Cancer Biomarkers - Volume 14, issue 2-3

Article Type: Introduction

DOI: 10.3233/CBM-130412

Citation: Cancer Biomarkers, vol. 14, no. 2-3, pp. 83-83, 2014

Authors: Berindan-Neagoe, I. | Paradiso, A.

Article Type: Editorial

DOI: 10.3233/CBM-130342

Citation: Cancer Biomarkers, vol. 14, no. 2-3, pp. 85-86, 2014

Authors: Mader, Robert M. | Brodowicz, Thomas | Zielinski, Christoph C.

Article Type: Research Article

Abstract: The rapidly evolving understanding of tumour biology offers novel opportunities for therapeutic interventions. This information already has been used to select appropriate systemic treatment. To take full advantage of this knowledge, however, the different levels of interaction in an organism need to be integrated to link cellular mechanisms, stromal effects and the implications for organs and the whole organism. Although very challenging and ambitious, this understanding would closely link tumour biology, biomarker validation and rational therapeutic decisions.

Keywords: Cancer biology, predictive biomarkers, translational research

DOI: 10.3233/CBM-130382

Citation: Cancer Biomarkers, vol. 14, no. 2-3, pp. 87-91, 2014

Authors: Pop, Laura-Ancuţa | Puscas, Emil | Pileczki, Valentina | Cojocneanu-Petric, Roxana | Braicu, Cornelia | Achimas-Cadariu, Patriciu | Berindan-Neagoe, Ioana

Article Type: Research Article

Abstract: Next-generation sequencing (NSG) is an important method for gathering large amounts of sequencing data for different types of applications regarding the diagnosis and response to treatment of different diseases. An important step in the NGS process is the quality control of sequencing libraries, which can influence the yield and efficiency of the sequencing run. This study evaluated two different methods for library quality control, Agilent Bioanalyzer and qPCR, and showed that both methods can be used. However, as is the case with any analytical method, they have their limitations. The Agilent Bioanalyzer quantifies only the high quality libraries, but it …underestimates their concentration, while qPCR also quantifies lower quality libraries, but it overestimates their concentration. Show more

Keywords: Agilent Bioanalyzer, qPCR, sequencing libraries, breast cancer

DOI: 10.3233/CBM-130358

Citation: Cancer Biomarkers, vol. 14, no. 2-3, pp. 93-101, 2014

Authors: Pinto, Rosamaria | De Summa, Simona | Petriella, Daniela | Tudoran, Oana | Danza, Katia | Tommasi, Stefania

Article Type: Research Article

Abstract: Advances in our understanding of the molecular basis of tumors, as well as in the technology of DNA analysis, are rapidly changing the landscape of these diseases. Traditional approaches such as sequencing methods and arrays have too many limits. These have been overcome by the advent of next generation sequencing (NGS) methods which facilitate and accelerate the analysis of multiple genes and samples. These technologies allow new applications in molecular biology and medicine, for example precise analysis of RNA transcripts for gene expression; profiling of small RNAs, DNA methylation patterns and histone modification analysis; identification of splicing isoforms …and of DNA regions that interact with regulatory proteins; pharmacogenomics studies and so on. In this review we describe recent applications of NGS in genomics, transcriptomics and epigenomics for a better comprehension of solid tumor metabolisms. Show more

Keywords: Next generation sequencing, genomics, transcriptomics and epigenomics

DOI: 10.3233/CBM-130328

Citation: Cancer Biomarkers, vol. 14, no. 2-3, pp. 103-117, 2014

Authors: Braicu, Cornelia | Berindan-Neagoe, Ioana | Pileczki, Valentina | Cojocneanu-Petric, Roxana | Pop, Laura-Ancuţa | Puscas, Emil | Mattioli, Eliseo | Irimie, Alexandru | Buiga, Rares

Article Type: Research Article

Abstract: The development of a breast tumor bank facilitates translational research. Easy access to biological specimens allows scientists to translate the outcomes of basic science into clinically useful knowledge. The breast tumor bank is particularly useful for triple negative breast cancer (TNBC) that is sporadic but exhibits the worst prognosis. It serves as a national resource that includes biological samples of paraffin-embedded and frozen tumor tissue with corresponding pathological and clinical data. During the first two years, the bank has accrued data and samples from more than 254 breast cancer cases. Based on this information, we observed a higher number of …samples with ER (estrogen receptor) and PR (progesterone receptor) positive and negative for Her2. Also, 30% of the total number of cases was defined as TNBC. The use of tumor banks in research and diagnosis allows for the design of different studies that can bring reliable results that may improve the lives of patients, especially those diagnosed with TNBC. Show more

Keywords: Breast cancer, tumor bank, clinicopathologic features

DOI: 10.3233/CBM-130309

Citation: Cancer Biomarkers, vol. 14, no. 2-3, pp. 119-127, 2014

Authors: Fetica, Bogdan | Balacescu, Ovidiu | Balacescu, Loredana | Rus, Meda | Berindan-Neagoe, Ioana

Article Type: Research Article

Abstract: Nowadays, HER2 testing in breast cancer represents a necessity for both prognostic and therapy. Despite widespread use of immunohistochemistry (IHC) for assessing HER2 status, there are some limitations to identify truly negative or positive HER2 cases. Fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) could solve the equivocal HER2 IHC cases but there is no consensus on which is the best method. Consequently, finding a sensitive method for HER2 testing is critical for the management of the disease. In addition, tumor heterogeneity is an important factor which could affect accuracy of molecular diagnostics. Laser capture micro-dissection (LCM) …is used to isolate pure cell populations from heterogeneous tumor tissue. The combination between LCM and quantitative polymerase chain reaction (Q-PCR), the gold standard in molecular biology for quantifying gene amplification levels, could define an important tool to improve the molecular diagnostics of HER2 status. In our pilot study we used LCM and Q-PCR to evaluate HER2 gene amplification for invasive breast carcinoma samples. The samples were selected based on HER2 status assessed by IHC and CISH. Our results demonstrated high sensitivity of Q-PCR for assessing HER2 DNA amplification as well as a good concordance between Q-PCR and IHC/ CISH assay. Show more

Keywords: Q-PCR, LCM, HER2, breast cancer

DOI: 10.3233/CBM-130311

Citation: Cancer Biomarkers, vol. 14, no. 2-3, pp. 129-135, 2014

Authors: Susman, Sergiu | Tomuleasa, Ciprian | Fekete, Zsolt | Pilato, Brunella | Irimie, Alexandru | Berindan-Neagoe, Ioana

Article Type: Research Article

Abstract: Breast cancer is one of the most diagnosed cancers in women. Despite outstanding progress over the past few years, breast cancer remains the second leading cause of cancer-related death among women. This fact emphasizes the need for improved diagnostic and prognostic markers, as well as improved understanding of cancer environment, including the crosstalk between epithelial and stromal cells. The tumor microenvironment is paramount in breast cancer progression and dissemination. Accumulating evidence indicates that epigenetic phenomena such as microRNAs are extremely important in cancer homeostasis. Through the improved understanding of the molecular mechanisms involved in the microenvironment-mediated promotion of cancer growth …and metastasis, novel targets for therapeutic intervention or early diagnosis may be identified. Show more

Keywords: Breast cancer, tumor microenvironement, microRNA

DOI: 10.3233/CBM-130318

Citation: Cancer Biomarkers, vol. 14, no. 2-3, pp. 137-144, 2014

Authors: Coget, Julien | Borrini, Francesco | Susman, Sergiu | Sabourin, Jean-Christophe

Article Type: Research Article

Abstract: Colorectal cancer (CRC) is the third cause of cancer worldwide after prostate cancer and breast cancer. Patients have a survival rate of 5 years, which varies between 10 and 95% depending on CRC stage. Today, the management of patients with CRC is based on parameters such as TNM and classic histologic parameters, but new molecular and cell markers have been created to improve treatment and survival. Determining the expression of a characteristic set of genes either from formalin-fixed paraffin-embedded tissue (Onco type DX test™) or from fresh tissues (AGENDIA© ColoPrint®) has led to encouraging results, but there is a need …for clinical validation on a large number of patients. Also, next-generation sequencing (NGS) technologies may be the next step in the molecular approach of CRC tumor samples, allowing tumor characterization by gene signature arrays. In addition to molecular markers, evaluation of the presence of cellular markers such as circulating tumor cells (CTC) in the blood of patients with CRC can optimize prognostic evaluation and response to treatment. CTC isolation methods used today have different sensitivities and specificities, due not only to the very small number of these cells but also to the epithelial-mesenchymal transitional process (EMT). This paper presents the preliminary results of our study conducted on CTC isolation in patients with CRC by filtration method (Screencells Cyto®). This fast and efficient method identifies CTCs and also isolates cells in EMT, which explains its high efficiency compared to technologies based on immunomagnetic and microfluidic separation reliant on EpCAM presence on the cell surface. Show more

Keywords: Colorectal carcinoma CRC,, circulating tumor cells CTC, epithelial-mesenchymal transitional process EMT, biomarkers

DOI: 10.3233/CBM-130378

Citation: Cancer Biomarkers, vol. 14, no. 2-3, pp. 145-150, 2014

Authors: Silvestris, Nicola | Marech, Ilaria | Brunetti, Anna Elisabetta | Azzariti, Amalia | Numico, Gianmauro | Cicero, Giuseppe | Delcuratolo, Sabina | De Luca, Raffaele | Burz, Claudia | Lorusso, Vito

Article Type: Research Article

Abstract: Most cancers are traditionally treated with either chemotherapeutic agents, radiotherapy, or both. Identification of specific molecular characteristics of tumors and the advent of molecular-targeted drugs not only enhance the efficacy but also decrease the toxicity of treatment. These new therapies may target pathways critical to tumor development or specific driver mutations in cancer cells. This understanding of the molecular pathways of cancer cells has led to the ability to predict cancer development, behaviour and prognosis, as well as response or resistance to current therapeutic agents. As a result, pathologic analyses play a vital role in the detection of cancer biomarkers, …which are important not only in the diagnosis of cancers but also in the selection of appropriate therapeutic agents and in the development of new targeted therapies. Show more

Keywords: Gastrointestinal cancer, targeted therapy, EGFR, HER2, VEGF

DOI: 10.3233/CBM-130327

Citation: Cancer Biomarkers, vol. 14, no. 2-3, pp. 151-162, 2014

Authors: Kontogeorgos, George

Article Type: Research Article

Abstract: Endocrine tumors were considered relatively infrequent neoplasms. However, during the last decades, their frequency gradually increased. The use of imaging techniques, guided FNA biopsy, an endoscope camera in the investigation of endocrine lesions, permits early diagnosis. At the histological level, new applications such as non-biotin containing immunohistochemical detection systems, tyramide amplification method, in situ hybridization, FISH, CGH, and other molecular techniques have provided better knowledge on the protein and molecular background. The investigation of somatostatin and dopamine receptors assists targeted therapy of endocrine tumors. Novel treatment modalities have emerged for the management of pituitary and gastroenteropancreatic tumors respectively. Despite this …progress, in some instances, the morphological diagnosis remains questionable. Similarities among normal elements, hyperplastic conditions and benign or malignant lesions can make separation difficult. The “gray zones” representing the overlapping in the sequence of normal parenchyma/ hyperplasia/ adenoma/ carcinoma signify a difficult and controversial diagnostic task, which merits special attention. Furthermore, in most endocrine tumors, the diagnosis of carcinoma is justified only in the presence of local or distant metastases. More precise guidelines are needed, by improving the currently available criteria, to minimize the “gray zones”, leading to a more accurate separation of such endocrine lesions. Show more

Keywords: Classification, endocrine, imaging, pathology, therapy

DOI: 10.3233/CBM-130353

Citation: Cancer Biomarkers, vol. 14, no. 2-3, pp. 163-167, 2014

Authors: Caponio, Maria Angela | Addati, Teresa | Popescu, Ondina | Petroni, Stella | Rubini, Vincenza | Centrone, Marilena | Trojano, Giuseppe | Simone, Giovanni

Article Type: Research Article

Abstract: Determining the primary site of uterine adenocarcinoma (ADC) may be problematic, especially with small specimens. This is particularly important in light of the increase of endocervical and endometrial adenocarcinoma and the decrease in incidence of squamous cell carcinoma. P16INK4a , a member of the INK4 family of cell cycle regulatory proteins, plays a critical role. It functions as a negative regulator of cell cycle progression and differentiation by controlling the activity of the tumor-suppressor protein retinoblastoma (pRb), which regulates the cell cycle. Its expression is variable according to the tumoral histotype and in metastasis. The aim …of this study was to investigate p16INK4a expression in endocervical, endometrial, and metastatic ADCs of extra-uterine origin. Fifty gynaecological biopsies (cervix or endometrium) comprised the study for p16INK4a determination. Cases were classified as (1) diffuse positive (P), in intense nuclear immunostaining and/or cytoplasmic in > 30% of neoplastic cells; (2) focal positive (FP), in intense immunostaining in 10% to 30% in isolated cells or small groups; and (3) negative (N), in absence of immunostaining or weak, sporadic immunostaining in < 10% of neoplastic cells. Included in the study were the following: 6 endocervical ADCs, 11 endometrioid-type endometrial ADCs, 5 endometrial serous papillary ADCs, 7 ovarian ADCs, 4 large intestine ADCs, 1 breast ADC, 12 not-otherwise-specified (NOS) ADCs, and 4 endocervical biopsy without atypia (as control). Diffuse, strong positivity with p16INK4a suggests an endocervical rather than an endometrial or metastatic ADC. In fact, a p16INK4a positive immunostaining pattern was prevalent in endocervical (83%) and serous papillary ADCs of endometrial or ovarian origin, whereas endometrioid ADCs such as metastatic non-ovarian lesions generally presented only focal or negative immunostaining. 10/12 cases of ADC-NOS were reclassified using p16INK4a immunostaining: 2 as endocervical ADCs (2 P), 4 as endometrioid-type endometrial ADCs (2 FP, 2 N), 3 as endometrial serous papillary ADCs (3 FP), and 1 as ovarian serous papillary ADC (1 FP). Show more

Keywords: Uterine adenocarcinoma, metastatic ADCs, NOS-ADCs, immumunohistochemistry, p16INK4a

DOI: 10.3233/CBM-130326

Citation: Cancer Biomarkers, vol. 14, no. 2-3, pp. 169-175, 2014

Authors: Saponaro, Concetta | Malfettone, Andrea | Dell'Endice, Teresa Stefania | Brunetti, Anna Elisabetta | Achimas-Cadariu, Patriciu | Paradiso, Angelo | Mangia, Anita

Article Type: Research Article

Abstract: NHERF1 (Na+ /H+ exchanger regulatory factor) is a scaffolding protein, consists of two tandem PDZ domains linked to a carboxyl-terminal ezrin-binding region. NHERF1 recruits macromolecular complexes at the apical membrane of epithelial cells in many epithelial tissues. It is involved in trafficking and regulation of transmembrane ion transporters and G protein-coupled receptors. Further, NHERF1 also linked other molecules involved in cell growth and cancer progression, such as PDGFR, PTEN, β-catenin, EGFR and HER2/neu. In this review, we focus on the role of NHERF1 during cancer development. Evidences of its involvement in cancer development are present in hepatocellular carcinoma, schwannoma, …glioblastoma, colorectal cancer and particularly in breast cancer. Recent findings obtained from our laboratory show that cytoplasmic NHERF1 expression increases gradually in breast cancer during carcinogenesis, and its overexpression is associated with aggressive clinical parameters, unfavourable prognosis, and increased tumor hypoxia. Interestingly, also nuclear NHERF1 expression seems to play a role both in carcinogenesis and progression of colorectal cancer. These data suggest that NHERF1 could be a new biomarker of advanced malignancies. Show more

Keywords: NHERF1, cancers, carcinogenesis, cancer progression

DOI: 10.3233/CBM-130329

Citation: Cancer Biomarkers, vol. 14, no. 2-3, pp. 177-184, 2014

Authors: Chiorean, Roxana | Braicu, Cornelia | Florian, Ioan Stefan | Leucuta, Daniel | Montefrancesco, Chiara | Crisan, Doinita | Berindan-Neagoe, Ioana | Cernea, Valentin

Article Type: Research Article

Abstract: Glioblastoma multiforme (GBM) represents a very aggressive brain tumor. Angiogenesis is the formation of a network of new blood vessels, from preexisting ones. It plays an important role in the formation of the tumor, as it supplies it with oxygen and nutrients. Angiogenesis and inflammation play essential roles in glioblastoma development. These processes are regulated by the balance of a few molecules, acting as pro- or antiangiogenic and pro- or anti-inflammatory factors. The purpose of our study was to evaluate the expression of 7 markers involved in angiogenesis and inflammation pathways in patients with glioblastoma. VEGF, PDGF-bb, IGF-1, TGF-β, TNF-α, …IL-6 and IL-8 levels were measured using the ELISA method, in the preoperative sera of 14 patients with histopathologically confirmed glioblastoma multiforme and 32 healthy patients. Serum levels of PDGF-bb, IGF-1 and IL-8 were significantly higher in patients with GBM, compared to the control group (p-value < 0.01). A statistically significant correlation has been found between IGF-1 and IL-6 levels (rho= −0.53, p-value < 0.05) and also between TNF-α and IL-6 levels (rho=0.60, p-value < 0.05). Statistically significant associations have been found between the presence of low levels of IL-8 and the development of coagulation necrosis (p-value < 0.05), high levels of VEGF and development of ischemic necrosis (p-value < 0.01) and high levels of IL-8 and the development of endothelial hyperplasia (p-value < 0.05). We have observed no statistically significant associations between the serum levels of the markers and the survival rates. Show more

Keywords: Glioblastoma multiforme, angiogenesis, inflammation, ELISA, histopathology, survival rates

DOI: 10.3233/CBM-130310

Citation: Cancer Biomarkers, vol. 14, no. 2-3, pp. 185-194, 2014

Authors: Sergio, Roman-Roman

Article Type: Other

DOI: 10.3233/CBM-130339

Citation: Cancer Biomarkers, vol. 14, no. 2-3, pp. 195-196, 2014