Cancer Biomarkers - Volume 13, issue 4

Authors: Mitra, Sanga | Das, Smarajit | Chakrabarti, Jayprokas

Article Type: Review Article

Abstract: Cancer systems-biology is an ever-growing area of research due to explosion of data; how to mine these data and extract useful information is the problem. To have an insight on carcinogenesis one need to systematically mine several resources, such as databases, microarray and next-generation sequences. This review encompasses management and analysis of cancer data, databases construction and data deposition, whole transcriptome and genome comparison, analysing results from high throughput experiments to uncover cellular pathways and molecular interactions, and the design of effective algorithms to identify potential biomarkers. Recent technical advances such as ChIP-on-chip, ChIP-seq and RNA-seq can be applied to …get epigenetic information transformed into a high-throughput endeavour to which systems biology and bioinformatics are making significant inroads. The data from ENCODE and GENCODE projects available through UCSC genome browser can be considered as benchmark for comparison and meta-analysis. A pipeline for integrating next generation sequencing data, microarray data, and putting them together with the existing database is discussed. The understanding of cancer genomics is changing the way we approach cancer diagnosis and treatment. To give a better understanding of utilizing available resources' we have chosen oral cancer to show how and what kind of analysis can be done. This review is a computational genomic primer that provides a bird's eye view of computational and bioinformatics' tools currently available to perform integrated genomic and system biology analyses of several carcinoma. Show more

Keywords: Cancer, database, microarray, next generation sequencing, system biology

DOI: 10.3233/CBM-130363

Citation: Cancer Biomarkers, vol. 13, no. 4, pp. 201-213, 2013

Authors: Xu, Ruobing | Wang, Fengliang | Wu, Liang | Wang, Jianming | Lu, Cheng

Article Type: Research Article

Abstract: Background: Inactivation of cell-cycle regulating gene p16, resulting from epigenetic alteration, is common in the carcinogenesis of human cancers. The aim of this study is to offer a systematic review on the aberrant methylation of p16 gene in esophageal cancer. Methods: We performed a meta-analysis referring to the guidelines of PRISMA. We searched for articles published from 1996 to 31 May 2012 using PubMed and China National Knowledge Infrastructure (CNKI) database. Additional database including Web of Science and EMBASE were also searched for related articles. The random or fixed effect model was applied to estimate the pooled frequency …of DNA methylation based on the heterogeneity analysis. Subgroup analyses were performed according to the histological type, study area, and tumor grade. Results: This meta-analysis included 39 articles related to the methylation studies on p16 gene in cancer tissues and 7 articles using blood samples. The summarized frequency of DNA methylation detected in cancer tissues was 0.53 (95% CI: 0.44–0.61). With the increase of tumor differentiation grades, the frequency of DNA methylation increased accordingly (well differentiated: 0.37; moderately differentiated: 0.61; poorly differentiated: 0.63). We further summarized the methylation of p16 gene detected in patient’s peripheral blood samples. The pooled frequency was 0.33 (95% CI: 0.17–0.49), which was lower than that detected in cancer tissues. Conclusion: This meta-analysis revealed the elevated frequency of DNA methylation of p16 gene in esophageal cancer, which indicated future potential application of this biomarker in early detection as well as the prognosis of the disease. Show more

Keywords: Genes, p16, methylation, esophageal neoplasms, meta-analysis

DOI: 10.3233/CBM-130355

Citation: Cancer Biomarkers, vol. 13, no. 4, pp. 215-226, 2013

Authors: Gallotta, Andrea | Ziglioli, Francesco | Ferretti, Stefania | Maestroni, Umberto | Moretti, Matteo | Aloe, Rosalia | Gnocchi, Cecilia | Di Palo, Mariella | Fassina, Giorgio

Article Type: Research Article

Abstract: Background: Prostate cancer (PCa) represents the most common solid tumor affecting men and its early detection remains the best approach to improve survival rates. The assessment of serum levels of PSA is currently used for PCa screening but the low specificity of the test results in a high number of false positives. Other forms of PSA may be detected in the bloodstream including PSA associated with immunoglobulin M (PSA-IgM) which, alone or combined with PSA, has shown diagnostic accuracy for PCa. Objectives: The aim of the study is to improve the diagnostic accuracy of PSA-IgM by developing a …multivariable model which includes serum biomarkers and routine diagnostic parameters to obtain a predictive index useful in the post-screening clinical practice. Patients and Methods: One hundred sixty male patients with clinical suspect of PCa underwent a trans-rectal ultrasound guided first prostate biopsy with a standardized sampling scheme. To generate the model, we assessed the presence of PSA and PSA-IgM complexes in sera of patients and the prostate volume of each patient. A novel predictive probability for PCa (iXip) was obtained combining non-overlapping biomarkers normalized with diagnostic parameters. Results: The study population included 49 patients with PCa diagnosed at biopsy and 111 controls in which prostate biopsy showed the presence of benign prostatic hyperplasia, inflammation, atypical small acinar proliferation or high-grade prostatic intraepithelial neoplasia. The iXip values for patients with PCa (mean ± SD=0.467 ± 0.160) were significantly higher (p-value < 0.001) than control subjects (mean ± SD=0.314 ± 0.098) and the iXip AUC (0.787) was significantly greater (p-value < 0.001) than the AUCs of each biomarker. Conclusions: iXip shows a significant increase in diagnostic performance compared to PSA and PSA-IgM and its post-screening use may facilitate decision-making in recommending for biopsy clinically suspected patients. Show more

Keywords: Benign prostatic hyperplasia, biomarker combination, biopsy, predictive probability, prostate cancer, PSA-IgM

DOI: 10.3233/CBM-130357

Citation: Cancer Biomarkers, vol. 13, no. 4, pp. 227-234, 2013

Authors: Martinez-Fierro, M.L. | Garza-Veloz, I. | Rojas-Martinez, A. | Ortiz-Lopez, R. | Castruita-de la Rosa, C. | Ortiz-Castro, Y. | Lazalde-Ramos, B.P. | Cervantes-Villagrana, A.R. | Castañeda-Lopez, M.E. | Gomez-Guerra, L. | Delgado-Enciso, I. | Martinez-Torres, A.A.

Article Type: Research Article

Abstract: Background: Vascular endothelial growth factor (VEGF) gene is an important angiogenesis regulator related to cancer development and progression. We evaluated the association between -2578 C/A (rs699947) VEGF polymorphism and PCa in Mexican subjects, to contribute to knowledge of VEGF role in genetic epidemiology of prostate cancer (PCa). Objective: The aim of this study was to evaluate the association between -2578 C/A VEGF variant and PCa in Mexican population. Methods: A total of 249 men (77 PCa cases and 172 controls) from the Northwestern region of Mexico were screened for the -2578 C/A VEGF variant. The polymorphism …was determined by polymerase chain reaction-based restriction analysis. Results: Genotype frequencies for C/C, C/A, and A/A, were 0.48, 0.49, 0.03 for cases and 0.41, 0.45, 0.14 for controls respectively. Genotype A/A of -2578 VEGF variant reduces the risk of PCa in an 84% among studied population (Odds Ratio 0.16; 95% CI: 0.04–0.71, P=0.007). C/C carriers showed an increased PCa risk of 6.1 times among the study population. Conclusions: Inheritance of -2578 A/A genotype of VEGF gene may modify PCa susceptibility risk in Mexican population. Show more

Keywords: Prostate cancer, VEGF, polymorphism, genetic susceptibility

DOI: 10.3233/CBM-130348

Citation: Cancer Biomarkers, vol. 13, no. 4, pp. 235-241, 2013

Authors: Sharma, Tusha | Jain, Smita | Verma, Ankur | Sharma, Nivedita | Gupta, Sanjay | Arora, Vinod Kumar | Dev Banerjee, Basu

Article Type: Research Article

Abstract: Urinary bladder cancer (UBC) is a common disease worldwide with a higher incidence rate in developed countries. Organochlorine pesticides (OCPs), potent endocrine disrupters, are found to be associated with several cancers such as prostate, breast, bladder, etc. Glutathione S-transferase (GST) is a polymorphic supergene family involved in the detoxification of numerous environmental toxins including OCPs. The present study was carried out in UBC subjects (n=50) and healthy control subjects (n=50) with an aim to determine the role of GSTM1 and GSTT1 polymorphism and its implication on the OCP detoxification or bioaccumulation which may increase the risk of UBC in humans. …This study was also designed to identify the “gene-environment interaction” specifically between gene polymorphism in xenobiotic metabolizing genetic enzyme(s) and blood OCP levels. GSTM1/GSTT1 gene polymorphism was analysed by using multiplex PCR. OCPs levels in whole blood were estimated by Gas chromatography equipped with electron capture detector. The results demonstrated a significant (p< 0.05) increase in frequency of GSTM1- /GSTT1- (null) genotype in UBC cases without interfering the distribution of other GSTT1/GSTM1 genotypes. The blood levels of alpha (α), Beta (β), Gamma (γ), total – Hexachlorcyclohexane (HCH) and para-para – dichlorodiphenyltrichloroetane (p,p'-DDT) were found to be significantly (p< 0.05) high in UBC cases as compared to controls. Multiple regression analysis revealed a significant interaction between β-HCH and GSTM1- genotype (p< 0.05) as well as in β-HCH and GSTT1- genotype (p< 0.05) respectively. These findings indicate that “gene-environment interaction” may play a key role in increasing the risk for UBC in individuals who are genetically more susceptible due to presence of GSTM1/GSTT1 null deletion during their routine encounter with or exposure to OCPs. Show more

Keywords: Gene environment interaction, urinary bladder cancer, Organochlorine pesticides, polymorphism, risk assessment, environmental toxins

DOI: 10.3233/CBM-130346

Citation: Cancer Biomarkers, vol. 13, no. 4, pp. 243-251, 2013

Authors: Eskandari-Nasab, Ebrahim | Hashemi, Mohammad | Hasani, Seyed-Shahaboddin | Omrani, Mohsen | Taheri, Mohsen | Mashhadi, Mohammad-Ali

Article Type: Research Article

Abstract: Human leukocyte antigen G (HLA-G) is a non-classic major histocompatibility complex (MHC) class I molecule that is highly expressed in cancer pathologies. A 14-bp insertion/deletion polymorphism in exon 8 of the 3' untranslated region (3'-UTR) of the HLA-G gene has been suggested to be associated with HLA-G mRNA stability and the expression of HLA-G. This study aimed to evaluate the association of 14-bp ins/del polymorphism in HLA-G gene and breast cancer in a south-east Iranian population. This study was performed using 236 patients with breast cancer and 203 healthy subjects. We designed a rapid and simple bi-directional PCR allele-specific amplification …(Bi-PASA) for detection of 14-bp ins/del polymorphism in the HLA-G gene. The results of our study revealed that the prevalence of HLA-G 14-bp homozygote deletion genotype was higher in breast cancer patients than in the control group (OR=2.06, 95%CI=1.23–3.44, P=0.006). The frequency of the Del allele was 56.4% in breast cancer patients and 46.5% in the control group and the difference was statistically significant (OR=1.48, 95%CI=1.13–1.94, P=0.004). Moreover we evaluated the possible correlation of the HLA-G 14-bp ins/del genotypes and clinical characteristics of the patients, but no statistically significant correlation was found (P> 0.05). Our findings, for the first time, suggest that the 14-bp insertion/deletion polymorphism in HLA-G gene could be a genetic risk factor for the susceptibility to breast carcinoma. Further studies on larger populations with different ethnicities are required to verify our findings. Show more

Keywords: Breast cancer, HLAG, insertion/deletion

DOI: 10.3233/CBM-130364

Citation: Cancer Biomarkers, vol. 13, no. 4, pp. 253-259, 2013

Authors: Yin, Hong | Lu, Cheng | Tang, Yongfeng | Wang, Haiyan | Wang, Hai | Wang, Jiandong

Article Type: Research Article

Abstract: Background: The Eph family of receptor tyrosine kinases and their ephrin ligands are membrane-bound cell-signaling proteins and they play critical regulatory roles in embryonic development and carcinogenesis. Eph receptors require direct cell to cell interaction for activation and they are divided into EphA and EphB receptor classes, depending on their preferential binding affinity for EphrinA or EphrinB ligands. Eph receptors have been documented in breast cancer, but the Ephrin ligands have not been thoroughly investigated. Materials and Methods: We conducted a systematic assessment of EphrinB1 expression in a set of 75 formalin-fixed paraffin-embedded breast cancers, using immunohistochemical staining …(IHC) with a specific antibody, and we examined the relationship between EphrinB1 expression, histopathological parameters, and the expression of estrogen (ER), progesterone (PR), and HER-2 receptors. Results: High level expression of EphrinB1 is positively associated with lymph node metastasis (P < 0.0001) and with the presence of HER-2 receptor (P=0.041) and it is more often detected in triple-negative breast carcinomas (P=0.038). No relation was apparent between EphrinB1 expression level and other histopathological parameters, but enhanced EphrinB1 expression is associated with shorter overall survival (P=0.015). Conclusion: Our analysis demonstrates that EphrinB1 expression is related to the metastasis of breast cancer and its enhanced expression confers a poor prognosis, suggesting that EphrinB1 may be a relevant therapeutic target in breast cancers. Show more

Keywords: EphrinB1, breast cancer, metastasis, triple-negative breast cancer

DOI: 10.3233/CBM-130356

Citation: Cancer Biomarkers, vol. 13, no. 4, pp. 261-267, 2013

Authors: Huang, Ming-Yii | Chen, Hung-Chang | Yang, I-Ping | Tsai, Hsiang-Lin | Wang, Tsu-Nai | Juo, Suh-Hang Hank | Wang, Jaw-Yuan

Article Type: Research Article

Abstract: Background: To investigate the different gene expression profiles in colorectal cancer (CRC) has important implications in understanding the correlation between candidate genes and clinical histopathological features, as well as in developing prognostic prediction markers. Objective: The purpose of this study was to identify the expression profiles of tumorigenesis and tumor progression related genes in Taiwanese CRC patients. Methods: In this study, we analyze 18 candidate gene expressions of 77 CRC tissues by a GeXP multiplexed assay. Results: The results showed VEGF (71.4%), SOX9 (68.8%), MYC (62.3%), CCND1 (59.7%), TP53 (59.4%), MMP9 (53.3%), and BIRC5 …(50.6%) as significantly overexpressed genes in CRC tissues. VEGF was the most highly overexpressed gene. In addition, VEGF was overexpressed in larger tumors (P=0.037, OR=2.981, 95% CI, 1.049–8.477). MMP9 overexpression was correlated to deeper tumor invasion (P=0.001, OR=11.022, 95% CI, 2.281–53.262), and BIRC5 was overexpressed in the presence of perineural invasion (P=0.026, OR=4.250, 95% CI, 1.240–14.562). Conclusions: The results of this study offered valuable information about the relationship between different gene expressions and clinical pathological features, and these biomarkers represent a potential role for CRC prognosis prediction and establishing therapeutic strategies. Show more

Keywords: Tumorigenesis, tumor progression, colorectal cancer, GeXP multiplexed assay

DOI: 10.3233/CBM-130350

Citation: Cancer Biomarkers, vol. 13, no. 4, pp. 269-279, 2013

Authors: Zhou, Hai-Tao | Shi, Zhi-Zhou | Zhou, Zhi-Xiang | Jiang, Yan-Yi | Hao, Jia-Jie | Zhang, Tong-Tong | Shi, Feng | Xu, Xin | Wang, Ming-Rong | Zhang, Yu

Article Type: Research Article

Abstract: Background: At present no objective parameters to identify the risk of liver metastasis after surgery have been established in rectal cancer. Objective: To identify the chromosomal aberrations that are correlated with liver metastasis of rectal cancer. Methods: Primary tumor tissues of rectal carcinoma were analyzed by array-based comparative genomic hybridization (array-CGH). Genomic aberrations were identified by Genomic Workbench and MD-SeeGH. Results: The most frequent gains in rectal cancer were at 20q11.21-q13.33, 8q11.21-q24.3, 13q12.11-q14.2 and losses in 5q13.2, 8p23.3-p22, 17p13.3-p13.2 and 18q11.2-q23. Seven amplifications at 6p21.1, 8q24.21, 8q24.3, 13q13.2 and 20q13.2-q13.32 and nine homozygous deletions …at 1q31.3, 4q12-q13.1, 4q32.3-q33, 5q13.2, 8p23.2, 8q11.23, 16p13.2, 19p13.11 and 19q13.41 were identified. Both frequency plot comparison and SAM (Significance analysis of microarray) methods indicated that losses at 1p35.3, 4p14, 14q23.1-q32.11 and 18p11.32-p11.21 were more frequent in patients without liver metastasis. Conclusions: These liver metastasis associated genomic changes may be useful to reveal the mechanism of metastasis and identify candidate biomarkers. Show more

Keywords: Array CGH, rectal cancer, liver metastasis, biomarker

DOI: 10.3233/CBM-130351

Citation: Cancer Biomarkers, vol. 13, no. 4, pp. 281-288, 2013

Authors: Hanada, Shoji | Kakehashi, Anna | Nishiyama, Noritoshi | Wei, Min | Yamano, Shotaro | Chung, Kyukwang | Komatsu, Hiroaki | Inoue, Hidetoshi | Suehiro, Shigefumi | Wanibuchi, Hideki

Article Type: Research Article

Abstract: To identify novel biomarkers for the diagnosis and prognosis of human primary lung squamous cell carcinoma (SCC), we compared the spectrum of proteins expressed in SCC and in the adjacent non-cancer tissue, using QSTAR Elite liquid chromatography with tandem mass spectrometry (LC-MS/MS), coupled with iTRAQ technology. We identified 410 proteins differentially expressed in more than 75% of patients, and validated the expression of candidate target proteins by immunohistochemistry. Based on the results of LC-MS/MS, Ingenuity Pathway Analysis and immunohistochemical analyses, myristoylated alanine-rich C-kinase substrate (MARCKS) (upregulated 2.28-fold, p< 0.005) was selected as a potential biomarker of human lung SCC. In …order to evaluate the association between patient prognosis and the expression of candidate biomarkers, univariate survival analysis was performed with disease-specific survival curves according to the Kaplan-Meier method, and differences in survival were assessed with the log-rank test. Immunohistochemical evaluation of MARCKS in 99 patients with lung SCC revealed a significant association between positive expression and poor prognosis compared with patients with negative expression (log-rank test; p=0.024). These results indicate that MARCKS may represent a potential biomarker for the prognosis of primary lung SCC. Show more

Keywords: Lung cancer, proteomics, squamous cell carcinoma

DOI: 10.3233/CBM-130354

Citation: Cancer Biomarkers, vol. 13, no. 4, pp. 289-298, 2013

Authors: Zhang, Yi | Yao, Xue | Jiang, Congqing | Yue, Junqiu | Guan, Jing | Cheng, Honglei | Hajirashid, Mohammed | Wang, Yan | Fan, Lifang

Article Type: Research Article

Abstract: Background: Small intestinal adenocarcinoma (SIA) is often diagnosed at an advanced stage due to its rarity and nonspecific clinical manifestations. Abnormal activation of the PI3K/Akt pathway may lead to various diseases including cancer. In this study, we explored the relationship between those pathways and SIA. Objective: To investigate the expression of PI3K, phospho-Akt (p-Akt) and PTEN in SIA to evaluate their clinical significance. Methods: Expression of PI3K, p-Akt and PTEN biomarkers were examined by quantum dots-based immunofluorescence histochemistry (QDs-IHC) and traditional immunohistochemistry (IHC). There are 53 SIA samples, 11 non-cancer tissue samples and 11 normal small …intestine tissues. Results: The positive frequencies of PI3K and p-Akt expression were significantly higher in the SIA group (77.4%, 41/53 and 77.4%, 41/53, respectively) than that in the non-cancer group (36.4%, 4/11 and 27.3, 3/11, respectively) and normal small intestine tissue group (36.4%, 4/11 and 18.2, 2/11, respectively). However, the difference of the positive rates of PTEN expression in three groups did not reach a statistical difference (P=0.761). The IHC results were in concordance with the QDs-IHC. Conclusions: These observations support that PI3K/Akt pathway is highly activated in SIA, which may implicate therapeutic targeting of the PI3K/Akt signaling pathway for its treatment. Show more

Keywords: Adenocarcinoma, PI3K, PTEN, p-Akt, quantum dots, small intestine

DOI: 10.3233/CBM-130352

Citation: Cancer Biomarkers, vol. 13, no. 4, pp. 299-305, 2013