Single nucleotide polymorphisms as prognostic and predictive biomarkers in renal cell carcinoma.

Despite major advances in the knowledge of the molecular basis of renal cell carcinoma, prognosis is still defined using clinical and pathological parameters. Moreover, no valid predictive biomarkers exist to help us selecting the best treatment for each patient. With these premises, we aimed to analyse the expression and to determine the prognostic and predictive value of 64 key single nucleotide polymorphisms in 18 genes related with angiogenesis or metabolism of antiangiogenics in two cohorts of patients with localized and advanced renal cell cancer treated at our institution. The presence of the selected single nucleotide polymorphisms was correlated with clinical features, disease free survival, overall survival and response rate. In patients with localized renal cell cancer, 5 of these polymorphisms in 3 genes involved in angiogenesis predicted for worse disease free survival (VEGFR2: rs10013228; PDGFRA: rs2228230) or shorter overall survival (VEGFR2: rs10013228; VEGFR3: rs6877011, rs307826) (p < 0.05). Rs2071559 in VEGFR2 showed a protective effect (p = 0.01). In the advanced setting, 5 SNPs determined inferior overall survival (IL8: rs2227543, PRKAR1B: rs9800958, PDGFRB: rs2302273; p = 0.05) or worse response rate (VEGFA: rs699947, rs3025010 p ≤ 0.01)). Additionally 1 single nucleotide polymorphism in VEGFB predicted for better response rate rs594942 (p = 0.03). Genetic analysis of renal cell carcinoma patients might provide valuable prognostic/predictive information. A set of SNPs in genes critical to angiogenesis and metabolism of antiangiogenics drugs seem to determine post-surgical outcomes and treatment response in our series.Junta de Andalucía PI-0427-201

Mouse p53-deficient cancer models as platforms for obtaining genomic predictors of human cancer clinical outcomes

Mutations in the TP53 gene are very common in human cancers, and are associated with poor clinical outcome. Transgenic mouse models lacking the Trp53 gene or that express mutant Trp53 transgenes produce tumours with malignant features in many organs. We previously showed the transcriptome of a p53-deficient mouse skin carcinoma model to be similar to those of human cancers with TP53 mutations and associated with poor clinical outcomes. This report shows that much of the 682-gene signature of this murine skin carcinoma transcriptome is also present in breast and lung cancer mouse models in which p53 is inhibited. Further, we report validated gene-expression-based tests for predicting the clinical outcome of human breast and lung adenocarcinoma. It was found that human patients with cancer could be stratified based on the similarity of their transcriptome with the mouse skin carcinoma 682-gene signature. The results also provide new targets for the treatment of p53-defective tumours

Quantum simulation of conductivity plateaux and fractional quantum Hall effect using ultracold atoms

We analyze the role of impurities in the fractional quantum Hall effect using a highly controllable system of ultracold atoms. We investigate the mechanism responsible for the formation of plateaux in the resistivity/conductivity as a function of the applied magnetic field in the lowest Landau level regime. To this aim, we consider an impurity immersed in a small cloud of an ultracold quantum Bose gas subjected to an artificial magnetic field. We consider scenarios corresponding to experimentally realistic systems with gauge fields induced by rotation of the trapping parabolic potential. Systems of this kind are adequate to simulate quantum Hall effects in ultracold atom setups. We use exact diagonalization for few atoms and to emulate transport equations, we analyze the time evolution of the system under a periodic perturbation. We provide a theoretical proposal to detect the up-to-now elusive presence of strongly correlated states related to fractional filling factors in the context of ultracold atoms. We analyze the conditions under which these strongly correlated states are associated with the presence of the resistivity/conductivity plateaux. Our main result is the presence of a plateau in a region, where the transfer between localized and non-localized particles takes place, as a necessary condition to maintain a constant value of the resistivity/conductivity as the magnetic field increases

Detection of EGFR mutations with mutation-specific antibodies in stage IV non-small-cell lung cancer

<p>Abstract</p> <p>Background</p> <p>Immunohistochemistry (IHC) with mutation-specific antibodies may be an ancillary method of detecting EGFR mutations in lung cancer patients.</p> <p>Methods</p> <p>EGFR mutation status was analyzed by DNA assays, and compared with IHC results in five non-small-cell lung cancer (NSCLC) cell lines and tumor samples from 78 stage IV NSCLC patients.</p> <p>Results</p> <p>IHC correctly identified del 19 in the H1650 and PC9 cell lines, L858R in H1975, and wild-type EGFR in H460 and A549, as well as wild-type EGFR in tumor samples from 22 patients. IHC with the mAb against EGFR with del 19 was highly positive for the protein in all 17 patients with a 15-bp (ELREA) deletion in exon 19, whereas in patients with other deletions, IHC was weakly positive in 3 cases and negative in 9 cases. IHC with the mAb against the L858R mutation showed high positivity for the protein in 25/27 (93%) patients with exon 21 EGFR mutations (all with L858R) but did not identify the L861Q mutation in the remaining two patients.</p> <p>Conclusions</p> <p>IHC with mutation-specific mAbs against EGFR is a promising method for detecting EGFR mutations in NSCLC patients. However these mAbs should be validated with additional studies to clarify their possible role in routine clinical practice for screening EGFR mutations in NSCLC patients.</p

Customized Treatment in Non-Small-Cell Lung Cancer Based on EGFR Mutations and BRCA1 mRNA Expression

BACKGROUND: Median survival is 10 months and 2-year survival is 20% in metastatic non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. A small fraction of non-squamous cell lung cancers harbor EGFR mutations, with improved outcome to gefitinib and erlotinib. Experimental evidence suggests that BRCA1 overexpression enhances sensitivity to docetaxel and resistance to cisplatin. RAP80 and Abraxas are interacting proteins that form complexes with BRCA1 and could modulate the effect of BRCA1. In order to further examine the effect of EGFR mutations and BRCA1 mRNA levels on outcome in advanced NSCLC, we performed a prospective non-randomized phase II clinical trial, testing the hypothesis that customized therapy would confer improved outcome over non-customized therapy. In an exploratory analysis, we also examined the effect of RAP80 and Abraxas mRNA levels. METHODOLOGY/PRINCIPAL FINDINGS: We treated 123 metastatic non-squamous cell lung carcinoma patients using a customized approach. RNA and DNA were isolated from microdissected specimens from paraffin-embedded tumor tissue. Patients with EGFR mutations received erlotinib, and those without EGFR mutations received chemotherapy with or without cisplatin based on their BRCA1 mRNA levels: low, cisplatin plus gemcitabine; intermediate, cisplatin plus docetaxel; high, docetaxel alone. An exploratory analysis examined RAP80 and Abraxas expression. Median survival exceeded 28 months for 12 patients with EGFR mutations, and was 11 months for 38 patients with low BRCA1, 9 months for 40 patients with intermediate BRCA1, and 11 months for 33 patients with high BRCA1. Two-year survival was 73.3%, 41.2%, 15.6% and 0%, respectively. Median survival was influenced by RAP80 expression in the three BRCA1 groups. For example, for patients with both low BRCA1 and low RAP80, median survival exceeded 26 months. RAP80 was a significant factor for survival in patients treated according to BRCA1 levels (hazard ratio, 1.3 [95% CI, 1-1.7]; P = 0.05). CONCLUSIONS/SIGNIFICANCE: Chemotherapy customized according to BRCA1 expression levels is associated with excellent median and 2-year survival for some subsets of NSCLC patients , and RAP80 could play a crucial modulating effect on this model of customized chemotherapy. TRIAL REGISTRATION: (ClinicalTrials.gov) NCT00883480

A prognostic DNA methylation signature for stage I non-small-cell lung cancer

Purpose Non-small-cell lung cancer (NSCLC) is a tumor in which only small improvements in clinical outcome have been achieved. The issue is critical for stage I patients for whom there are no available biomarkers that indicate which high-risk patients should receive adjuvant chemotherapy. We aimed to find DNA methylation markers that could be helpful in this regard. Patients and Methods A DNA methylation microarray that analyzes 450,000 CpG sites was used to study tumoral DNA obtained from 444 patients with NSCLC that included 237 stage I tumors. The prognostic DNA methylation markers were validated by a single-methylation pyrosequencing assay in an independent cohort of 143 patients with stage I NSCLC. Results Unsupervised clustering of the 10,000 most variable DNA methylation sites in the discovery cohort identified patients with high-risk stage I NSCLC who had shorter relapse-free survival (RFS; hazard ratio [HR], 2.35; 95% CI, 1.29 to 4.28; P = .004). The study in the validation cohort of the significant methylated sites from the discovery cohort found that hypermethylation of five genes was significantly associated with shorter RFS in stage I NSCLC: HIST1H4F, PCDHGB6, NPBWR1, ALX1, and HOXA9. A signature based on the number of hypermethylated events distinguished patients with high-and low-risk stage I NSCLC (HR, 3.24; 95% CI, 1.61 to 6.54; P = .001). Conclusion The DNA methylation signature of NSCLC affects the outcome of stage I patients, and it can be practically determined by user-friendly polymerase chain reaction assays. The analysis of the best DNA methylation biomarkers improved prognostic accuracy beyond standard staging. (C) 2013 by American Society of Clinical Oncology

Biología molecular del cáncer de próstata resistente a la castración

[Objeticos] El cáncer de próstata resistente a la castración (CPRC) es una enfermedad heterogénea de la que estamos empezando a conocer sus bases moleculares en profundidad. Hay diversas vías y dianas en estudio en estos momentos y probablemente otras tantas por caracterizar. En este trabajo revisamos los conocimientos mas recientes relativos a la biología molecular del CPRC con un foco especial en la aplicación terapéutica de este conocimiento.[Métodos] Se ha llevado a cabo una revisión de la literatura utilizando Pubmed como motor de búsqueda, incluyendo los siguientes términos: “castration-resistant prostate cancer”, “genomics”, “molecular biology”, “AR”, “WNT”, “mTOR”, “PTEN”, “cell-cycle”, “DNA damage repair gene” y “chromatin modifier genes”.[Resultados] El CPRC tiene una alta carga de alteraciones genéticas, probablemente derivadas de la presión terapéutica. Las alteraciones más frecuentes afectan al receptor androgénico (RA) [60-70%] y a la vía de PI3K-AKT-mTOR [40-60%], si bien se han identificado alteraciones relevantes de otras vías como aquellas relativas al control del ciclo celular [25%], en genes de reparación de lesiones en el ADN [20%] y en otras vías como la de WNT-βcatenina [15-22%]. El conocimiento de estas alteraciones esta sirviendo como base para el desarrollo de terapias especificas a nuevas dianas terapéuticas con resultados prometedores y multiples estudios en curso.[Conclusiones] En la ultima década el avance en el conocimiento de las bases moleculares del CPRC ha sido muy relevante. Si bien las alteraciones del RA son las mas frecuentes y mejor caracterizadas, anomalías en otras vías han sido también identificadas como destacadas en la biología del CRPC y han derivado en un desarrollo terapéutico notable.[Objectives] Castration resistant prostate cancer (CRPC) is an heterogeneous disease the molecular basis of which we are starting to know in depth. Currently, there are various pathways and targets under study, and probably many others to be characterized. In this paper, we review the most recent knowledge concerning the molecular biology of CRPC with a special focus on the therapeutic application of this knowledge.[Methods] We performed a bibliographic review using PUBMED as the search engine, including the following terms: “Castration resistant prostate cancer”, “genomics”, “molecular biology”, “AR”, “WNT”, “mTOR”, “PTEN”, cell-cycle”, “DNA damage repair gene” and “chromatin modifier genes”.[Results] CRPC has a high load of genetic alterations, probably derived from therapeutic pressure. The most frequent alterations involve the androgen receptor (RA) [60-70%] and the PI3K- AKT-mTOR [40-60%], even though other relevant pathways alterations have been identified such as those relative to cellular cycle [25%], DNA lesion repair genes [20%] and other pathway like WNT-βcatenin [15-22%]. The knowledge of these pathways is helping as a base for development of new therapeutic targets with promising results and multiple ongoing studies.[conclusions] Over the last decade, the progress in the knowledge of the molecular bases of CRPC has been very relevant. Even though AR alterations are the most frequent and best characterized, anomalies in other pathways have been also identified as important in the biology of CRPC and derived a notable therapeutic development.Peer reviewe

Combined VEGF-A and VEGFR-2 concentrations in plasma: diagnostic and prognostic implications in patients with advanced NSCLC

Introduction: The vascular endothelial growth factor (VEGF) family of ligands and receptors (VEGFR) play an important role in tumor angiogenesis. Increased expression of angiogenic factors in tumors or in blood is associated with poor prognosis. The aim of this study was to investigate the role of VEGF-A and soluble VEGFR-2 (sVEGFR-2) as biomarkers in advanced non-small-cell lung cancer (NSCLC). Methods: We studied 432 patients with advanced NSCLC (stages IIIB-IV) treated with cisplatin and docetaxel and 89 healthy age-matched controls. Blood samples were collected before chemotherapy, and VEGF-A and sVEGFR-2 levels were determined by ELISA. Results: VEGF-A and sVEGFR-2 levels were higher in NSCLC patients than in the controls, but VEGF-A behaves as a better diagnostic biomarker. There were no significant associations between VEGF-A and sVEGFR-2 concentrations and clinical characteristics, such as ECOG-PS, gender, stage, histology, metastases, and treatment response. A patient subgroup characterized by a combination of high VEGF-A and low sVEGFR-2 levels exhibited the worst patient prognoses in terms of TTP and OS. Conclusions: VEGF-A and sVEGFR-2 levels were significantly higher in patients than in the controls. A combination of VEGF-A and sVEGFR-2 can be used as an independent prognostic biomarker in advanced NSCLC. © 2011 Elsevier Ireland Ltd.This work was supported in part, by a grant [PI06/104] from Instituto de Salud Carlos III and a grant [RD06/0020/1024] from Red Tematica de Investigacion Cooperativa en Cancer (RTICC), Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation and European Regional Development Fund (ERDF) "Una manera de hacer Europa".Jantus Lewintre, E.; Sanmartin, E.; Sirera Pérez, R.; Blasco, A.; Sanchez, JJ.; Taron, M.; Rosell, R.... (2011). Combined VEGF-A and VEGFR-2 concentrations in plasma: diagnostic and prognostic implications in patients with advanced NSCLC. Lung Cancer. 74(2):326-331. https://doi.org/10.1016/j.lungcan.2011.02.016S32633174