Cancer Biomarkers - Volume 11, issue 2-3

Authors: Chatterjee, Madhumita | Dyson, Greg | Levin, Nancy K. | Shah, Jay P. | Morris, Robert | Munkarah, Adnan | Tainsky, Michael A.

Article Type: Research Article

Abstract: Ovarian cancer (OVCA) has a high incidence of recurrence and a high rate of mortality. We performed a pilot study to evaluate the usefulness of tumor autoantibodies to tumor associated antigens (TAA) to predict OVCA recurrence. A validation study with 56 antigens, previously identified in the initial phase of the study, along with 13 known tumor antigens on protein arrays was performed on an independent cohort of recurrent and non-recurrent OVCA patients. Statistical analyses revealed that a panel of 3 antigens predicted recurrence at a median time of 9.07 months prior to clinical recurrence in a study population, where majority …of patients had CA125 values less than 35 U/ml, with an average sensitivity, specificity and accuracy of 94.7%, 86.7% and 93.3% respectively. One of the top 3 antigens has been associated with the development of polymyositis (PM) which has been shown in some cases to precede the occurrence of ovarian carcinoma. Our results indicate that these 3 antigens have potential for predicting recurrence at an early time and may have better prognostic utility than CA125 alone for early therapeutic intervention. These biomarkers could guide us to identify those patients that could benefit most from maintenance or consolidation therapy. Show more

Keywords: Ovarian cancer, recurrence, humoral immune response, tumor autoantibodies, protein arrays

DOI: 10.3233/CBM-2012-0265

Citation: Cancer Biomarkers, vol. 11, no. 2-3, pp. 59-73, 2012

Authors: Cheol Kim, Dae | Thorat, Mangesh A. | Lee, Mi Ri | Cho, Se Heon | Vasiljević, Nataša | Scibior-Bentkowska, Dorota | Wu, Keqiang | Ahmad, Amar S. | Duffy, Stephen | Cuzick, Jack M. | Lorincz, Attila T.

Article Type: Research Article

Abstract: Background: The need for new prognostic factors in breast cancer is ever increasing as breast cancer management evolves. Aberrant DNA methylation plays a pivotal role in cancer development and progression; DNA methylation-based biomarkers may provide independent prognostic information. We used pyrosequencing to investigate the prognostic potential of quantitative DNA methylation of a large set of candidate genes in a Korean single-institution series of operable breast cancer. Methods: Absolute DNA methylation in 20 candidate genes from an initial set of 30 genes was measured by pyrosequencing of bisulfite converted DNA in 121 fresh frozen breast cancer cases. Survival analyses …used continuous and categorized (quintile-based) gene methylation data with time to recurrence (TTR) as an endpoint. Prognostic abilities of gene-only and risk-score models were explored. Results: Median follow-up was 5.1 years; 25 recurrences (21%) were observed. Nodal status, methylation of TWIST1, SLIT2 (both as continuous and categorized variables) and APC, HLA-A, NKX2-5, SERPINB5, SFN (as categorized variables) were significantly prognostic; grade showed a prognostic trend. A multivariate model containing nodal status, grade and TWIST1 was a best fit (p< 0.001) in stepwise regression; risk-score based on this model separated patients into 3 distinct risk-groups (p< 0.001). A gene-only model based on TWIST1 and SFN also classified patients into distinct risk-groups (p=0.009). Conclusions: This study shows that accurate quantitative measurement of DNA methylation by pyrosequencing identifies a small set of genes with independent prognostic potential in breast cancer. These genes complement the current clinico-pathological prognostic factors and appear to be potential biomarkers that warrant further validation. Show more

Keywords: Breast cancer, prognosis, DNA Methylation, pyrosequencing, biomarker

DOI: 10.3233/CBM-2012-0266

Citation: Cancer Biomarkers, vol. 11, no. 2-3, pp. 75-88, 2012

Authors: Agostini, M. | Enzo, M.V. | Bedin, C. | Belardinelli, V. | Goldin, E. | Del Bianco, P. | Maschietto, E. | D'Angelo, E. | Izzi, Leo | Saccani, A. | Zavagno, G. | Nitti, D.

Article Type: Research Article

Abstract: Purpose: We undertook the current study with untreated breast cancer to (1) role the variations in the plasma levels of cfDNA and the size distribution in early stage, (2) determine the frequency in plasma of methylation of three candidate genes, RASSF1A, MAL, and SFRP1, and (3) to determine whether detection of cfDNA variations and methylation changes in plasma might have specific clinical utility. Methods and materials: Thirty-nine patients woman patients (median age 64 years; range, 36–90 years) who underwent surgery for primary BR and 49 healthy females’ subjects (control group without any breast lesion) were evaluated. The cfDNA …levels were analyzed using quantitative real-time polymerase chain reaction of β -globin. Based on the ALU repeats, the cfDNA was considered as either total (fragments of 115 bp, ALU115) or tumoral (fragments of 247 bp, ALU247). The association between the levels of the ALU247, ALU115 repeat, and ALU 247/115and the pathologic tumor characteristics was analyzed. Used methylight qPCR method, cfDNA from plasma samples of healthy donors and patients with breast cancer were evaluated for the diagnotic value of the methylation status of three genes (RASSF1A, MAL, SFRP1) frequently methylated in breast cancer. Results: The baseline levels of cfDNA were significantly higher in the patients with cancer, and the level of ALU247 was the most accurate circulating cfDNA marker in discriminating the cancer from non-cancer subjects. A high statistical significance was found by considering the T stage and patients with regional LN metastasis positive cancers showed significantly higher cfDNA level of ALU247. Moreover, patients with methylation of at least one of the gene under investigate showed a higher quantity of cfDNA ALU115 (p< 0.0001) and ALU247 level (p< 0.0001). Conclusions: We observed that necrosis could be a potential source of circulating tumour-specific cfDNA ALU247; and that cfDNA ALU247 and methylated cfDNA (RASSF1A, MAL and SFRP1) are both a phenotypic feature of tumour biology. Show more

Keywords: Breast cancer, regional LN metastasis, cfDNA

DOI: 10.3233/CBM-2012-0263

Citation: Cancer Biomarkers, vol. 11, no. 2-3, pp. 89-98, 2012

Authors: Feng, Xiao | Chen, Kequan | Ye, Shicai | Wang, Hao | Wei, Guoli | Tan, Wenkai | Cheng, Si | Zhang, Yali | Liu, Side | Zhou, Yu

Article Type: Research Article

Abstract: Background: The Drosophila discs large tumor suppressor homologue-3 (MPP3), a putative tumor suppressor involved in cell adhesion and cell polarity, is frequently inactivated in several carcinomas due to promoter hypermethylation. The alteration of MPP3 methylation in colorectal carcinogenesis has not been investigated. Objective: To determine the role of inactivated MPP3 in colorectal tumorigenesis and the potential clinical application as a novel epigenetic marker. Methods: We measured MPP3 mRNA expression and promoter methylation in 6 colorectal cancer cell lines, 23 primary colorectal carcinomas and corresponding non-cancerous tissues. The correlations between MPP3 expression, DNA methylation and clinicopathological characteristics …were evaluated. Results: Loss of MPP3 expression was observed in 2 of 6 (33.3%) colorectal cancer cell lines and 10 of 23 (43.5%) primary colorectal carcinomas. MPP3 promoter hypermethylation also occurred in the same colorectal cancer cell lines (SW1116 and LoVo) and 9 of 23 (39.1%) primary colorectal carcinomas. Among tumors loss of MPP3 mRNA expression, the promoter hypermethylation rate was 80%, which was significantly higher than tumors with over-expressed MPP3 (7.7%, P=0.001). After treated with 5-aza-dC, two cell lines (SW1116 and LoVo) revealed significant restoration of MPP3 expression. MPP3 promoter methylation was also significantly higher in advanced colorectal carcinoma (57.1%) compared with early stage tumor (11.1%). Conclusion: These preliminary data suggested that epigenetic inactivation of MPP3 frequently occurred during the development of colorectal cancer and might also be a potential biomarker for molecular classification of colorectal cancer patients. Show more

Keywords: Tumor suppressor gene, MPP3, methylation, colorectal cancer

DOI: 10.3233/CBM-2012-0264

Citation: Cancer Biomarkers, vol. 11, no. 2-3, pp. 99-106, 2012

Authors: Shu, Guo-Shun | Yang, Le-Ping | Yang, Zhu-Lin | Jiang, Song

Article Type: Research Article

Abstract: Purpose: Gallbladder cancers are cancers with high disease-specific mortality rates due to the lack of early diagnosis and effective therapy. In this study, we evaluated whether CDC6 and GDF-9 could be a marker for early diagnosis and target therapy. Methods: CDC6 and GDF-9 expressions in 108 gallbladder adenocarcinomas, 15 gallbladder polyps, 35 chronic cholecystitis tissues, and 46 peritumoral tissues were detected using immunohistochemistry (IHC). Results: We demonstrated that positive CDC6 and GDF-9 expressions were significantly higher in adenocarcinomas than that in peritumoral tissues, polyps, and chronic cholecystitis (p < 0.01). Benign lesions with positive CDC6 and …negative GDF-9 expression showed moderately- or severely-atypical hyperplasia. The positive rates of CDC6 were significantly lower in cases with well-differentiated adenocarcinoma, small tumor mass, no metastasis of the lymph node, and no invasion of regional tissues (p < 0.05 or p < 0.01). In contrast, GDF-9 expression was significantly lower in the cases with poorly-differentiated adenocaarcinoma, lymph node metastasis, and invasion (p < 0.05 or p < 0.01). Univariate Kaplan-Meier analysis showed that CDC6 (p=0.046) or GDF-9 (p=0.032) expression was associated with decreased overall survival. Multivariate Cox regression analysis showed that increased expression of CDC6 (p=0.042) or decreased expression of GDF-9 (p=0.031) was an independent poor-prognostic predictor in gallbladder adenocarcinoma. Conclusion: CDC6 and GDF-9 might be closely related to the carcinogenesis, clinical biological behaviors, and prognosis of gallbladder adenocarcinoma. The positive expression of CDC6 and negative expression of GDF-9 have poor-prognosis in gallbladder carcinoma. Show more

Keywords: Gallbladder neoplasms, gallbladder polyp, chronic cholecystitis, cell division cycle 6, growth differentiation factor 9, immunohistochemistry

DOI: 10.3233/CBM-2012-0267

Citation: Cancer Biomarkers, vol. 11, no. 2-3, pp. 107-114, 2012

Authors: Liu, Hai Yan | Liu, Chun Xi | Han, Bo | Zhang, Xin Ying | Sun, Ruo Peng

Article Type: Research Article

Abstract: Astrocyte elevated gene 1 (AEG-1), a novel gene that was cloned in 2002, has emerged in recent years as a potentially crucial mediator of tumor malignancy and aberrant elevation of AEG-1 expression frequently occurs in several human cancers, including breast cancer, prostate cancer, gastric cancer. However, whether AEG-1 deregulation also occurs in neuroblastoma remains unclear. In previous study we reported that AEG-1 was over expressed in neuroblastoma cell lines and knockdown of AEG-1 inhibits proliferation and enhancing chemo-sensitivity to cisplatin or doxorubicin in neuroblastoma cells. In this study, we investigated the expression of AEG-1 and evaluate its prognostic significance by …correlating AEG-1 expression levels with clinic pathologic features and survival in 32 archived neuroblastoma patients We found that positive AEG-1 immunoreactivities were present in all neuroblastoma cases, 75% showed high expression of AEG-1. And high expression of AEG-1 was commonly seen in vascular endothelial cells and glandula in neuroblastoma samples. AEG-1 expression was strongly correlated with age at diagnosis (P=0.012), clinical stage (P=0.030) and tumor histology stage (P=0.041). However, our analyses did not show significant associations between AEG-1 expression and other clinical features including gender and primary tumor site. Importantly, our data presented in this report provide, for the first time, evidence that elevated expression of AEG-1 protein is correlated with poor prognosis and reduced survival of patients with neuroblastoma (P= 0.031). Overall, the data support the notion that AEG-1 might be used as a biomarker for neuroblastoma patients. Show more

Keywords: Astrocyte elevated gene 1, neuroblastoma, survival, outcome

DOI: 10.3233/CBM-2012-0268

Citation: Cancer Biomarkers, vol. 11, no. 2-3, pp. 115-121, 2012

Authors: Bondgaard, Anna-Louise Reinert Ørsum | Poulsen, Thomas Tuxen | Poulsen, Hans Skovgaard | Skov, Birgit Guldhammer

Article Type: Research Article

Abstract: Background: Enhancer of Zeste Homolog 2 (EZH2) and B lymphoma Mo-MLV Insertion region 1 polycomb ring finger (BMI1) are involved in malignant transformation of many human carcinomas. Still, in neuroendocrine tumors of the lung (NELT) their expression pattern is largely unknown. This study evaluated their expression in 96 NELT and correlated it to clinical features including survival. Materials and methods: Paraffin embedded material from 50 typical carcinoids (TC), 13 atypical carcinoids (AC), 23 large cell neuroendocrine carcinomas (LCNEC) and 10 small cell lung carcinomas (SCLC) was evaluated by immunohistochemisty. Results: Significantly higher expression of EZH2 was …found in high grade NELT (LCNEC + SCLC) versus low grade NELT (TC + AC) (p < 0.0001). High expression of BMI1 was observed in low grade NELT (TC + AC) in contrast to the expression in high grade NELT (LCNEC+SCLC) (p=0.004). In multivariate models, diagnosis was the strongest predictor of survival. Conclusion: The immunohistochemical expression of EZH2 and BMI1 are significantly different in low versus high grade NELT. This difference might be related to NELT tumorigenesis. These markers have no independent prognostic impact in NELT. Whether EZH2 could become target in new treatments strategies against NELT remains to be elucidated. Show more

Keywords: Neuroendocrine tumors of the lung, small-cell lung cancer, carcinoids, large cell neuroendocrine carcinoma, EZH2, BMI1, Ki67

DOI: 10.3233/CBM-2012-0269

Citation: Cancer Biomarkers, vol. 11, no. 2-3, pp. 123-128, 2012