BACKGROUND: Around 50% of cutaneous melanomas harbor the BRAF V600E mutation and can be treated with BRAF inhibitors. DNA carrying this mutation can be released into circulation as cell-free BRAF

The ultimate goal of cancer proteomics is to adapt proteomic technologies for routine use in clinical laboratories for the purpose of diagnostic and prognostic classification of disease states, as well as in evaluating drug toxicity and efficacy. The novel technologies allows researchers to facilitate the comprehensive analyses of genomes, transcriptomes, and proteomes in health and disease. The information that is expected from such technologies may soon exert a dramatic change in cancer research and impact dramatically on the care of cancer patients. Analysis of tumor-specific proteomic profiles may also allow better understanding of tumor development and the identification of novel targets for cancer therapy. The localization of gene products, which is often difficult to deduce from the sequence, can be determined experimentally. Mechanisms, such as regulation of protein function by proteolysis, recycling, and isolation in cell compartments, affect gene products, not genes. Finally, protein-protein interactions and the molecular composition of cellular structures can be determined only at the protein level. The biological variability among patient samples as well as the great dynamic range of biomarker concentrations are currently the main challenges facing efforts to deduce diagnostic patterns that are unique to specific disease states. While several strategies exist to address this problem, we have tried to offer a wide perspective about the current possibilities.

Colorectal cancer is the third most common cancer and is highly fatal. During the last several years, research has been primarily based on the study of expression profiles using microarray technology. But now, investigators are putting into practice proteomic analyses of cancer tissues and cells to identify new diagnostic or therapeutic biomarkers for this cancer. Because the proteome reflects the state of a cell, tissue or organism more accurately, much is expected from proteomics to yield better tumor markers for disease diagnosis and therapy monitoring. This review summarizes the most relevant applications of proteomics the biomarker discovery for colorectal cancer.

The t(11;22)(q24;q12) translocation is present in up to 95% of Ewing tumor patients and results in the formation of an EWS-FLI-1 fusion gene that encodes a chimeric transcription factor. Many alternative forms of EWS-FLI-1 exist because of variations in the location of the EWS and FLI-1 genomic breakpoints. Previous reports have shown that the type 1 fusion is associated with a significantly better prognosis than the other fusion types. It has been suggested that the observed clinical discrepancies result from different transactivation potentials of the various EWS-FLI-1 fusion proteins. In an attempt to identify genes whose expression levels are differentially modulated by structurally different EWS-FLI-1 transcription factors, we have used microarray technology to interrogate 19,000 sequence genes to compare gene expression profile of type 1 or non-type 1 Ewing sarcoma cell lines. Data analysis showed few qualitative differences on gene expression; expression of only 41 genes (0.215% of possible sequences analyzed) differed significantly between Ewing tumor cell lines carrying EWS-FLI-1 fusion type 1 with respect to those with non-type 1 fusion.

Pancreatic ductal adenocarcinoma, which represents 80% of pancreatic cancers, is mainly diagnosed when treatment with curative intent is not possible. Consequently, the overall five-year survival rate is extremely dismal—around 5% to 7%. In addition, pancreatic cancer is expected to become the second leading cause of cancer-related death by 2030. Therefore, advances in screening, prevention and treatment are urgently needed. Fortunately, a wide range of approaches could help shed light in this area. Beyond the use of cytological or histological samples focusing in diagnosis, a plethora of new approaches are currently being used for a deeper characterization of pancreatic ductal adenocarcinoma, including genetic, epigenetic, and/or proteo-transcriptomic techniques. Accordingly, the development of new analytical technologies using body fluids (blood, bile, urine, etc.) to analyze tumor derived molecules has become a priority in pancreatic ductal adenocarcinoma due to the hard accessibility to tumor samples. These types of technologies will lead us to improve the outcome of pancreatic ductal adenocarcinoma patients.

BackgroundInguinal orchiectomy is curative in 70–80% of clinical stage I testicular germ cell tumours (CS I TGCT). The identification of patients who are at low risk of relapse is critical to avoid unnecessary treatment. The aim of this study is to explore EGFR, hMLH-1/hMSH-2 and microsatellite instability (MSI) as potential prognostic factors of recurrence in CS I TGCT.MethodsFifty-six CS I TGCT patients who underwent inguinal orchiectomy were included in this study. We analysed the relationship between clinicopathological and molecular factors with survival. Analysis of hMLH1, hMSH2 and EGFR expression was carried out by immunohistochemistry. Methylation status of the hMLH1 promoter was determined by pyrosequencing analysis in selected cases. EGFR exons 19, 20, 21 were analysed by PCR labeled-fragments and MSI status was determined using standard Multiplex MSI assays.ResultsClassical pathological factors such as lymphovascular invasion, high percentage of embryonal carcinoma, rete testis invasion or tumour size ≥4 cm showed a significant relationship with a higher risk of relapse. Additionally, it was found that an epididymis invasion proved to be a significant independent poor prognostic factor of recurrence (p = 0.001). hMLH1 or hMSH2 expression showed no significant association with risk of relapse and no MSI was found. EGFR expression was observed in 30.4% of samples and its expression was associated with higher risk of relapse (HR 3.5; 95% CI 1.3–9.8; p = 0.016). None of the cases presented EGFR kinase domain mutations.ConclusionsEpididymis invasion and EGFR expression, but not hMLH-1/hMSH-2 or MSI, could be potentially useful as new prognostic factors of recurrence for CS I TGCT.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1162-3) contains supplementary material, which is available to authorized users.

Introduction: In recent years, an emerging role for microRNAs (miRNAs) in human cancer has been proposed. Our group has previously identified miR-451 as a potential tumor suppressor microRNA involved in cell cycle progression and radiation response. We hypothesized whether miRNAs may be involved in drug resistance mechanisms among cytotoxic agents commonly used in metastatic colorectal cancer (mCRC). Experimental Design: miR-451 was overexpressed by ectopically synthetic pre-miR-451 transient transfection and by generating stable-miR-451 overexpressed cells through retroviral vectors. The role of miR-451 on chemosensitivity to 5-fluorouracil (5FU), oxaliplatin (LOHP) and SN38, an active metabolite of irinotecan, was characterized by MTS. We sought to determine links between miR-451 and cancer stem cells (CSCs) by colonspheres generation, soft-agar cell invasion and xenograft in vivo experiments. Down-stream targets involved in drug-resistance mechanisms were also identified. Results: Overexpression of miR-451 significantly increased the sensitivity of CRC cell lines to SN38. The IC50 values were significantly lower in pre-miR-451-transfected cells, including DLD1, LoVo and RKO than in controls (950 nM versus 460 nM for DLD1; 10 nM versus 1.4 nM for LoVo and 20 nM versus 5.9 nM for RKO). No changes were detected for 5-FU and LOHP response. ATP-binding cassette transporter protein 1 (ABCB1) proved to be miR-451-target directly associated with SN38 sensitivity. Moreover, restoring miR-451 levels translated into a reduced tumorigenicity in a xenograft model and a decreased ability of CRC cells to growth under anchorage-independent conditions in soft agar. These results suggest that miR-451 down-regulation in CRC cells may be involved in CSCs generation. Indeed, overexpression of miR-451 was able to reduce the number and size of CRC cells-derived colonspheres. The phenotype of formed colonspheres was confirmed evaluating overexpression of several putative CSCs markers (CD133, CD44, EpCam and CD166). We also found colonspheres to be more resistant to SN38 treatment and to express higher levels of ABCB1 than parental cells. Finally, miR-451 restoration levels reverted CSCs resistance to SN38 through ABCB1 down-regulation. Conclusions: Our findings suggest that miR-451 is involved in SN38 resistance through suppression of ABCB1 and regulation of CRC stem-like cell phenotype. Therefore, miR-451 may represent a novel potential candidate target to circumvent drug resistance in CRC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3549.

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