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BACKGROUND: The identification of prognostic biomarkers for lung squamous-cell carcinoma (SCC) pathology is crucial because of its poor prognosis. A variant of the FGFR4 (fibroblast growth factor receptor 4) gene, FGFR4-388Arg, has been associated with prognosis and is linked to oncogenesis in vitro in several types of cancer. We analyzed the association of this variant with prognosis and downstream signaling alteration in lung SCC patients. METHODS: The presence of the FGFR4-388Arg variant was determined in 114 formalin-fixed, paraffin-embedded lung SCC tissue samples by DNA genotyping and was correlated with clinicopathologic data. The activation of the protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways was determined by immunohistochemistry, and its association with the presence of FGFR4-388Arg was analyzed. RESULTS: We found that tumor differentiation status and adjuvant chemotherapy administration could be independent prognostic factors for overall survival (OS) in lymph node-affected patients, as expected. The progression-free survival and OS of patients with lymph node involvement (n = 41) and the FGFR4-388Arg genotype were significantly lower than those of patients lacking this variant (P = .035 and P = .042, respectively). Importantly, multivariate analysis supported the independent prognostic role of the FGFR4-388Arg genotype in OS (P = .025). Regarding downstream signaling, the FGFR4-388Arg genotype was not correlated with altered AKT signaling but was associated with increased MAPK activation in the SCC tumor samples (P = .017). CONCLUSION: The FGFR4-388Arg variant may represent a promising prognostic biomarker in SCC patients with lymph node involvement. For these patients, FGFR4 may be a potential therapeutic target. ; L.P.A. was funded by Instituto de Salud Carlos III (PI14/01964, PIE15/00076, C316/12/00442, and R12/0036/0028) and cofun- ded by European Union (ERDF/ESF, " Investing in Your Future " ). S.M.P. is funded by Consejería de Salud y Bienestar Social (PI-0046-2012) and Fundación Mutua Madrileña (2014). I.F. is funded by AECC (AIO2015) and Consejería de Igualdad, Salud y Políticas Sociales de la Junta de Andalucía (PI-0029-2013), andInstituto de Salud Carlos III (PI16/01311) and cofunded byEuropean Union (ERDF/ESF,"Investing in Your Future"). A.Q. isfunded by Instituto de Salud Carlos III (FI12/00429) and cofundedby European Union (ERDF/ESF,"Investing in Your Future"). The authors thank the donors and the HUVR-IBiS Biobank (Andalusian Public Health System Biobank and ISCIII-Red de Biobancos PT13/ 0010/0056) for the human specimens used in this study ; Sí

The FGFR4-388Arg variant has been related to poor prognosis in several types of cancer, including lung cancer. The mechanism underlying this association has not been addressed in detail in patients with this pathology. Here, we report that this FGFR4 variant induces MAPK and STAT3 activation and causes pro-oncogenic effects in NSCLC in vitro and in vivo. This variant induces the expression of EMT-related genes, such as N-cadherin, vimentin, Snail1 and Twist1. Indeed, the induction of N-cadherin protein expression by this variant is essential for its pro-tumorigenic role. The presence of the FGFR4-388Arg variant correlates with higher N-cadherin expression levels in clinical NSCLC samples and with poorer outcome in patients with FGFR expression. These results support the prognostic role of this FGFR variant in lung cancer and show that these effects may be mediated by the induction of N-cadherin expression and an EMT phenotype. ; L.P.A. was funded by ISCIII (PI14/01964 and PIE15/00076), CIBER (CB16/12/00442) and RTICC (R12/0036/0028) and co-funded by European Union (ERDF/ESF, "Investing in your future"). The laboratory of A.C. was supported by grants from the Spanish Ministry of Economy and Competitiveness, PN I+D+I 2008-2011, PE I+D+I 2013-2016, ISCIII (PI15/00045 and CB16/12/00275), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0096-2014). S.M.P. is funded by Consejería de Salud y Bienestar Social (PI-0046-2012), ISCIII (PI17/00033) and co-funded by European Union (ERDF/ESF, "Investing in your future"), and Fundación Mutua Madrileña (2014). I.F. is funded by AECC (AIO2015) and Consejería de Igualdad, Salud y Políticas Sociales de la Junta de Andalucía (PI-0029-2013) and FIS (PI16/01311). A.Q. is funded by ISCIII (FI12/00429). L.O. is funded by Ministerio de Educación, Cultura y Deporte (FPU13/02595). ; Peer reviewed

Lung tumors represent a major health problem. In early stage NSCLC tumors, surgical resection is the preferred treatment, but 30-55% of patients will relapse within 5 years after surgery. Thus, the identification of prognostic biomarkers in early stage NSCLC patients, especially those which are therapeutically addressable, is crucial to enhance survival of these patients. We determined the immunohistochemistry expression of key proteins involved in tumorigenesis and oncogenic signaling, p53, EGFR, pAKT and pERK, and correlated their expression level to clinicopathological characteristics and patient outcome. We found EGFR expression is higher in the squamous cell carcinomas than in adenocarcinomas (p=0.043), and that nuclear p53 staining correlated with lower differentiated squamous tumors (p=0.034). Regarding the prognostic potential of the expression of these proteins, high pERK levels proved to be an independent prognostic factor for overall (p<0.001) and progression-free survival (p<0.001) in adenocarcinoma patients, but not in those from the squamous histology, and high p53 nuclear levels were identified as independent prognostic factor for progression-free survival (p=0.031) only in squamous cell carcinoma patients. We propose a role as early prognostic biomarkers for pERK protein levels in adenocarcinoma, and for nuclear p53 levels in squamous cell lung carcinoma. The determination of these potential biomarkers in the adequate histologic context may predict the outcome of early stage NSCLC patients, and may offer a therapeutic opportunity to enhance survival of these patients. ; L.P.A. was funded by Instituto de Salud Carlos III (PI14/01964, PIE15/00076, CB16/12/00442, and R12/0036/0028) and co-funded by the European Union (ERDF/ESF, "Investing in your future"). The laboratory of A.C. was supported by grants from the Spanish Ministry of Economy and Competitiveness (PN I+D+I 2008-2011 and PE I+D+I 2013-2016), Instituto de Salud Carlos III (PI15/00045 and CB16/12/00275) and co-funded by the European Union (ERDF/ESF, "Investing in your future"), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0096-2014). S.M.P. is funded by Fundación Mutua Madrileña (2014) and Instituto de Salud Carlos III (PI17/00033) and co-funded by the European Union (ERDF/ESF, "Investing in your future"). I.F. is funded by AECC (AIO2015) and Consejería de Igualdad, Salud y Políticas Sociales de la Junta de Andalucía (PI-0029-2013) and Instituto de Salud Carlos III (PI16/01311) and co-funded by the European Union (ERDF/ESF, "Investing in your future"). A.Q. is funded by Instituto de Salud Carlos III (FI12/00429) and co-funded by the European Union (ERDF/ ESF, "Investing in your future"). ; Sí

The FGFR4-388Arg variant has been related to poor prognosis in several types of cancer, including lung cancer. The mechanism underlying this association has not been addressed in detail in patients with this pathology. Here, we report that this FGFR4 variant induces MAPK and STAT3 activation and causes pro-oncogenic effects in NSCLC in vitro and in vivo. This variant induces the expression of EMT-related genes, such as N-cadherin, vimentin, Snail1 and Twist1. Indeed, the induction of N-cadherin protein expression by this variant is essential for its pro-tumorigenic role. The presence of the FGFR4-388Arg variant correlates with higher N-cadherin expression levels in clinical NSCLC samples and with poorer outcome in patients with FGFR expression. These results support the prognostic role of this FGFR variant in lung cancer and show that these effects may be mediated by the induction of N-cadherin expression and an EMT phenotype. ; The authors thank the donors and the HUVR-IBiS Biobank (Andalusian Public Health System Biobank and ISCIII-Red de Biobancos PT13/0010/0056) for the human specimens used in this study. L.P.A. was funded by ISCIII (PI14/01964 and PIE15/00076), CIBER (CB16/12/00442) and RTICC (R12/0036/0028) and co-funded by European Union (ERDF/ESF, "Investing in your future"). The laboratory of A.C. was supported by grants from the Spanish Ministry of Economy and Competitiveness, PN I + D + I 2008-2011, PE I + D + I 2013-2016, ISCIII (PI15/00045 and CB16/12/00275), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0096-2014). S.M.P. is funded by Consejería de Salud y Bienestar Social (PI- 0046-2012), ISCIII (PI17/00033) and co-funded by European Union (ERDF/ESF, "Investing in your future"), and Fundación Mutua Madrileña (2014). I.F. is funded by AECC (AIO2015) and Consejería de Igualdad, Salud y Políticas Sociales de la Junta de Andalucía (PI-0029-2013) and FIS (PI16/01311). A.Q. is funded by ISCIII (FI12/00429). L.O. is funded by Ministerio de Educación, Cultura y Deporte (FPU13/02595) ; Sí

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al. ; Squamous cell lung cancer (SCC) and adenocarcinoma are the most common histological subtypes of non-small cell lung cancer (NSCLC), and have been traditionally managed in the clinic as a single entity. Increasing evidence, however, illustrates the biological diversity of these two histological subgroups of lung cancer, and supports the need to improve our understanding of the molecular basis beyond the different phenotypes if we aim to develop more specific and individualized targeted therapy. The purpose of this study was to identify microRNA (miRNA)-dependent transcriptional regulation differences between SCC and adenocarcinoma histological lung cancer subtypes. In this work, paired miRNA (667 miRNAs by TaqMan Low Density Arrays (TLDA)) and mRNA profiling (Whole Genome 44 K array G112A, Agilent) was performed in tumor samples of 44 NSCLC patients. Nine miRNAs and 56 mRNAs were found to be differentially expressed in SCC versus adenocarcinoma samples. Eleven of these 56 mRNA were predicted as targets of the miRNAs identified to be differently expressed in these two histological conditions. Of them, 6 miRNAs (miR-149, miR-205, miR-375, miR-378, miR- 422a and miR-708) and 9 target genes (CEACAM6, CGN, CLDN3, ABCC3, MLPH, ACSL5, TMEM45B, MUC1) were validated by quantitative PCR in an independent cohort of 41 lung cancer patients. Furthermore, the inverse correlation between mRNAs and microRNAs expression was also validated. These results suggest miRNA-dependent transcriptional regulation differences play an important role in determining key hallmarks of NSCLC, and may provide new biomarkers for personalized treatment strategies. ; LPA is funded by Fondo de Investigación Sanitaria (PI081156, PI1102688 and R12/0036/0028), Proyecto de Excelencia de la Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía (P08-CVI-04090), and the Roche Fellowship in 75th Anniversary, Spain. SMP is funded by Fondo de Investigación Sanitaria (CD1100153), Fundación Científica de la Asociación Española Contra el Cáncer, Consejería de Salud, Servicio Andaluz de Salud (PI-0224/2009 and PI-0046/2012), and Fundación Mutua Madrileña (2009). MDP is funded by Fondo de Investigación Sanitaria (CD0900148). RGC is funded by Fondo de Investigación Sanitaria (PI10/02164). GMB is funded by SAF2010-20175 and Madrid Regional Government (S2010/BMD-2303). AC lab was supported by grants to from the Spanish Ministry of Economy and Competitivity, ISCIII (PI12/00137, RTICC: RD12/0036/0028), Consejeria de Ciencia e Innovacion (CTS-6844) and Consejeria de Salud of the Junta de Andalucia (PI-0135-2010 and PI-0306-2012). ; Peer reviewed

Cancer treatment involves the participation of multiple medical specialties and, as our knowledge of the disease increases, this fact becomes even more apparent. The degree of multidisciplinarity is determined by several factors, which include the severity and type of disease, the increasing diversity in the available pharmacological and non-pharmacological therapies, and the range of specialists involved in cancer therapy, such as medical oncologists, radiotherapists, gynecologists, gastroenterologists, urologists, surgeons, and pneumologists, among others. Across Europe, the situation of cancer care can be variable due to the diversity of health systems, differences in drug reimbursement, and the degree of establishment of Medical Oncology as a medical specialty in the European Union states.

[Rationale]: The characterization of new genetic alterations is essential to assign effective personalized therapies in non–small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is essential for successful personalized therapies. Molecular alterations of YES1, a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found in a significant subset of patients with lung cancer. ; [Objectives]: To evaluate YES1 (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) genetic alteration as a therapeutic target and predictive biomarker of response to dasatinib in NSCLC. ; [Methods]: Functional significance was evaluated by in vivo models of NSCLC and metastasis and patient-derived xenografts. The efficacy of pharmacological and genetic (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 [CRISPR-associated protein 9]) YES1 abrogation was also evaluated. In vitro functional assays for signaling, survival, and invasion were also performed. The association between YES1 alterations and prognosis was evaluated in clinical samples. ; [Measurements and Main Results]: We demonstrated that YES1 is essential for NSCLC carcinogenesis. Furthermore, YES1 overexpression induced metastatic spread in preclinical in vivo models. YES1 genetic depletion by CRISPR/Cas9 technology significantly reduced tumor growth and metastasis. YES1 effects were mainly driven by mTOR (mammalian target of rapamycin) signaling. Interestingly, cell lines and patient-derived xenograft models with YES1 gene amplifications presented a high sensitivity to dasatinib, an SFK inhibitor, pointing out YES1 status as a stratification biomarker for dasatinib response. Moreover, high YES1 protein expression was an independent predictor for poor prognosis in patients with lung cancer. ; [Conclusions]: YES1 is a promising therapeutic target in lung cancer. Our results provide support for the clinical evaluation of dasatinib treatment in a selected subset of patients using YES1 status as predictive biomarker for therapy. ; Supported by Fundación para la Investigación Médica Aplicada (FIMA), Spanish Ministry of Economy and Innovation and Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional grants 12/02040, PI13/00806, PI16/01821, PI16/00280, RTICC RD12/0036/0040, and SAF2015-6455-R; Centro de Investigación Biomédica en Red de Cáncer grants CB16/12/00390, CB16/12/00390, CB16/12/00442, and CB16/12/00443; Asociación Española Contra el Cáncer (AECC) Scientific Foundation grant GCB14-2170; Bristol-Myers Squibb (preclinical research agreement); AECC and a fellowship from the Basque Government (I.G.); the Castilla-León Government grant CSI049 U16 , the Ministry of Economy and Competitiveness grant SAF2015-64556-R , the Fundación Ramón Areces, Worldwide Cancer Research grant 14-1248 , and AECC Scientific Foundation grant GC16173472GARC (X.R.B.); and the Spanish Ministry of Science, Innovation and Universities (MCIU, RTI 2018-094507-B-100), La Caixa Foundation and Caja Navarra Foundation (F.L.). ; Peer reviewed

Rapid and continuing advances in biomarker testing are not being matched by take-up in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. This paper sets out the potential of biomarker testing, the unfolding precision and range of possible diagnosis and prediction, and the many obstacles to adoption. It offers case studies of biomarker testing in breast, ovarian, prostate, lung, thyroid and colon cancers, and derives specific lessons as to the potential and actual use of each of them. It also draws lessons about how to improve access and alignment, and to remedy the data deficiencies that impede development. And it suggests solutions to outstanding issues − notably including funding and the tangled web of obtaining reimbursement or equivalent coverage that Europe's fragmented health system implies. It urges a European evolution towards an initial minimum testing scenario, which would guarantee universal access to a suite of biomarker tests for the currently most common conditions, and, further into the future, to an optimum testing scenario in which a much wider range of biomarker tests would be introduced and become part of a more sophisticated health system articulated around personalised medicine. For exploiting genomics to the full, it argues the need for a new policy framework for Europe. Biomarker testing is not an issue that can be treated in isolation, since the purpose of testing is to improve health. Its use is therefore always closely linked to specific health challenges and needs to be viewed in the broader policy context in the EU and more widely. The paper is the result of extensive engagement with experts and decision makers to develop the framework, and consequently represents a wide consensus of views on how healthcare systems should respond from push and pull factors at local, national and cross-border and EU level. It contains strong views and clear ...

Rapid and continuing advances in biomarker testing are not being matched by take-up in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. This paper sets out the potential of biomarker testing, the unfolding precision and range of possible diagnosis and prediction, and the many obstacles to adoption. It offers case studies of biomarker testing in breast, ovarian, prostate, lung, thyroid and colon cancers, and derives specific lessons as to the potential and actual use of each of them. It also draws lessons about how to improve access and alignment, and to remedy the data deficiencies that impede development. And it suggests solutions to outstanding issues - notably including funding and the tangled web of obtaining reimbursement or equivalent coverage that Europe's fragmented health system implies. It urges a European evolution towards an initial minimum testing scenario, which would guarantee universal access to a suite of biomarker tests for the currently most common conditions, and, further into the future, to an optimum testing scenario in which a much wider range of biomarker tests would be introduced and become part of a more sophisticated health system articulated around personalised medicine. For exploiting genomics to the full, it argues the need for a new policy framework for Europe. Biomarker testing is not an issue that can be treated in isolation, since the purpose of testing is to improve health. Its use is therefore always closely linked to specific health challenges and needs to be viewed in the broader policy context in the EU and more widely. The paper is the result of extensive engagement with experts and decision makers to develop the framework, and consequently represents a wide consensus of views on how healthcare systems should respond from push and pull factors at local, national and cross-border and EU level. It contains strong views and clear recommendations springing from the convictions of patients, clinicians, academics, medicines authorities, HTA bodies, payers, the diagnostic, pharmaceutical and ICT industries, and national policy makers.