavior. Epidemiologically, several genetic and epigenetic factors contribute to the development of lung cancer. Angiogenesis, a critical process in tumor progression has become an important target for anti-cancer therapy particularly in lung cancer. Besides commercially available angiogenic inhibitors, numerous anti-angiogenic therapies have been developed to limit tumor growth, although, most of them have not proved beneficial in terms of long-term survival. Despite, logical advances in treatment strategies, NSCLC still remains a major health concern due to poor prognosis of the diseases state. This …calls for a comprehensive analysis of signaling processes governing tumor angiogenesis and treatment options available thereof for development of a sustainable strategy to control cancer. In this review, several aspects of lung cancer have been discussed starting from its pathological characterization to the development of modern therapeutics. Show more

Keywords: Lung cancer, angiogenesis, VEGF receptors

DOI: 10.3233/CBM-150502

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 619-633, 2015

Authors: Wang, Yunchao | Lu, Janice | Zhao, Xia | Feng, Yu | Lv, Shuzhen | Mu, Ying | Wang, Dandan | Fu, Hui | Chen, Yizhi | Li, Yanping

Article Type: Research Article

Abstract: AIM: To explore the correlation between Ubiquilin1 (UBQLN1) expression and clinicopathological characteristics and determine its prognostic significance in patients with breast cancer. METHODS: UBQLN1 expression was evaluated by immunohistochemistry in 125 invasive breast cancer samples. The association between UBQLN1 and clinicopathological parameters and prognosis of breast cancer were detected. RESULTS: The UBQLN1 protein was overexpressed in breast cancer samples (68/125) and associated with tumor size (P = 0.034), lymph node metastasis (P = 0.035), TNM stage (P = 0.049) and vascular invasion (P = 0.003). The DFS and OS rates at 5 years were …27.7% and 48.7% for UBQLN1 positive patients compared with 49.6% and 77.4% for UBQLN1 negative patients, respectively (both P = 0.001). Multivariate analyses revealed that UBQLN1 was an independent prognostic factor for overall survival (hazard ratio, 2.416; 95% CI, 1.134-5.149, P= 0.022) and disease-free survival (hazard ratio, 2.113; 95% CI, 1.203-3.709, P= 0.009). Furthermore, UBQLN1 overexpression was associated with poor prognosis in patients without lymph node metastasis (DFS 35 months vs 62 months, P = 0.005; OS 68 months vs 72 months, P = 0.017). CONCLUSION: The expression level of UBQLN1 and prognosis in breast cancer is clarified for the first time and UBQLN1 seems to be a novel molecular marker to predict poor prognosis in breast cancer. Show more

Keywords: Breast cancer, UBQLN1, prognosis

DOI: 10.3233/CBM-150503

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 635-643, 2015

Authors: He, Yi | Chen, Xi | Liu, Hao | Xiao, Haibo | Kwapong, William Robert | Mei, Ju

Article Type: Research Article

Abstract: BACKGROUND: Matrix-remodeling associated 5 (MXRA5) has recently been one of the frequently mutated gene but its role in non-small cell lung cancer (NSCLC) remains unclear. OBJECTIVE: To identify whether MXRA5 could be applied as a novel prognostic marker for NSCLC. METHODS AND RESULTS: In this study, we proved that mRNA and protein expression of MXRA5 in 166 NSCLC patients' tissues by Quantitative Real-Time PCR and immunohistochemical staining respectively. Moreover, the correlation between MXRA5 protein expression and clinicopathological features and prognosis in NSCLC patients was evaluated. Our results revealed that the over-expression of MXRA5 was …significantly correlated with age (P= 0.049), differentiation (P= 0.003), tumor-node-metastasis (TNM) stage (P= 0.017) and smoking cigarette (P= 0.007). In addition, it also showed that patients with higher MXRA5 protein expression had significantly shorter overall survival (P < 0.001). Multivariate analysis indicated that over-expression of MXRA5 protein was an independent prognostic factor for NSCLC. CONCLUSIONS: MXRA5 protein is aberrantly expressed in NSCLC and the high MXRA5 expression is correlated with tumor progression and overall survival. These results indicated the potential value of MXRA5 as a novel therapeutic target for the treatment of NSCLC. Show more

Keywords: Matrix-remodeling associated 5, non-small cell lung cancer, prognosis, biomarker

DOI: 10.3233/CBM-150504

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 645-651, 2015

Authors: Aljada, Ahmad | Saleh, Ayman M. | Al-Aqeel, Suliaman M. | Shamsa, Heba Bani | Al-Bawab, Ahmad | Dubayee, Mohammed Al | Ahmed, Altayeb Abdalla

Article Type: Research Article

Abstract: BACKGROUND: The mature human insulin receptor (INSR) has two isoforms: The A isoform and the B isoform. INSR upregulation has been suggested to play a role in cancer. OBJECTIVE: To establish quantitative PCR method for INSR transcript variants and examine their differential expression as a diagnostic tumor marker in breast cancer. METHODS: The differential expression of IR-A and IR-B were evaluated by TaqMan qRT-PCR assay in the commercially available Breast Cancer Disease cDNA and Cancer Survey cDNA arrays. RESULTS: The mRNA expression levels of IR-A was statistically significantly higher in breast cancer …when compared to normal breast tissue while IR-B mRNA expression was down regulated significantly in breast cancer. Stratification of patients into groups according to metastatic stages indicated statistically significantly higher levels of IR-A mRNA in clinical stage (CS)-IV, and lower IR-B levels in CS-IIA, CS-IIIB and CS-IIIC. However, IR-A:IR-B ratio showed a statistically significant increase in all stages. Cancer Survey cDNA array demonstrated lower levels of IR-B mRNA in breast adenocarcinoma, liver carcinoma and lung carcinoma only while IR-A expression was significantly altered in kidney carcinoma without any significant differences in IR-A:IR-B ratios. CONCLUSIONS: The results demonstrate an increased IR-A:IR-B ratio in all clinical stages of breast cancer. Thus, IR-A:IR-B ratio may have a diagnostic biomarker utility in breast cancer. Show more

Keywords: Insulin receptor (INSR), IR-A, IR-B, breast cancer, metastasis, cDNA arrays

DOI: 10.3233/CBM-150505

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 653-661, 2015

Authors: Wang, Xu | Cui, Jiuwei | Gu, Jingkai | He, Hua | Li, Biao | Li, Wei

Article Type: Research Article

Abstract: BACKGROUND: The association between vitamin D levels and lung cancer risk varies among distinct demographic populations; however, whether vitamin D levels are related to the risk of lung cancer in Chinese population is unknown. OBJECTIVE: We aimed to elucidate the association of plasma 25-hydroxyvitamin D [25(OH)D] level with the risk of non-small cell lung cancer (NSCLC) in a Chinese population. METHODS: A total of 100 NSCLC patients and, 100 age-, gender-, blood-collection-season- and resident area-matched, cancer-free controls were recruited. Plasma 25(OH)D2 and 25(OH)D3 levels were measured by LC/MS/MS mass spectrometry and HPLC. A logistic …regression model was applied to estimate the association between 25(OH)D concentrations and NSCLC risk. RESULTS: Multivariable analysis showed that smoking history, and 25(OH)D deficiency (< 20 ng/mL) were related to a higher risk of NSCLC (P= 0.03). In addition, late stage (stage IIIB-IV) NSCLC was associated with lower 25(OH)D levels, as indicated by univariate analysis. Similarly, multivariate analysis showed that late stage (IIIB-IV) NSCLC was related to 25(OH)D deficiency. CONCLUSIONS: Plasma 25(OH)D deficiency is significantly associated with a higher risk of NSCLC, specifically late stage NSCLC. Show more

Keywords: 25-hydroxyvitamin D, lung cancer, non-small cell lung cancer

DOI: 10.3233/CBM-150506

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 663-668, 2015

Authors: Brentnall, Adam R. | Vasiljevic, Natasa | Scibior-Bentkowska, Dorota | Cadman, Louise | Austin, Janet | Cuzick, Jack | Lorincz, Attila T.

Article Type: Research Article

Abstract: BACKGROUND: Persistent infection %by with high risk human papillomavirus (hrHPV) types causes cervical cancer but most women who test positive are at very low risk of neoplasia. Strategies are needed which can retain high sensitivity of hrHPV testing but reduce the number of false-positives. We showed previously that a combination DNA methylation triage assay for HPV types 16, 18 and 31 and human gene EPB41L3 was useful to identify high grade cervical lesions. OBJECTIVE: Assess whether measurement of DNA methylation in HPV type 33 can improve the previous classifier. METHODS: A London colposcopy …referral group of 1493 women of whom 556 (37%) had histologically-confirmed CIN (cervical intraepithelial neoplasia) 2 or 3 that included 114 HPV33 positive women with methylation measured for three L2 CpGs 5557, 5560 and 5566. Discrimination performance was assessed for the new classifier S5, built by adding HPV33 to the earlier classifier. RESULTS: HPV33 methylation measurement improved prediction among HPV33 positive women. Receiver operating characteristic analyses showed an area under the curve (AUC) for HPV33 methylation of 0.68 (95% CI 0.57-0.78). The earlier risk score was significantly improved by HPV33 methytlation (AUC = 0.82 vs 0.80; P < 0.001). For 90% sensitivity the specificity for CIN2/3 was 49% (95% CI 46-52%). CONCLUSIONS: Measurement of HPV33 DNA methylation contributes independent diagnostic information to EPB41L3 and HPV16, HPV18 and HPV31, and is superior to genotyping. Other HPV and human methylation target regions might be useful to further improve S5. Show more

Keywords: Cervical intraepithelial neoplasia, DNA methylation, early detection of cancer, human papillomavirus 33, human papillomavirus DNA tests, uterine cervical neoplasms

DOI: 10.3233/CBM-150507

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 669-675, 2015

Authors: Zhao, Yunsheng | Wang, Meng | Cui, Chenying | Zhang, Lina | Liao, Fei | Li, Hongchen | Wu, Xia

Article Type: Research Article

Abstract: BACKGROUND: The most practical serum biomarker AFP is negative in 80% patients with small tumor in the early stage of primary hepatocellular carcinoma (PHC). OBJECTIVE: To investigate significance of combined tests of serum golgi glycoprotein 73 (GP73), lens culinaris agglutinin-reactive alpha-fetoprotein (AFP-L3), glypican 3 (GPC3), des-gamma-carboxy prothrombin (DCP), CA199, ferritin (FER) and carcinoembryonic antigen (CEA) in diagnosis of small PHC with negative AFP. METHODS: A total of 50 cases of small PHC, 60 cases of non-PHC digestive system disorders and 40 cases of healthy controls were collected. Serum GP73, GPC3 and DCP were analyzed …by enzyme-1inked immunosorbent assay. AFP-L3 was separated by microspincolumn; the levels of CA199, FER, CEA, AFP-L3 and total AFP were quantified by electrochemiluminescence immunoassays; percentage of AFP-L3 to total AFP was calculated. RESULTS: Levels of those biomarkers except FER were all significantly different among three groups (P < 0.01). Positive detection rates of seven biomarkers in PHC were higher than other groups (P < 0.01). In individual detection, the highest sensitivity, accuracy rate and area under ROC curve were 72.0%, 86.7% and 0.826 by GP73 and the highest specificity was 98.0% by GPC3. In combined detection with those seven biomarkers, the sensitivity, specificity, accuracy rate and area under ROC curve were 82.0%, 95.0%, 90.1% and 0.884. CONCLUSIONS: GP73 and AFP-L3 are superior biomarkers to aid the diagnosis of small PHC with negative AFP. The combined detection of biomarkers improved the diagnostic accuracy. Show more

Keywords: Primary hepatocellular carcinoma, biomarkers, combined detection, diagnosis

DOI: 10.3233/CBM-150508

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 677-683, 2015

Authors: Malisic, Emina J. | Krivokuca, Ana M. | Boljevic, Ivana Z. | Jankovic, Radmila N.

Article Type: Research Article

Abstract: OBJECTIVE: The polymorphic variations of DNA repair genes may contribute to functional deficiencies in DNA repair processes increasing susceptibility to cancer. We aimed to investigate the impact of 135G>C RAD51 and XRCC1 Arg399Gln polymorphisms on ovarian carcinoma risk in Serbian women. METHODS: The study included 50 ovarian carcinoma samples and 78 cervical swabs of gynecologically healthy age-matched controls. RAD51 G135C and XRCC1 Arg399Gln polymorphisms were determined by PCR-RFLP. Deviations of the genotype frequencies from Hardy-Weinberg equilibrium were assessed using the χ 2 test. The allele- and genotype-specific risks were estimated as …odds ratios with 95% confidence intervals. RESULTS: RAD51 135C and XRCC1 Arg allele are associated with ovarian carcinoma [OR (95% CI): 2.54 (1.22-5.29) for C vs . G; 2.64 (1.53-4.55) for Arg vs . Gln]. RAD51 C exerts its effect in dominant (CC plus GC vs . GG) [OR (95% CI): 2.83 (1.21-6.62], while XRCC1 Arg in dominant (ArgArg plus ArgGln vs . GlnGln) [OR (95% CI): 4.76 (1.69-13.42)] and recessive model (ArgArg vs. ArgGln plus GlnGln) [OR (95% CI): 2.21 (1.07-4.56)]. CONCLUSION: The results suggest that the RAD51 G135C and XRCC1 Arg399Gln polymorphisms could be biomarkers of susceptibility for ovarian carcinoma development. Further larger case-control study is needed to confirm our findings. Show more

Keywords: DNA repair, ovarian carcinoma, RAD51 G135C polymorphism, XRCC1 Arg399Gln polymorphism

DOI: 10.3233/CBM-150509

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 685-691, 2015

Authors: Li, Junfeng | Wei, Feng

Article Type: Research Article

Abstract: OBJECTIVE: To investigate the relationship between the expression of transforming growth factor β 1 (TGF-β 1) and thyroid lesions by retrospective analysis in patients with thyroidectomy. METHODS: Immunohistochemical analyses of TGF-β 1 were performed with 120 archived formalin-fixed and paraffin-embedded thyroid resection tissue samples that included 60 cases of thyroid cancers (papillary thyroid carcinoma, follicular thyroid carcinoma), 14 cases of nodular goiter (NG), 16 cases of thyroid adenoma, 15 cases of Graves disease, 15 cases of Hashimoto's thyroiditis. RESULTS: The pathological analysis of resection thyroid showed a high coincidence with that diagnosed by preoperative …fine needle aspiration biopsy (FNAB), with coincidence rate of 84.48%. The results showed that the expressions of TGF-β 1 in the thyroid cancers were significantly higher than in other benign thyroid lesions and normal thyroid tissues (P< 0.05). Moreover, high expression of TGFβ 1 was found to closely related with the occurrence of thyroid cancers, while there was no significant difference of TGFβ 1 expression between different thyroid cancers. CONCLUSION: The overexpression of TGF-β 1 is associated with the occurrence of thyroid cancer, which can be used as a candidate for the diagnosis and prognosis of thyroid cancer. Show more

Keywords: Thyroid cancer, fine needle aspiration biopsy (FNAB), transforming growth factor-β 1, diagnosis

DOI: 10.3233/CBM-150510

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 693-698, 2015

Authors: Gutiérrez-Monreal, Miguel A. | Villela, Luis | Baltazar, Severiano | Perfecto-Avalos, Yocanxochitl | Cardineau, Guy A. | Scott, Sean-Patrick

Article Type: Research Article

Abstract: BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma. Presently, one of the most important clinical predictors of survival in DLBCL patients is the International Prognostic Index (IPI). Circadian rhythms are the approximate 24 hour biological rhythms with more than 10 genes making up the molecular clock. OBJECTIVE: Determine if functional single nucleotide polymorphism in circadian genes may contribute to survival status in patients diagnosed with diffuse large B-cell lymphoma. METHODS: Sixteen high-risk non-synonymous polymorphisms in circadian genes (CLOCK, CRY2, CSNK1E, CSNK2A1, NPAS2, PER1, PER2, PER3, PPP2CA, and TIM) …were genotyped by screening PCR. Results were visualized by agarose gel electrophoresis and confirmed by two-direction sequencing. Clinical variables were compared between mutated and non-mutated groups. LogRank survival analysis and Kaplan-Meier method were used to calculate the overall survival. RESULTS: PER3 rs10462020 variant showed significant difference in overall survival between patients containing mutated genotypes and those with non-mutated genotypes (p = 0.047). LDH levels (p = 0.021) and IPI score (p < 0.001) also showed differences in overall survival. No clinical differences were observed in mutated vs. non-mutated patients. CONCLUSIONS: This work suggests a role of PER3 rs10462020 in predicting a prognosis in DLBCL overall survival of patients. Show more

Keywords: Circadian rhythm, single nucleotide polymorphism, diffuse large B-cell lymphoma, PER3, survival, biomarker

DOI: 10.3233/CBM-150511

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 699-705, 2015

Authors: Xia, Zongjiang | Duan, Fujiao | Jing, Chang | Guo, Zhihua | Nie, Changfu | Song, Chunhua

Article Type: Research Article

Abstract: BACKGROUND: DNA methyltransferase 3B (DNMT3B) has been discovered to play an important role in tumorigenesis. However, the association between DNMT3B -579G>T and the cancer risk has not been demonstrated. OBJECTIVE: The aim of this study is to provide a precise quantification for the association between DNMT3B -579G>T and the cancer susceptibility. METHODS: We performed a systematic literature review and assessed the methodological quality of included case-control designed studies based on Newcastle-Ottawa Scale (NOS). Pooled odds ratios (ORs) and corresponding 95% confidence intervals (95%CIs) were calculated to assess the strengths of the association. …RESULTS: We identified 18 studies for pooled analyses. Overall, the results demonstrated that the DNMT3B -579G>T polymorphism was significantly associated with a subtly decreased cancer risk (GT vs TT: OR = 0.78, 95%CI: 0.70-0.87, P< 0.01; GT + GG vs TT: OR = 0.81, 95%CI: 0.68-0.97, P= 0.02), especially in the Asian population and in colorectal cancer subgroup. In addition, when stratified for source of controls, the results of population-based subgroup showed the GT genotype might have a significantly decreased cancer risk, but not hospital-based subgroups. CONCLUSIONS: DNMT3B -579G>T polymorphism might contribute to the susceptibility of cancers especially in the Asian population and for colorectal cancer. Show more

Keywords: DNMT3B, polymorphism, cancer, quantitative assessment

DOI: 10.3233/CBM-150512

Citation: Cancer Biomarkers, vol. 15, no. 5, pp. 707-716, 2015