Cancer Biomarkers - Volume 15, issue 6

Authors: Cao, Xinguang | Zhao, Ruihua | Chen, Qiong | Zhao, Yuzhou | Zhang, Bin | Zhang, Yanzhen | Yu, Juan | Han, Guangsen | Cao, Wei | Li, Jiansheng | Chen, Xiaobing

Article Type: Research Article

Abstract: BACKGROUND: Recent studies have demonstrated that MALAT1 is involved in cancer metastasis and recurrence and it is up-regulated in cervical cancer, hepatocellular carcinoma, non-small cell lung cancer (NSCLC) and colorectal cancer. However, the role of MALAT1 in esophageal squamous cell carcinoma (ESCC) is still unclear. METHODS: The expression of MALAT1 was evaluated in cancer tissue and paired adjacent normal tissue samples from 77 middle thoracic ESCC patients who received radical surgical resection using QRT-PCR. The correlations between the expression levels of MALAT1 and clinical-pathological features and Patients' survival were also analysed. RESULTS: MALAT1 expression …was increased in ESCC tissue than in adjacent normal tissue samples (P< 0.001). MALAT1 level was positively related to pT stage (P= 0.01). Kaplan-Meier analysis showed high expression levels of MALAT1 ware correlated with poor prognosis in ESCC patients. Patients with a high level of MALAT1 had a shorter DFS and OS than those with low MALAT1 expression (P= 0.04 and 0.038, respectively). On Multivariate analysis, The HR of MALAT1 expression was 1.76 (95% CI = 0.97-3.21, P= 0.06) for DFS and 1.81 (95% CI = 0.97-3.41, P$=0.06) for OS. CONCLUSIONS: Our results showed that MALAT1 expression may serve as a predictive marker for middle thoracic ESCC patients who have been received radical resection. Show more

Keywords: Esophageal squamous cell carcinoma, long non-coding RNA, MALAT1

DOI: 10.3233/CBM-150513

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 717-723, 2015

Authors: Vlachostergios, Panagiotis J. | Oikonomou, Katerina G. | Gibilaro, Eugene | Apergis, George

Article Type: Research Article

Abstract: BACKGROUND: Hyperlactatemia with or without type B lactic acidosis is a rare complication of cancer, previously observed most often in hematological malignancies. The aim of this study was to assess the prognostic value of lactic acid (LA) in patients with metastatic lung cancer. METHODS: Patients diagnosed with stage IV non-small cell lung cancer (NSCLC) and extensive stage small cell lung cancer (SCLC), were included in this single center retrospective study. Arterial and venous LA level, anion gap (AG), serum LDH and presence of urine ketones were recorded for each patient and their associations with demographic and …clinical data and overall survival (OS) were examined. RESULTS: Eighty-five patients (43 males, median age 74, range 45-96 years) were studied. The maximal levels of arterial or venous LA were significantly associated with presence of ≥ 2 metastatic sites (p= 0.001), ICU admission or transfer (p= 0.016), intubation (p= 0.029), elevated serum anion gap (p< 0.001) and LDH levels (p< 0.001). Hyperlactatemia (≥ 1.4 mmol/L) was associated with shorter OS (log-rank p< 0.001). In a multivariate model including LA, ICU, intubation, AG as well as other known prognostic factors of NSCLC and SCLC, including age, sex, smoking status, number and location of metastases, histologic type, performance status (PS), chemotherapy and LDH, LA retained its prognostic value (OR: 1.3; 95%CI: 1.082-1.561; p= 0.005), along with PS (p= 0.039) and chemotherapy (p= 0.039). CONCLUSIONS: The results of the study suggest that a high lactic acid level (≥ 1.4 mmol/L) is associated with significantly shorter overall survival in patients with metastatic non-small cell lung cancer and extensive stage small cell lung cancer. Hyperlactatemia is an independent predictor of poor survival in metastatic lung cancer patients. Show more

Keywords: Lactic acid, prognosis, survival, lung cancer, lactate, tumor

DOI: 10.3233/CBM-150514

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 725-734, 2015

Authors: Liu, Chun | Yang, Zhulin | Li, Daiqiang | Liu, Ziru | Miao, Xiongying | Yang, Leping | Zou, Qiong | Yuan, Yuan

Article Type: Research Article

Abstract: BACKGROUND: Approximately 80% of patients with pancreatic ductal adenocarcinoma (PDAC) have metastatic disease with poor prognosis, but clinically available markers have not yet been identified. OBJECTIVE: In this study, we investigated the expression of B2M and ALK7 in 106 PDACs compared to precursor lesions of the pancreas. METHODS: Immunohistochemistry was used to detect B2M and ALK7 protein expression. RESULTS: Positive B2M expression was significantly higher, while positive expression of ALK7 was significantly lower in PDAC than in precursor lesions (p < 0.01 or p < 0.001). Positive B2M expression was also significantly …higher, while positive ALK7 expression was significantly lower in cases with well-differentiated adenocarcinoma, small tumor mass, no-metastasis of the lymph node, no-invasion of regional tissues, and TNM I or II stage disease than in cases having poorly-differentiated adenocarcinoma, large tumor mass, with metastasis and invasion, and TNM stage III or IV stage disease (p < 0.01). Univariate Kaplan-Meier analysis showed that B2M overexpression (p < 0.001), but lack of ALK7 expression (p < 0.001) was significantly associated with shorter overall survival. Cox multivariate analysis showed that differentiation, tumor mass, lymph node metastasis, invasion, TNM stage, and B2M levels negatively correlated with overall survival. In contrast, ALK7 level positively correlated with overall survival. Positive B2M and negative ALK7 expression are poor prognostic factors in PDAC patients. CONCLUSIONS: B2M and ALK7 might be important biological markers involved in the carcinogenesis, metastasis, invasion, and prognosis of PDAC. Show more

Keywords: Pancreatic ductal adenocarcinoma, immunohistochemistry, B2M, ALK7

DOI: 10.3233/CBM-150515

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 735-743, 2015

Authors: Rabi, Zaki Abu | Todorović-Raković, Nataša | Vujasinović, Tijana | Milovanović, Jelena | Nikolić-Vukosavljević, Dragica

Article Type: Research Article

Abstract: BACKGROUND: Cancer progression and metastasis are complex processes, dependent of molecules involved in inflammation, degradation and invasion. These molecules can be used as prognostic indicators to single out patients with higher risk of recurrence. Interleukin-8 (IL-8) has a role in inflammation, urokinase plasminogen activator (uPA), plasminogen activator inhibitor type-1 (PAI-1) and matrix metalloproteinase-2, -9 have a decisive part in the process of degradation and invasion, while vascular endothelial growth factor (VEGF) is consequential for angiogenesis. OBJECTIVES: Aim of our study is to determine relations between IL-8, uPA, PAI-1, MMP-2, -9, VEGF as their prognostic significance in …terms of recurrence free survival. METHODS: This study included 91 untreated patients with lymph node negative (N0) primary breast cancer. RESULTS: Patients with higher levels of uPA (p= 0.05), PAI-1 (0.05), MMP2 (p= 0.05) and IL-8 (p= 0.02) have a poor prognosis. Positive correlations were found between ER - PR, uPA - PAI-1, uPA - MMP9, PAI-1 - IL-8, MMP9 - IL-8, MMP9 - VEGF. Negative correlations were found between ER - IL-8, uPA - IL-8, MMP2 - VEGF. CONCLUSIONS: Higher concentrations of IL-8, uPA, PAI-1 and MMP2, as is MMP9 and VEGF, confirmed aggressive phenotype and poor prognosis in different subgroups. Show more

Keywords: Breast cancer, prognostic markers, progression, lymph node, interleukin 8, plasminogen activator, matrix metalloproteinase

DOI: 10.3233/CBM-150516

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 745-754, 2015

Authors: Shi, Zhi-Zhou | Shang, Li | Jiang, Yan-Yi | Shi, Feng | Xu, Xin | Wang, Ming-Rong | Hao, Jia-Jie

Article Type: Research Article

Abstract: BACKGROUND: At present no objective prognostic biomarkers have been established in esophageal squamous cell carcinoma (ESCC). OBJECTIVE: To identify the genomic biomarkers associated with clinicopathological factors and prognosis of ESCCs. METHODS: Real-time PCR was used to analyze the copy number change and mRNA expression of genes. The survival curves were plotted according to Kaplan-Meier method and checked by log-rank test. RESULTS: We revealed the copy number increase of CACNA1C (12p13.33) and MRPL21 (11q13.2) as well as decrease of VIPR2 (7q36.3) and MAP3K7 (6q15) in ESCC by Real-time PCR, and also found that …MRPL21 was significantly overexpressed and VIPR2 was underexpressed in ESCC. Gain of CACNA1C was significantly associated with differentiation (P = 0.043), and loss of VIPR2 was significantly linked with good prognosis (P = 0.016). Most importantly, we revealed that loss of MAP3K7 was significantly correlated with good prognosis in ESCC patients (n = 159, P = 0.004), especially in Grade II and pN0 patients (n = 76, P = 0.005 and n = 74, P = 0.024). Multivariate analysis confirmed that MAP3K7 loss provided prognostic information in ESCC (HR, 0.454; 95% CI: 0.208-0.995; P = 0.048). CONCLUSIONS: Loss of MAP3K7 may be a candidate prognostic factor in ESCC. Show more

Keywords: Esophageal squamous cell carcinoma, MAP3K7, prognosis, biomarker

DOI: 10.3233/CBM-150517

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 755-761, 2015

Authors: Maragh, Samantha | Veltri, Robert W. | Lund, Steven P. | Mangold, Leslie | Isharwal, Sumit | Christudass, Christhunesa S. | Partin, Alan W. | Humphreys, Elizabeth B. | Sorbara, Lynn | Srivastava, Sudhir | Wagner, Paul D.

Article Type: Research Article

Abstract: BACKGROUND: A 3.4kb deletion (3.4kbΔ ) in mitochondrial DNA (mtDNA) found in histologically normal prostate biopsy specimens has been reported to be a biomarker for the increased probability of prostate cancer. Increased mtDNA copy number is also reported as associated with cancer. OBJECTIVE: Independent evaluation of these two potential prostate cancer biomarkers using formalin-fixed paraffin-embedded (FFPE) prostate tissue and matched urine and serum from a high risk cohort of men with and without prostate cancer. METHODS: Biomarker levels were detected via qPCR. RESULTS: Both 3.4kbΔ and mtDNA levels were significantly higher …in cancer patient FFPE cores (p= 0.045 and p= 0.070 respectively at > 90% confidence). Urine from cancer patients contained significantly higher levels of mtDNA (p= 0.006, 64.3% sensitivity, 86.7% specificity). Combining the 3.4kbΔ and mtDNA gave better performance of detecting prostate cancer than either biomarker alone (FFPE 73.7% sensitivity, 65% specificity; urine 64.3% sensitivity, 100% specificity). In serum, there was no difference for any of the biomarkers. CONCLUSIONS: This is the first report on detecting the 3.4kbΔ in urine and evaluating mtDNA levels as a prostate cancer biomarker. A confirmation study with increased sample size and possibly with additional biomarkers would need to be conducted to corroborate and extend these observations. Show more

Keywords: Prostate, cancer, biomarker, mitochondrial DNA, 3.4kb deletion, urine, serum, FFPE, NIST, EDRN

DOI: 10.3233/CBM-150518

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 763-773, 2015

Authors: Krivokuca, Ana | Yanowski, Kira | Rakobradovic, Jelena | Benitez, Javier | Brankovic-Magic, Mirjana

Article Type: Research Article

Abstract: BACKGROUND: In 2010 an important finding was published showing that heterozygous mutations in RAD51C were highly penetrant and were able to confer an increased risk for breast and ovarian cancers. The role of possible third high penetrance breast cancer susceptibility gene was assigned to RAD51C . OBJECTIVE: Because of its rising importance in breast cancer development and the lack of information about RAD51C in Slavic populations, our goal was to identify potential population specific mutations in this gene in order to determine more detailed genetic screening strategy and breast cancer risk assessment. METHODS: …The study included 55 females from Serbian hereditary breast/ovarian cancer families negative for sequence alterations and large genomic rearrangements in BRCA1 /2 genes. Whole coding region and exon-intron boundaries of RAD51C were analyzed by dHPLC. All mutations were confirmed by Sanger sequencing. SIFT and Polyphen were used to predict possible impact of non-synonymous variants. RESULTS: We found 5 variants in RAD51C including two missense, one intronic, one in the 5'UTR and one variant in the promoter region of the gene. Three detected variants are common - c.1-118G>A (rs16943176, MAF = 0,203); c.1-26C>T (rs12946397, MAF = 0,207) and c.904+34T>C (rs28363318, MAF = 0,186). We detected two missense variants, c.790G>A (p.Gly264Ser) in exon 5 and c.859A>G (p.Thr287Ala) in exon 6. Both of them were previously shown to exhibit reduced protein function but their contribution to cancer risk is still unknown. CONCLUSIONS: Although the initial reports implied that RAD51C might be promising candidate for next high penetrance breast cancer susceptibility gene, lack of confirmation suggested that RAD51C mutations are not as common as expected. Our study did not reveal truncating mutations in RAD51C suggesting that other breast cancer susceptibility genes may account for the increased susceptibility in our cohort of high-risk BRCA1 /2 negative families. Show more

Keywords: RAD51C, hereditary breast/ovarian cancer, dHPLC, sequencing

DOI: 10.3233/CBM-150519

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 775-781, 2015

Authors: Bager, C.L. | Willumsen, N. | Leeming, D.J. | Smith, V. | Karsdal, M.A. | Dornan, D. | Bay-Jensen, A.C.

Article Type: Research Article

Abstract: BACKGROUND: During cancer the otherwise tightly controlled homeostasis of the extracellular matrix (ECM) is disturbed. The protein composition changes, the ECM stiffens and increased levels of proteases are secreted. The combination of these processes result in release of specific protein fragments (e.g. collagens) to the circulation, which when measured may reflect disease pathogenesis. OBJECTIVE: To investigate if biomarkers of protease-degraded collagen could differentiate ovarian and breast cancer patients from healthy controls when measured in serum. METHODS: The levels of markers reflecting MMP-degradation of type I (C1M), type III (C3M) and type IV (C4M, C4M12) …collagen were assessed in serum from ovarian cancer patients (n= 10), breast cancer patients (n= 14) and healthy controls (n= 49) using validated ELISAs. The markers were compared using one way ANOVA and AUC was calculated. RESULTS: All markers were significantly elevated in serum from ovarian cancer patients (p< 0.0001) and breast cancer patients (p< 0.04-0.0001) compared to healthy controls. Furthermore, diagnostically the markers were able to differentiate ovarian (AUROC 90%-93%) and breast cancer patients (AUROC 76%-93%) from healthy controls, with C1M being the strongest differentiator of disease vs. controls. CONCLUSION: Four serum biomarkers reflecting altered MMP-mediated collagen turnover were able to differentiate ovarian and breast cancer patients from healthy controls. Show more

Keywords: Cancer, extracellular matrix, collagen, biomarkers, breast cancer, ovarian cancer, matrix metalloproteinase, degradation, remodeling, tumor microenvironment

DOI: 10.3233/CBM-150520

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 783-788, 2015

Authors: Miyata, Yukinaga | Kumagai, Kenichi | Nagaoka, Tomoko | Kitaura, Kazutaka | Kaneda, Goro | Kanazawa, Hideki | Suzuki, Satsuki | Hamada, Yoshiki | Suzuki, Ryuji

Article Type: Research Article

Abstract: BACKGROUND: Colorectal cancer (CRC) is one of the most commonly diagnosed cancers, and novel effective treatments and diagnostic tools are urgently required. OBJECTIVE: The selection of appropriate targeting tumor-associated antigens (TAAs) is critical for immunotherapy. Therefore, we analyzed TAA expression levels and investigated their relationship with clinical factors in adjacent normal mucosa (ANM) and CRC tissue. METHODS: We obtained specimens of CRC primary tumors and matched ANM from 137 patients with CRC who underwent surgical resection. The mRNA levels of seven TAAs, Wilms' tumor gene (WT1 ), kinetochore associated-2 (KNTC2 ), cell division cycle …associated-1 (CDCA1) , M phase phosphoprotein-1 (MPHOSPH1 ), DEP domain-containing 1 (DEPDC1 ), 34-kDa translocase of the outer mitochondrial membrane (TOMM34 ) and ring finger protein-43 (RNF43 ), were analyzed using quantitative real-time reverse transcription-polymerase chain reaction, and their relationships with clinicopathological factors and the cell cycle were analyzed. RESULTS: The expression levels of all seven TAAs were significantly higher in CRC tissues than in ANM. Expression levels of WT1 in CRC tissues did not correlate with the cell cycle. Furthermore, WT1 expression in CRC tissues was significantly related to tumor progression, lymph node metastasis, distant metastasis and clinical stage. CONCLUSIONS: WT1 is a potential marker for prognosis and tumor progression in CRC. Show more

Keywords: Colorectal cancer, tumor-associated antigens, Wilms' tumor gene

DOI: 10.3233/CBM-150521

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 789-797, 2015

Authors: Wang, Xu-Liang | Wang, Yu-Yong | He, Hua-Dong | Xie, Xi | Yu, Zhi-Jian | Pan, Yu-Ming

Article Type: Research Article

Abstract: BACKGROUND: Adrenomedullin levels in the peripheral blood are associated with prognosis of some cancers. Intermedin is structural similarities to adrenomedullin. OBJECTIVE: The current study aimed to investigate the prognostic value of plasma intermedin levels for progression and distant metastasis in prostate cancers. METHODS: This study included 218 patients undergoing radical prostatectomy for localized prostatic cancer and 218 age-matched healthy men. Plasma intermedin levels were measured using radioimmunoassay. The relationships between plasma intermedin levels and 5-year progression and 5-year distant metastasis were evaluated using a multivariate analysis. RESULTS: Plasma intermedin levels were markedly …higher in all patients than in healthy men. Patients with Gleason score ≥ 7, tumor node metastasis stage T2, organ unconfined, present extra-prostatic extension, seminal vesicle invasion or positive lymph node had higher intermedin levels. Intermedin was identified as a prognostic predictor for 5-year progression and 5-year metastasis. Under receiver operating characteristic curves, intermedin had high predictive values for 5-year progression and 5-year metastasis. CONCLUSIONS: Elevated plasma intermedin levels are independently associated with long-term recurrence and distant metastasis of prostate cancer and intermedin has potential to be a prognostic predictive biomarker for prostate cancer. Show more

Keywords: Prostate cancer, recurrence, metastasis, intermedin

DOI: 10.3233/CBM-150523

Citation: Cancer Biomarkers, vol. 15, no. 6, pp. 799-805, 2015