Cancer Biomarkers - Volume 15, issue 3

Authors: Wang, Yuhan | Wang, Jie | Huang, Yuanshuai

Article Type: Review Article

Abstract: Head and neck cancers are the sixth most common cancer in the world and the predominant type of which consist of squamous cell carcinomas (head and neck squamous cell carcinoma, HNSCC). Besides tobacco smoking and alcohol consumption, human papilloma virus (HPV) infection is the third leading cause of the occurrence of HNSCC. The presence of HPV is a distinct group of head and neck cancers exhibiting epidemiological, histopathological, clinical and prognostic differences opposed to the typical HNSCC. HPV positive HNSCC normally have a favorable prognosis compared with HPV negative HNSCC, so biomarkers suitable for the early detection of HPV positive …HNSCC should be developed urgently to improve patient outcomes. HPV DNA screening is sensitive, but probably not useful because of the high prevalence of oral HPV and low risk of HNSCC. MicroRNAs (miRNAs) constitute a class of small non-coding RNAs that act as post-transcriptional regulators of gene expression. Since miRNAs have a role in the cancer development and HPV status may affect the miRNAs expression pattern in HNSCC, the specific of miRNAs' expression in HPV positive HNSCC may expound the role of HPV in HNSCC and be new biomarkers for the early detection of HNSCC. More excitingly, saliva as proximal biofluid in the context of HNSCC contains a good deal of miRNAs. These miRNAs are stabile and may be suitable for noninvasive biomarkers of HNSCC. Show more

Keywords: Head and neck cancers, microRNAs, human papilloma virus, biomarkers, saliva

DOI: 10.3233/CBM-150464

Citation: Cancer Biomarkers, vol. 15, no. 3, pp. 213-218, 2015

Authors: Zhao, Jun | Zhang, Yisheng | Zhao, Guohai

Article Type: Review Article

Abstract: Colorectal cancer (CRC) is one of the most common types of cancers worldwide. In spite of much progress in surgery, chemotherapy and molecular targeted therapy, the mortality rate has only decreased slightly over the past years. MicroRNAs are 18-25 nucleotide, noncoding RNA molecules that regulate the translation of many …genes. Evidence suggests that miRNAs may play an important role in a variety of cellular biological processes, such as cell growth, differentiation, metabolism, invasion, angiogenesis. Recently, miR-21 is found to be aberrantly expressed in CRC and miR-21 has been recognized to perform significantly in CRC, where miR-21 can regulate several different target genes and pathways involving tumor proliferation, invasion and metastasis. In this study, we will focus on the critical role of miR-21 in CRC. Hopefully, the information obtained may lead to a better understanding of the pathogenesis and development of novel therapeutic strategies for this disease. Show more

Keywords: microRNA-21, colorectal cancer, biomarker

DOI: 10.3233/CBM-150468

Citation: Cancer Biomarkers, vol. 15, no. 3, pp. 219-226, 2015

Authors: Naghibalhossaini, Fakhraddin | Mokarram, Pooneh | Khalili, Eslam | Naghibalhossaini, Samaneh

Article Type: Research Article

Abstract: OBJECTIVE: DNMT3B overexpression has been linked with the CpG island methylator phenotype in various cancers. Considering the role of the DNMT3b -149C/T promoter polymorphism on the gene expression, we evaluated the associations of this polymorphism with colorectal cancer (CRC) risk and hypermethylation of six tumor suppressor genes in CRC tumors. METHODS: The DNMT3b was genotyped by PCR-RFLP in 108 sporadic CRC patients and 185 healthy controls and methylation of genes' promoter was determined by methylation specific PCR. RESULTS: In comparison to controls, the TT genotype was strongly associated with a high …risk of cancer incidence (OR = 3.3, 95% CI = 1.6-6.9). The frequency of methylated hMLH1 was significantly higher in patients with the DNMT3b CT genotype (p= 0.03), especially in male subjects. The frequency of hMLH1 methylation was significantly higher in young patients (< 60 years) with the CT/TT genotypes. The combined CT/TT genotypes also showed significant associations with the ECAD methylation in the entire group of patients (p= 0.04), in patients with distal tumors, and in old cases. The DNMT3b genotype was not associated with methylation of other genes examined in this study. CONCLUSIONS: Our results suggest that DNMT3b polymorphism is involved in the development of colon cancer and non-random genes promoter methylation among Iranian population. Show more

Keywords: Colorectal cancer, methylation, DNMT3B, polymorphism, tumor suppressor genes

DOI: 10.3233/CBM-150463

Citation: Cancer Biomarkers, vol. 15, no. 3, pp. 227-233, 2015

Authors: Wei, Yuanxiu | Li, Li | Gao, Jian

Article Type: Research Article

Abstract: BACKGROUND: Accumulating evidence has demonstrated that single nucleotide polymorphisms (SNPs) in microRNAs (miR-146a rs2910164 and miR-196a2 rs11614913) might be connected with the risk of gastric cancer (GC). However, the studies are controversial and inconclusive. We performed this meta-analysis to assess the potential association between two SNPs and susceptibility to GC systematically and comprehensively. METHODS: Through a systematic literature search, eight case-control studies for rs2910164 and seven case-control studies for rs11614913 were identified and included in this meta-analysis. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to investigate the association between the two …SNPs and the GC risk. Additionally, a subgroup analysis and a publication bias test were performed. RESULTS: Our results showed that the only significant association between the miR-146a rs2910164 polymorphism and susceptibility to gastric cancer was found in the heterozygous model (OR = 0.884, 95% CI: 0.795-0.983, Ph = 0.326, P = 0.022). Similarly, when stratified by ethnicity, there was an obvious correlation in the heterozygous model (OR = 0.734, 95% CI: 0.542-0.993, Ph = 0.441, P = 0.045) in Caucasians but not in Asians. For miR-196a2, this meta-analysis suggested that neither the allele frequency nor the genotype distribution of the polymorphism was associated with GC risk in the five genetic models. Similarly, the subgroup analysis by ethnicity showed no association with susceptibility to GC. CONCLUSION: Our studies suggested that the miR-146a rs2910164 polymorphism might marginally contribute to a decreased risk of gastric cancer, especially in Caucasians, whereas the miR-196a2 rs11614913 polymorphism might not be associated with susceptibility to GC. Show more

Keywords: MicroRNA, miR-146a, rs2910164, miR-196a2, rs11614913, single-nucleotide polymorphism, gastric cancer, meta-analysis

DOI: 10.3233/CBM-150470

Citation: Cancer Biomarkers, vol. 15, no. 3, pp. 235-248, 2015

Authors: Gu, Wei | Gao, Tian | Sun, Ying | Zheng, Xiong | Wang, Ji | Ma, Jin | Hu, Xiaoying | Li, Jian | Hu, Meijie

Article Type: Research Article

Abstract: Gastric cancer ranks the second highest death rate and is the highest morbidity digestive system malignancy in China. Few reports have elucidated the role of long non-coding RNAs (lncRNAs) in the gastric cancer pathogenesis. The present study was aimed to identify aberrantly expressed lncRNAs involved in the progression of gastric cancer and explored their potential functions. A total of 1,297 lncRNAs and 2,037 mRNAs that showed significantly differential expression level between gastric tumor samples and matched adjacent normal tissues were identified in six pairs of samples using microarray assay. To further explore their functions, lncRNAs were classified into different subgroups …and mRNAs were clustered into several pathways. The expression level of 4 lncRNAs: UCA1, lincRNA-BBOX1-2, CR594506 and BC015134 were further confirmed in another cohort of 10 gastric patients by real-time PCR assay. A coding-non-coding co-expression network revealed that the four validated lncRNAs were correlated with twenty-six mRNAs which gave clues about the potential roles of these lncRNAs in the process of gastric cancer progression. Show more

Keywords: Gastric cancer, long non-coding RNA, expression profile, UCA1

DOI: 10.3233/CBM-150460

Citation: Cancer Biomarkers, vol. 15, no. 3, pp. 249-258, 2015

Authors: Xie, Xing-Ming | Deng, Jing-Yu | Hou, Ya-Chao | Cui, Jing-Li | Wu, Wei-Peng | Ying, Guo-Guang | Dong, Qiu-Ping | Hao, Xi-Shan | Liang, Han

Article Type: Research Article

Abstract: BACKGROUND: E3 ubiquitin ligase Ring finger protein 180 (RNF180) has been identified as a novel tumor suppressor in gastric cancer and the methylated CpG site count of RNF180 DNA promoter can predict the prognosis for gastric cancer patients. OBJECTIVE: In the previous study, we demonstrated that methylated CpG site count of RNF180 DNA promoter was significantly associated with the survival of patients with gastric cancer using the bisulfite genomic sequencing (BGS) in the gastric cancer tissue with five clones per sample. It was so complicate for each patient underwent the BGS detection with clones. It is …important to explore a simple, rapid and accurate method to detect methylated CpG site count to predicting the prognosis for gastric cancer patients. METHODS: At present study, we detected hypermethylated and hypomethylated CpG site count of RNF180 DNA promoter in samples of 480 gastric cancer patients by direct bisulfite sequencing. RESULTS: We found that patients who possessed seven or less hypermethylated CpG sites of RNF180 DNA promoter had much better survival (p= 0.008), which was similar to our previous research results by using the BGS with clones. With the multivariate survival analysis, we found that T stage, N stage and hypermethylated CpG site count of RNF180 DNA promoter were the independent predictors of prognosis for gastric cancer patients. CONCLUSIONS: hypermethylated CpG site count of RNF180 DNA promoter for evaluating the prognosis of gastric cancer was reasonable by using the direct bisulfite sequencing. Show more

Keywords: Ring finger protein 180, methylation, direct bisulfite genomic sequencing, prognosis, gastric cancer

DOI: 10.3233/CBM-150466

Citation: Cancer Biomarkers, vol. 15, no. 3, pp. 259-265, 2015

Authors: Han, Bin | Xie, Ruifei | Wu, Shixiu | Li, Lihua | Zhu, Lei

Article Type: Research Article

Abstract: Variation in the expression of genes arises from a variety of sources. It is important to remove sources of variation between arrays of non-biological origin. Non-biological variation, caused by lurking confounding factors, usually attracts little attention, although it may substantially influence the expression profile of genes. In this study, we proposed a method which is able to identify the potential confounding factors and highlight the non-biological variations. We also developed methods and statistical tests to study the confounding factors and their influence on the homogeneity of microarray data, gene selection, and disease classification. We explored an ovarian cancer gene expression …profile and showed that data batches and arraying conditions are two confounding factors. Their influence on the homogeneity of data, gene selection, and disease classification are statistically analyzed. Experiments showed that after normalization, their influences were removed. Comparative studies further showed that the data became more homogeneous and the classification quality was improved. This research demonstrated that identifying and reducing the impact of confounding factors is paramount in making sense of gene-disease association analysis. Show more

Keywords: Microarray, confounding factors, obscuring variation, gene-disease association analysis

DOI: 10.3233/CBM-150462

Citation: Cancer Biomarkers, vol. 15, no. 3, pp. 267-280, 2015

Authors: Goufman, Eugene I. | Iakovlev, Vasily N. | Tikhonova, Natalia B. | Lokshin, Anna E.

Article Type: Research Article

Abstract: BACKGROUND: The investigation of autoantibodies which may play a role in the processes of angiogenesis and tumorogenesis is important in the early diagnostis of cancer. OBJECTIVE: This study aimed to investigate the levels of autoantibodies to Glu-plasminogen (Pg) in plasma of patients with tumors. METHODS: Plasma samples from healthy volunteers were compared with samples from patients with prostate cancer using 2D electrophoresis and MALDI-TOF mass spectrometry. Plasma samples from 25 patients with prostate cancer, 15 patients with benign prostatic hyperplasia (BPH), 29 patients with breast cancer, and 43 healthy volunteers were tested using ELISA …to anti-Pg IgG autoantibodies. Affinity chromatography on Pg-sepharoses was used to assess the quantity of anti-Pg IgG in control plasma and plasma of prostate cancer patients. ATTESTAT program was used for nonparametric analysis. RESULTS: Using 2D electrophoresis, marker spots below 50 kD were detected in prostate cancer samples. These spots were identified as fragments of Pg and IgG. Using affinity chromatography on Pg-sepharose, the quantity of IgG bound to Pg versus total IgG was determined to be 9% in control and 27% in prostate cancer samples. The frequency of occurence of elevated levels of anti-Pg IgG was 84% in prostate cancer samples, 69% in breast cancer samples, 40% in BPH samples, and 11% in healthy plasma. CONCLUSIONS: Autoantibodies to Pg may be involved in tumorogenesis and elevated levels of anti-Pg IgG antibodies may be a risk factor for tumor development. Show more

Keywords: Plasminogen, autoantibodies to Pg, cancer, ELISA, biomarkers

DOI: 10.3233/CBM-150469

Citation: Cancer Biomarkers, vol. 15, no. 3, pp. 281-287, 2015

Authors: Han, Li | Guo, Xiaojuan | Bian, Hua | Zhou, Yubing | Li, Ting | Yang, Jingke

Article Type: Research Article

Abstract: BACKGROUND: Multi-drug resistance (MDR) remains to be a major obstacle toward successful chemotherapy of NHL patients. P-glycoprotein (P-gp), a classical protein associated with MDR, has been observed in peripheral blood CD56 + cells with high expression and activity. While the CD56 expression has been shown to …be associated with a highly aggressive clinical course and chemoresistance in Non-Hodgkin lymphoma (NHL). OBJECTIVE: To investigate the role of peripheral blood CD56 + cells in predicting the MDR of NHL by determining the P-gp expression and function of the CD56 + cells. METHODS: The expression levels of MDR1 mRNA and MRP1 mRNA and the function of P-gp in the CD56 + cells were evaluated by RT-qPCR and flow cytometry respectively in 52 chemoresistant and 47 chemosensitive NHL patients and 48 healthy donors. RESULTS: In the chemoresistant group, the mRNA expression level of MDR1 elevated about 2∼ 8 fold (mean = 4.24 ± 0.17) in the purified CD56^+ cells, whereas there was only about 1∼ 2.5 fold (mean = 1.69 ± 0.41) elevated for the MRP1 gene. The mean fold change of MDR1 mRNA expression in the chemoresistant group significantly increased when compared with that in the chemosensitive patients (P < 0.001). The mean fluorescence intensities (MFI) in the total gated CD56^{ + } and Rho123 double positive cells in the chemoresistant patients statistically decreased compared with that in the healthy controls and the chemosensitive NHL patients (P < 0.01). CONCLUSIONS: Determining the P-gp expression and function of the peripheral blood CD56^{ + } cells may help predict the MDR of NHL, thus has profound guiding significance for NHL treatment. Show more

Keywords: Non-Hodgkin lymphoma, multi-drug resistance, P-glycoprotein, CD56 + cells

DOI: 10.3233/CBM-150467

Citation: Cancer Biomarkers, vol. 15, no. 3, pp. 289-297, 2015

Authors: Luna-Aguirre, Claudia Maribel | de la Luz Martinez-Fierro, Margarita | Mar-Aguilar, Fermín | Garza-Veloz, Idalia | Treviño-Alvarado, Víctor | Rojas-Martinez, Augusto | Jaime-Perez, Jose Carlos | Malagon-Santiago, Guadalupe Ismael | Gutierrez-Aguirre, Cesar Homero | Gonzalez-Llano, Oscar | Salazar-Riojas, Rosario | Hidalgo-Miranda, Alfredo | Martinez-Rodriguez, Herminia Guadalupe | Gomez-Almaguer, David | Ortiz-Lopez, Rocio

Article Type: Research Article

Abstract: BACKGROUND: Acute lymphoblastic leukemia (ALL) is a highly diverse disease characterized by cytogenetic and molecular abnormalities, including altered microRNA (miRNA) expression signatures. AIM: We perform and validate a plasma miRNA expression profiling to identify potential miRNA involved in leukemogenesis METHODS: MiRNA expression profiling assay was realized in 39 B-ALL and 7 normal control plasma samples using TaqMan Low Density Array (TLDA) plates on Applied Biosystems 7900 HT Fast Real-Time PCR System. MiRNA validation was done for six miRNA differentially expressed by quantitative real-time PCR. RESULTS: Seventy-seven circulating miRNA differentially expressed: hsa-miR-511, -222, …and -34a were overexpressed, whereas hsa-miR-199a-3p, -223, -221, and -26a were underexpressed (p values < 0.005 for both sets). According to operating characteristic curve analysis, hsa-miR-511 was the most valuable biomarker for distinguishing B-ALL from normal controls, with an area under curve value of 1 and 100% for sensitivity, and specificity respectively. CONCLUSIONS: Measuring circulating levels of specific miRNA implicated in regulation of cell differentiation and/or cell proliferation such as hsa-miRNA-511, offers high sensitivity and specificity in B-ALL detection and may be potentially useful for detection of disease progression, as indicator of therapeutic response, and in the assessment of biological and/or therapeutic targets for patients with B-ALL. Show more

Keywords: Biomarkers, hematological malignancies, qRT-PCR, signaling pathway

DOI: 10.3233/CBM-150465

Citation: Cancer Biomarkers, vol. 15, no. 3, pp. 299-310, 2015

Authors: Tsaur, Igor | Hennenlotter, Joerg | Oppermann, Elsie | Munz, Marita | Kuehs, Ursula | Stenzl, Arnulf | Schilling, David

Article Type: Research Article

Abstract: BACKGROUND: Extent of pelvic lymph node (LN) dissemination is a critical prognostic feature for patients with prostate cancer (PCa) maintaining extended pelvic lymphadenectomy (LAD) as the gold standard for LN-staging. Unfortunately, conventional histopathological assessment may miss micrometastasis and recently presented immunocytochemical approach of the single cell analysis is still intricate. OBJECTIVE: To comparatively assess the potential of Prostate cancer gene 3 (PCA3) and prostate specific antigene (PSA) to perform as markers for tumor cell load. METHODS: Patients with high risk PCa for LN metastasis undergoing either a sentinel LN-guided staging LAD or retropubic radical …prostatectomy with sentinel-guided pelvic LN dissection were included. LNs were investigated by routine histopathology. Tumor cell load was quantified by %immunocytochemistry. immunocytochemical single cell analysis. Gene activity was determined by qRT-PCR. RESULTS: Twenty four out of 226 LNs were positive in routine histopathology and 51 in single cell analysis. PSA mRNA level correlated with tumor cell density in patients with a positive immunocytochemistry. Gene activity of PCA3 was upregulated in metastatic LNs and correlated with tumor cell density in patients with tumor-invaded LNs as detected by immunocytochemistry. CONCLUSIONS: PCA3 gene expression discriminates LN metastasis and might outperform PSA gene activity in reflecting tumor cell burden in pelvic LNs of PCa patients. Show more

Keywords: Prostate cancer, lymph node metastases, molecular marker, tumor cell load, PSA, PCA3

DOI: 10.3233/CBM-150461

Citation: Cancer Biomarkers, vol. 15, no. 3, pp. 311-316, 2015

Authors: Kaynar, Mehmet | Yildirim, Mehmet Erol | Gul, Murat | Kilic, Ozcan | Ceylan, Kadir | Goktas, Serdar

Article Type: Research Article

Abstract: BACKGROUND: The aim of the current study is to evaluate NLR and PLR inflammation markers in PCa and BPH. METHODS: Clinical and pathological data such as age, prostate volume, PSA, NLR, and PLR levels of 201 patients were retrospectively reviewed. Pathological sample results of these patients were categorized either as benign or malign. The benign group consisted of chronic prostatitis and BPH and the malign group of PCa. The PSA levels were divided into three categories as PSA: 0-4 ng/ml, PSA: 4-10 ng/ml, and 10 ng/ml and above. RESULTS: In the benign …category, the mean PLR values for PSA: 0-4 ng/ml is 131.8 ± 31.2, for PSA: 4-10 ng/ml 124.7 ± 83.9 and 10 ng/ml and above 124 ± 53 in chronic prostatitis group and in the BPH group for PSA: 4-10 ng/ml 120.3 ± 45.1, for PSA: 4-10 ng/ml 126 ± 54.2, and 10 ng/ml and above 191.4 ± 176.1. In the malign category, the mean PLR values of PCa patients is for PSA: 0-4 ng/ml 122.8 ± 43.8, for PSA: 4-10 ng/ml 123 ± 43.8, and above 10 ng/ml 179.1 ± 94. Related to the variables of age, NLR, and mean prostate volume, there were no statistically significant differences. Statistically significant differences were observed in the mean PLR values only if the PSA level was 10 ng/ml and above (p: 0.044) in the BPH and PCa groups. The correlation of the PCa Gleason score and PSA, NLR and PLR parameters in the malign category revealed no statistically significant differences (P > 0.05). CONCLUSION: Effective malign and benign differentiation of prostate pathologies based on noninvasive inflammation biomarkers such NLR and PLR necessitate clinical studies with larger patient series. Show more

Keywords: Benign prostatic hyperplasia, prostate cancer, platelet to lymphocyte ratio

DOI: 10.3233/CBM-150458

Citation: Cancer Biomarkers, vol. 15, no. 3, pp. 317-323, 2015

Authors: Zhou, Jun | Xie, Ming | He, Hanjiang | Shi, Ying | Luo, Baihua | Gong, Guanghui | Li, Juanni | Wang, Junpu | Wu, Xiaoying | Wen, Jifang

Article Type: Research Article

Abstract: BACKGROUND: Serous epithelial ovarian cancer is the most common variety of ovarian cancer and is currently diagnosed using serum CA-125 levels. HMGA1 a small 10.6-12 kDa protein, has been implicated as a potentially important tumor biomarker and may enter the urinary trace, thus potentially able to serve as a disease biomarker. OBJECTIVE: To determine if urine HMGA1 can be detected and potentially serve as a clinical diagnostic biomarkers. METHOD: Urine was collected from 20 healthy normal control patients, 20 patients with benign gynecological disease and 55 epithelial ovarian specimens of which 20 exhibited G1/2 …ovarian cancer and 35 G3 ovarian cancers. Serum was also collected from 20 healthy normal control patients and 55 serous epithelial ovarian cancers patients. HMGA1 levels were examined via enzyme-linked immunosorbent assay (ELISA) and were reported independently and normalized to urine creatinine levels. Serum CA-125 levels were examined via enzyme assay and the data was analyzed via box and ROC analysis. RESULTS: Urine HMGA1 was significantly elevated in serous epithelial ovarian cancer specimen relative to healthy control specimens with G3 specimens exhibiting higher levels than G1-G2 specimens. ROC analysis revealed a high degree of sensitivity and specificity for urine HMGA1 detection in ovarian cancer, with a higher AUC value noted for urine HMGA1 than serum CA-125. Furthermore, urine HMGA1 and serum CA-125 combined AUC indicated that urine HMGA1 is an excellent diagnostic biomarker for serous epithelial ovarian cancer. CONCLUSION: Our data indicates that measuring urine HMGA1 may serve as a useful diagnostic tool. Show more

Keywords: HMGA1, urine, biomarker, epithelial ovarian cancer, noninvasive

DOI: 10.3233/CBM-150457

Citation: Cancer Biomarkers, vol. 15, no. 3, pp. 325-331, 2015

Authors: Choi, Sung Hyouk | Jang, Ki Seok | Chung, Min Sung

Article Type: Research Article

Abstract: Idiopathic granulomatous mastitis (IGM) and Tuberculosis mastitis (TM) are rare inflammatory diseases of the breast that can clinically mimic malignancy causing misdiagnosis as breast cancer. We present a rare case of bilateral granulomatous mastitis with a different etiology. An initial lesion developed in the right breast was diagnosed as IGM, which was treated with antibiotics and surgery. A subsequent lesion developed in the contralateral breast 5 months later and was diagnosed as TM, which also completely responded to antituberculosis medication without surgical excision. Differential diagnosis was made using the results of the polymerase chain reaction for tuberculosis (TBC-PCR) of both …of the breast lesions in addition to typical pathologic findings of IGM in the right breast and an antituberculosis medication response in the left breast. To the best of our knowledge, this is the first case of bilateral granulomatous mastitis with a different etiology. Show more

Keywords: Granulomatous mastitis, tuberculosis mastitis, idiopathic granulomatous mastitis

DOI: 10.3233/CBM-140447

Citation: Cancer Biomarkers, vol. 15, no. 3, pp. 333-338, 2015