Cancer Biomarkers - Volume 15, issue 1

Authors: Franklin, Oskar | Öhlund, Daniel | Lundin, Christina | Öman, Mikael | Naredi, Peter | Wang, Wanzhong | Sund, Malin

Article Type: Research Article

Abstract: Background: A lack of disease-specific symptoms and good tumour markers makes early detection and diagnosis of pancreatic ductal adenocarcinoma (PDAC) challenging. Objective: To analyse the tissue expression and circulating levels of four stroma-derived substances (type IV collagen, endostatin/type XVIII collagen, osteopontin and tenascin C) and four conventional tumour markers (CA 19-9, TPS, CEA and Ca 125) in a PDAC cohort. Methods: Tissue expression of markers in normal pancreas and PDAC tissue was analysed with immunofluorescence. Plasma concentrations of markers were measured before and after surgery. Patients with non-malignant disorders served as controls. Results: The …conventional and stromal substances were expressed in the cancer cell compartment and the stroma, respectively. Although most patients had increased levels of many markers before surgery, 2/12 (17%) of patients had normal levels of Ca 19-9 at this stage. High preoperative endostatin/type XVIII collagen, and postoperative type IV collagen was associated with short survival. Neither the pre- nor postoperative levels of TPS, Ca 125 or CA 19-9 were associated to survival. Conclusions: PDAC is characterized by an abundant stroma. These initial observations indicate that the stroma can be a source of PDAC tumour markers that are found in different compartments of the cancer, thus reflecting different aspects of tumour biology. Show more

Keywords: Pancreatic ductal adenocarcinoma (PDAC), tumour markers, stroma, type IV collagen, type XVIII collagen, endostatin, osteopontin, tenascin C, TPS, Ca 125, Ca 19-9, CEA

DOI: 10.3233/CBM-140430

Citation: Cancer Biomarkers, vol. 15, no. 1, pp. 1-10, 2015

Authors: Schussel, Juliana Lucena | Kalinke, Luciana Puchalski | Sassi, Laurindo Moacir | de Oliveira, Benedito Valdecir | Pedruzzi, Paola A.G. | Olandoski, Marcia | Alvares, Lucia Elvira | Garlet, Gustavo Pompermaier | Trevilatto, Paula Cristina

Article Type: Research Article

Abstract: Background: DACT genes regulates Wnt as well TGF-β pathway, and were already associated with hepatocellular and lung cancer. Alterations on Wnt/β -catenin were associated with head and neck cancer through β -catenin cytoplasmatic accumulation. Objective: The aim of the study was to evaluate DACT1 and DACT2 expression and methylation on oral squamous cell cancer (OSCC). Methods: 47 samples of salivary rinse and tissue were collected from 29 OSCC and 18 control patients. qMSP and RT-PCR reactions were performed in order to detect hypermethylation and expression of DACT1 and DACT2 genes. Statistical analysis was conducted to …evaluate these genes as possible biomarkers for OSCC. Results: As expected man over 60 years old with tobacco and alcohol consumption history were associated with OSCC. There was no statistical difference between groups concerning DACT1 and DACT2 either in promoter hypermethylation or transcript levels. Age was associated with DACT2 promoter hypermethylation, especially over 56 years old. Conclusion: Patients older than 56 years old were about 5 times more likely to have DACT2 promoter hypermethylation. These findings could partially explain why older subjects are more prone to carcinogenesis. Wnt/β -catenin pathway plays an important role in carcinogenesis, and the study of their regulators may help understand malignant transformation. Show more

Keywords: Head and neck, oral cancer, hypermethylation, DACT

DOI: 10.3233/CBM-140436

Citation: Cancer Biomarkers, vol. 15, no. 1, pp. 11-17, 2015

Authors: Pérez-Sayáns, Mario | Suárez-Peñaranda, José Manuel | Iruegas, Elena Padín | de Almeida, Miguel Reis | Barros-Angueira, Francisco | Torreira, Mercedes Gallas | García-García, Abel

Article Type: Research Article

Abstract: Objectives: Downregulation of p21Waf1/CIP1 (a cyclin-dependent kinase inhibitor) has been reported for mouth cancer. The goal of this article is to quantitatively report expression of p21Waf1/CIP1 and evaluate its relationship with the clinical and prognostic factors. Materials and Methods: this is a retrospective study of 68 patients diagnosed with OSCC. We constructed a tissue microarray to develop an immunohistochemical assessment of p21Waf1/CIP1 expression. A multivariate analysis using a forward-selection stepwise regression model (Cox, 1972) for predicting survival was performed. Results: The quantitative expression of p21Waf1/CIP1 showed a statistically significant relationship with the …risk of lymph node metastasis, showing a higher expression in patients with homolateral single nodes of less than 3 cm (N1) (X2 =6.58; p< 0.05). We found no statistically significant relationship with any other clinical or pathological parameters. The Cox univariate regression analysis verifies that the effect of the value of p21Waf1/CIP1 on survival was not statistically significant (p=0.6). The best predictive multivariate Cox analysis included the covariates: recurrence, p21Waf1/CIP1 , gender, stage, and dysplasia in the adjacent margin. All these variables showed a statistically significant relationship with survival, except p21Waf1/CIP1 . Conclusion: quantitative determination of p21Waf1/CIP1 standardizes and facilitates its analysis. Although its expression increases in patients with N1 regional metastasis, the loss of p21Waf1/CIP1 does not seem to have any relationship with the clinical and pathological variables of the tumors. Show more

Keywords: p21Waf1/CIP1, oral squamous cell carcinoma, cyclin-dependent kinases inhibitors, multivariate model of survival

DOI: 10.3233/CBM-140440

Citation: Cancer Biomarkers, vol. 15, no. 1, pp. 19-26, 2015

Authors: Wang, Ruixia | Zhu, Longbiao | Zhang, Yu | Miao, Limin | Ma, Hongxia | Yuan, Hua | Chen, Ning

Article Type: Research Article

Abstract: Background: A recent study synthesized several published genome-wide association studies (GWAS) on three types of cancers and identified variants at 6p21.1 and 7p15.3 as candidate susceptibility loci for multiple types of human cancers. However, the role of these loci in the development of head and neck cancer (HNC) is still unclear. Methods: To evaluate the relationships between genetic variants in these regions and HNC risk, we genotyped two common SNPs rs2494938 at 6p21.1 and rs2285947 at 7p15.3 in a case-control study with a total of 503 HNC cases and 900 controls in Han Chinese. Results: We …found that rs2494938 at 6p21.1 was associated with a significantly increased risk of HNC in our population [AA vs. GG: adjusted odds ratio (OR)=1.84, 95% confidence interval (CI)=1.13–3.00, P=0.014; AAvs.GA/GG: adjusted OR=1.78, 95% CI=1.10–2.87, P=0.018]. However, no significant association was observed between rs2285947 at 7p15.3 and HNC risk. Conclusion: Our results suggest that genetic variants at 6p21.1 may play an important role in HNC development in Han Chinese, and rs2494938 may be a candidate marker for HNC susceptibility. Show more

Keywords: Variants, head and neck cancer, risk, susceptibility

DOI: 10.3233/CBM-140442

Citation: Cancer Biomarkers, vol. 15, no. 1, pp. 27-32, 2015

Authors: Sun, Mei | Fang, Sheng | Li, Weiwei | Li, Chengqian | Wang, Luan | Wang, Fang | Wang, Yangang

Article Type: Research Article

Abstract: Background: Human miRNAs have emerged as potentially useful diagnostic and prognostic markers in cancer within the past decade. Abnormal expression of microRNA-146 (miR-146) has been found in several classes of cancers. Objective: To explore expression and clinical associations of miR-146a and miR-146b in papillary thyroid carcinoma. Methods: We investigated expressions of miR-146a and miR-146b in tissues and peripheral blood among 128 patients with primary PTC, 120 patients with nodular goiter and 120 healthy controls by RT-PCR. Furthermore, the associations between the miR-146a and miR-146b expression and clinical parameters of PTC were analyzed. Results: Levels …of miR-146a and miR-146b expression in PTC tissues were higher compared to the nodular goiter tissues (P=0.014 and 0.001) and perineoplastic thyroid tissues (P=0.023 and 0.002). Positive associations were found between levels of miR-146a expression in PTC tissues and gender (female), cervical lymph node metastasis, multifocality, extra tyroidal invasion and advanced clinical TNM stages (III and IV). For miR-146b, there were positive association between levels of miR-146b expression and female, extra tyroidal invasion and advanced clinical TNM stages. Conclusions: Up-regulation of miR-146a and miR-146b expression in tissues was related to carcinogenesis and deterioration of PTC. MicroRNA-146a and miR-146b expressed in thyroid tissue may act as potential biomarkers for PTC patients. Show more

Keywords: Papillary thyroid carcinoma, miR-146a, miR-146b, RT-PCR

DOI: 10.3233/CBM-140431

Citation: Cancer Biomarkers, vol. 15, no. 1, pp. 33-40, 2015

Authors: Zapatero, Almudena | Morente, Manuel | de Vidales, Carmen Martín | Adrados, Magdalena | Lopez, Consuelo | Nieto, Santiago | González, María Jesús Artiga | Arellano, Ramón | Conde, Alfonso Cruz | Vicente, Feliciano Garcia

Article Type: Research Article

Abstract: Purpose: To analyze the expression of hypoxia inducible factor 1 alpha (HIF1A) and its correlation with clinical outcome in men with localized prostate cancer (PC) treated with dose escalation radiotherapy (RT) and androgen deprivation (AD). Methods: Between 1996 and 2004, 129 PC patients who had diagnostic biopsies pre-treatment and 24–36 months following RT were enrolled in this study. Median follow-up was 129 months. Suitable archival diagnostic tissue was obtained from 86 patients. Correlation analysis was done to assess association between HIF1A expression and clinical outcome. Results: HIF1A expression was observed in 25/86 (29%) of diagnostic biopsies, …and in 5/14 (36%) of post-RT biopsies. No significant association was noted between HIF1A expression and clinical and treatment parameters. We also failed to show a significant correlation between HIF1A overexpression and outcome. A borderline significant relationship was observed between expression of HIF1A and overall survival (OS) (HR 0.03, p=0.08). Conclusion: To our knowledge this is the first study assessing the pattern of change of HIF1A staining in biopsies of patients prior and following treatment. While we did not find significant variations in the expression of HIF1A following radio-hormone therapy, a high HIF1A expression was unexpectedly associated with a borderline improved OS. Show more

Keywords: Prostate cancer, radiotherapy, androgen deprivation, molecular markers, HIF1A

DOI: 10.3233/CBM-140439

Citation: Cancer Biomarkers, vol. 15, no. 1, pp. 41-46, 2015

Authors: Shan, Liuqun | Ji, Qian | Cheng, Gongming | Xia, Jianguo | Liu, Delin | Wu, Changde | Zhu, Benlei | Ding, Yongbin

Article Type: Research Article

Abstract: Background: MicroRNA-21 (miR-21) is highly expressed in the plasma of colorectal cancer (CRC) patients. Thus, miR-21 may be a useful novel diagnostic biomarker for CRC. This meta-analysis aims to verify the diagnostic value of circulating miR-21 in CRC patients. Methods: A literature search was conducted for publications that evaluated the diagnostic value of miR-21 for CRC. The quality of each study was scored with the Quality Assessment of Diagnostic Accuracy Studies. The bivariate meta-analysis model was employed to summarize the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). Receiver operating characteristic …curves were used to check the overall test performance. Results: Five publications with six studies involving 579 patients and 266 controls were included in this meta-analysis. The pooled sensitivity was 77.4% [95% confidence interval (CI): 67.2%–85.1%], specificity was 84.6% (95% CI: 79.7%–88.5%), PLR was 5.02 (95% CI: 3.73–6.75), NLR was 0.27 (95% CI: 0.18–0.40), and DOR was 18.77 (95% CI: 10.41–33.83). The area under the summary ROC curve was 0.86. In addition, the results became prominent in the CRC group when a study that explored the advanced adenoma was excluded. Conclusion: Circulating miR-21 may be a suitable diagnostic biomarker for CRC with moderate sensitivity and specificity. Further studies should evaluate the diagnostic value of miR-21 for CRC in the future. Show more

Keywords: miR-21, circulating, colorectal cancer, diagnosis

DOI: 10.3233/CBM-140437

Citation: Cancer Biomarkers, vol. 15, no. 1, pp. 47-56, 2015

Authors: Xu, Liping | Tang, Wenru

Article Type: Research Article

Abstract: Background: Many studies have explored the associations between microRNAs (miRNAs) polymorphisms and lung cancer susceptibility. However, due to their limited statistical sizes, some discrepancies were discovered in these studies. This article summarized eligible studies to identify the roles of miRNAs polymorphisms in lung cancer, and analyzed the associations of polymorphisms in mir-196a2, mir-146a and mir-149 with lung cancer risk respectively. Methods: The PubMed, Web of Science, ScienceDirect and CNKI databases were searched updated to May 30, 2014. The complete data of three miRNAs polymorphisms for lung cancer were analyzed by odd ratios (ORs) and 95% confidence intervals (CIs). …Finally, four studies about mir-196a2 single nucleotide polymorphism (SNP), two studies about mir-146a SNP, three studies about mir-149 SNP were investigated in this analysis. Results: The mir-196a2 polymorphism was revealed to be associated with lung cancer susceptibility (additive model: OR=1.120, 95%CI 1.030 ∼ 1.217, P=0.008; dominant model: OR=1.118, 95%CI 1.039 ∼ 1.357, P=0.011; recessive model: OR=1.133, 95%CI 0.987 ∼ 1.300, P=0.077). However, no relationships were discovered between mir-146a or mir-149 polymorphism and lung cancer risk. Conclusions: This meta-analysis demonstrates that mir-196a2 SNP influences the susceptibility of lung cancer. Mir-146a and mir-149 SNP do not play a role in lung cancer risk. These findings need more validation by larger studies. Show more

Keywords: mir-196a2, mir-146a, mir-149, lung cancer, SNP

DOI: 10.3233/CBM-140433

Citation: Cancer Biomarkers, vol. 15, no. 1, pp. 57-63, 2015

Authors: Liu, Qingyun | Yu, Zubin | Xiang, Ying | Wu, Na | Wu, Long | Xu, Bin | Wang, Liang | Yang, Ping | Li, Yafei | Bai, Li

Article Type: Research Article

Abstract: Background: It remains controversial whether thymidylate synthase (TS) protein expression is associated with survival for patients with non-small cell lung cancer (NSCLC). Objective: To evaluate prognostic and predictive significance of tumor TS protein level in NSCLC. Methods: Electronic searches were performed for relevant studies in PubMed, EMBASE, Web of Science, and Chinese Biomedical Literature Database. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were pooled for meta-analysis. Subgroup and sensitivity analyses were performed. Publication bias was evaluated by funnel plot and Begg’s test. Results: Twenty-four studies, including 2280 patients, were eligible. …This analysis showed that patients with low TS expression had statistically significantly longer OS and PFS than those with high TS (HR=0.51 and HR=0.49, respectively). Based on TS-targeted drug use status, TS expression was significantly associated with OS in pemetrexed (HR=0.42) and 5-Fluorouracil subgroups (HR=0.34), but not in no TS-targeted drug subgroup. There were similar results for PFS analyses. Sensitivity analysis indicated that the results were robust. Begg’s test did not reveal any publication bias. Conclusion: Low TS protein expression is a favorable predictive factor for better OS/PFS in NSCLC patients treated with TS-targeted drugs. Prognostic value of TS protein expression needs further validation. Show more

Keywords: Non-small cell lung cancer, thymidylate synthase, prognosis, predictive factor

DOI: 10.3233/CBM-140432

Citation: Cancer Biomarkers, vol. 15, no. 1, pp. 65-78, 2015

Authors: Sonkin, Dmitriy | Palmer, Michael | Rong, Xianhui | Horrigan, Kim | Regnier, Catherine H. | Fanton, Christie | Holash, Jocelyn | Pinzon-Ortiz, Maria | Squires, Matthew | Sirulnik, Andres | Radimerski, Thomas | Schlegel, Robert | Morrissey, Michael | Cao, Z. Alexander

Article Type: Research Article

Abstract: Background: The JAK-STAT pathway is an important signaling pathway downstream of multiple cytokine and growth factor receptors. Dysregulated JAK-STAT signaling has been implicated in the pathogenesis of multiple human malignancies. Objective: Given this pivotal role of JAK-STAT dysregulation, it is important to identify patients with an overactive JAK-STAT pathway for possible treatment with JAK inhibitors. Methods: We developed a gene signature assay to detect overactive JAK-STAT signaling. The cancer cell line encyclopedia and associated gene-expression data were used to correlate the activation status of STAT5 with the induction of a set of STAT5 target genes. …Results: Four target genes were identified (PIM1, CISH, SOCS2, and ID1), the expression of which correlated significantly with pSTAT5 status in 40 hematologic tumor cell lines. In pSTAT5-positive models, the expression of the gene signature genes decreased following ruxolitinib treatment, which corresponded to pSTAT5 downmodulation. In pSTAT5-negative cell lines, neither pSTAT5 modulation nor a change in signature gene expression was observed following ruxolitinib treatment. Conclusions: The gene signature can potentially be used to stratify or enrich for patient populations with activated JAK-STAT5 signaling that might benefit from treatments targeting JAK-STAT signaling. Furthermore, the 4-gene signature is a predictor of the pharmacodynamic effects of ruxolitinib. Show more

Keywords: Ruxolitinib, JAK-STAT, pSTAT5, gene signature

DOI: 10.3233/CBM-140434

Citation: Cancer Biomarkers, vol. 15, no. 1, pp. 79-87, 2015