Epigenetic homogeneity within colorectal tumors predicts shorter relapse-free and overall survival times for patients with locoregional cancer

Background & aims: there are few validated biomarkers that can be used to predict outcomes for patients with colorectal cancer. Part of the challenge is the genetic and molecular heterogeneity of colorectal tumors not only among patients, but also within tumors. We have explored intratumor heterogeneity at the epigenetic level, due to its dynamic nature. We analyzed DNA methylation profiles of the digestive tract surface and the central bulk and invasive front regions of colorectal tumors. Methods: we determined the DNA methylation profiles of >450,000 CpG sites in 3 macrodissected regions of 79 colorectal tumors and 23 associated liver metastases, obtained from 2 hospitals in Spain. We also analyzed samples for KRAS and BRAF mutations, 499,170 single nucleotide polymorphisms, and performed immunohistochemical analyses. Results: we observed differences in DNA methylation among the 3 tumor sections; regions of tumor−host interface differed the most from the other tumor sections. Interestingly, tumor samples collected from areas closer to the gastrointestinal transit most frequently shared methylation events with metastases. When we calculated individual coefficients to quantify heterogeneity, we found that epigenetic homogeneity was significantly associated with short time of relapse-free survival (log-rank P = .037) and short time of overall survival (log-rank P = .026) in patients with locoregional colorectal cancer. Conclusions: in an analysis of 79 colorectal tumors, we found significant heterogeneity in patterns of DNA methylation within each tumor; the level of heterogeneity correlates with times of relapse-free and overall survival

Actividades educativas en el yacimiento de vertebrados miócenos de Somosaguas (Universidad Complutense, Pozuelo de Alarcón, Madrid)

Depto. de Geodinámica, Estratigrafía y PaleontologíaFac. de Ciencias GeológicasTRUEpu

Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR

Metastasis is respoMetastasis is responsible for most cancer-related deaths, and, among common tumor types, melanoma is one with great potential to metastasize. Here we study the contribution of epigenetic changes to the dissemination process by analyzing the changes that occur at the DNA methylation level between primary cancer cells and metastases. We found a hypomethylation event that reactivates a cryptic transcript of the Rab GTPase activating protein TBC1D16 (TBC1D16-47 kDa; referred to hereafter as TBC1D16-47KD) to be a characteristic feature of the metastatic cascade. This short isoform of TBC1D16 exacerbates melanoma growth and metastasis both in vitro and in vivo. By combining immunoprecipitation and mass spectrometry, we identified RAB5C as a new TBC1D16 target and showed that it regulates EGFR in melanoma cells. We also found that epigenetic reactivation of TBC1D16-47KD is associated with poor clinical outcome in melanoma, while conferring greater sensitivity to BRAF and MEK inhibitors

Analysis of mutant allele fractions in driver genes in colorectal cancer - biological and clinical insights

Sequencing of tumors is now routine and guides personalized cancer therapy. Mutant allele fractions (s, or the 'mutation dose') of a driver gene may reveal the genomic structure of tumors and influence response to targeted therapies. We performed a comprehensive analysis of s of driver alterations in unpaired primary and metastatic colorectal cancer () at our institution from 2010 to 2015 and studied their potential clinical relevance. Of 763 samples, 622 had detailed annotation on overall survival in the metastatic setting (met) and 89 received targeted agents matched to ( inhibitors), ( inhibitors), or 3 mutations (3K pathway inhibitors). s of each variant were normalized for tumor purity in the sample (adjs). We found lower adjs for 600E and 3 than for , , and non-V600 variants. 53 and 600E adjs were higher in metastases as compared to primary tumors, and high adjs were found in metastases of patients with wild-type primary tumors previously exposed to antibodies. Patients with - or 600E -mutated tumors, irrespective of adjs, had worse met. There was no significant association between adjs and time to progression on targeted therapies matched to , , or 3 mutations, potentially related to the limited antitumor activity of the employed drugs (overall response rate of 4.5%). In conclusion, the lower 600E and 3 adjs in subsets of primary tumors indicate subclonality of these driver genes. Differences in adjs between metastases and primary tumors suggest that approved therapies may result in selection of 600E - and -resistant clones and an increase in genomic heterogeneity with acquired 53 alterations. Despite significant differences in prognosis according to mutations in driver oncogenes, adjs levels did not impact on survival and did not help predict benefit with matched targeted agents in the metastatic setting

Uso de los servicios para.TI@UCM para mejorar la gestión académica en los departamentos

En este proyecto pretendemos poner en práctica las distintas posibilidades de gestión académica a nivel departamental que ofrecen las herramientas de Google y que han sido integradas en el conjunto de servicios para.TI@UCM (Gmail, Hangouts, Docs, Drive, Calendar, etc.), con el fin de agilizar y facilitar los distintos niveles de gestión que los departamentos realizan hoy en día

Los fósiles de Vertebrados de Somosaguas (Pozuelo, Madrid)

Dos yacimientos de vertebrados, situados en el Campus de Somosaguas de la Universidad Complutense (Pozuelo de Alarcón, Madrid), han proporcionado unos 600 restos identificables en estados de conservación muy variados, pertenecientes a unas veinte especies de tamaños muy diversos, desde mastodontes a musarañas. Su estudio permite fechar su edad en unos 14 m.a. y reconstruir un periodo árido en la cuenca de Madrid, ocupada durante el Mioceno medio por bosques y sabanas subtropicales con fuertes avenidas y sin ríos permanentes. En estos yacimientos se puede realizar una enseñanza práctica de la Paleontología de Vertebrados, para formación de estudiantes universitarios en el estudio y la gestión del Patrimonio Paleontológico. [ABSTRACT] Two vertebrate fossil sites, situated in the Universidad Complutense Campus of Somosaguas, (Pozuelo de Alarcón, Madrid, Spain) have yielded about 600 identifiable rests in different preservation states, belonging to about twenty species of highly diverse sizes, from mastodons to shrews. Their study allows dating at about 14 m.y., and reconstructing an arid climate epoch in the Madrid basin during middle Miocene times, occupied by subtropical woodlands and savannahs with strong floods and without permanent rivers. These fossil sites allow practical teaching of Vertebrate Palaeontology, and preparing university students in the Palaeontological Heritage study and management

Monitoring of RAS mutant clones in plasma of patients with RAS mutant metastatic colorectal cancer.

Some patients with histologically confirmed primary mCRC and mutated RAS reported undetectable RAS mutant clones in plasma after receiving anti-VEGF treatment. The aim was to prospectively assess it with its potential therapeutic implications. RAS mutant genes in solid biopsy (before first-line treatment: FOLFOX/CAPOX + bevacizumab) were compared in liquid biopsy (before second-line treatment: panitumumab + FOLFIRI), using Idylla™ system. Discordant results between solid/liquid biopsies were assessed by the next-generation sequencing (NGS) test (solid/liquid biopsies). Twenty-three patients were assessed (seven had RAS mutant discrepancies between solid/liquid biopsies). The NGS test confirmed that 3/23 (13%) patients had undetectable RAS mutant clones in liquid biopsy and 3/23 (13%) presented discrepancies in solid biopsy (Idylla™ system vs. NGS test). Thirteen percentage of patients had undetectable RAS mutant clones in liquid biopsy after first-line treatment. However, some discrepancies between solid and liquid biopsies have been observed. These results suggest a need to improve accuracy of RAS analyses, especially in solid biopsies

Epigenetic homogeneity within colorectal tumors predicts shorter relapse-free and overall survival times for patients with locoregional cancer

Background & aims: there are few validated biomarkers that can be used to predict outcomes for patients with colorectal cancer. Part of the challenge is the genetic and molecular heterogeneity of colorectal tumors not only among patients, but also within tumors. We have explored intratumor heterogeneity at the epigenetic level, due to its dynamic nature. We analyzed DNA methylation profiles of the digestive tract surface and the central bulk and invasive front regions of colorectal tumors. Methods: we determined the DNA methylation profiles of >450,000 CpG sites in 3 macrodissected regions of 79 colorectal tumors and 23 associated liver metastases, obtained from 2 hospitals in Spain. We also analyzed samples for KRAS and BRAF mutations, 499,170 single nucleotide polymorphisms, and performed immunohistochemical analyses. Results: we observed differences in DNA methylation among the 3 tumor sections; regions of tumor−host interface differed the most from the other tumor sections. Interestingly, tumor samples collected from areas closer to the gastrointestinal transit most frequently shared methylation events with metastases. When we calculated individual coefficients to quantify heterogeneity, we found that epigenetic homogeneity was significantly associated with short time of relapse-free survival (log-rank P = .037) and short time of overall survival (log-rank P = .026) in patients with locoregional colorectal cancer. Conclusions: in an analysis of 79 colorectal tumors, we found significant heterogeneity in patterns of DNA methylation within each tumor; the level of heterogeneity correlates with times of relapse-free and overall survival

ESI-07 ShakeMaps for instrumental and historical events in the Betic Cordillera (SE Spain): An approach based on geological data and applied to seismic hazard

Parte especial del número: "Quaternary Earthquakes: Geology and Palaeoseismology for Seismic Hazard Assessment"This work presents high-resolution ShakeMaps for three earthquakes occurred in the Betic Cordillera (SE Spain): the 2011 CE Lorca event (VIII ESI-07), the 1863 CE Huércal-Overa event (VIII ESI-07) and the 1829 CE Torrevieja event (X ESI-07). Detailed field characterizations and mapping of their coseismic environmental effects (EEEs) are catalogued and classified following the ESI-07 scale. The resulting macroseismic information reaches up to ten times the existing information based on conventional damage-based scales (e.g. EMS-98), providing a better constrain towards more realistic ground-motion scenarios. The 2011 Lorca earthquake has been used as a calibration event, since there is a relevant record of instrumental measures on source, and ground-motion parameters allowing a direct comparison with the modelled PGA values. From a methodological standpoint, the obtained ShakeMaps follow the basic guidelines and methodology proposed by the USGS ShakeMap Program. The two historical earthquakes analysed in this paper produced a wide variety of secondary EEEs but no surface faulting was reported. These effects need to be properly identified by high-resolution DTMs (5 m/pixel), far from the c. 900 m/pixel terrain models used by USGS program. Additionally, the proposed ESI-07 ShakeMaps incorporate correction factors to solve inconsistencies derived from the large scale terrain models considered in standard USGS program workflows: (1) empirical slope-derived Vs30 models result in overestimations of the PGA values in flat terrains in absence of unconsolidated deposits; (2) the topographic amplification factor included here, explains the occurrence of rock-falls and landslides in steep areas, where ground motion is underestimated by the sole use of slope-derived Vs30 models. Basic geological and geomorphological information need to be implemented in the modelling workflow in both cases. To prevent PGA overestimations in flat terrains a correction factor related to the spatial distribution and thickness of the Quaternary unconsolidated deposits has been incorporated (i.e. isopach maps). To correct PGA underestimations in steep terrains an amplification factor was modelled following standard guidelines of seismic topographic amplification. The comparison via iteration of the spatial distribution of both ESI effects and EMS macroseismic data, with the obtained ground-motion spatial distribution, enables a better definition of the geological parameters for the studied historical earthquakes. A more accurate location and/or size of the suspect seismic sources are obtained for these historical earthquakes, providing scenarios more realistic than those resulting from old intensity maps. Quaternary Geology and Geomorphology are behind the implementation of the proposed ESI-07 ShakeMaps, being especially useful when exploring historic or ancient moderate earthquakes with scarce damage-based macroseismic data, but with sufficient paleoseismic or archaeoseismic records. In summary, the methodological workflow proposed here contemplates the implementation of a computational configuration seismologically relevant and able to test repeated seismic scenarios, with different parametric data, in a controlled GIS environment useful to reproduce historical events.Departamento de Geología, Universidad de Salamanca, EspañaDepartamento de Geología y Geoquímica, Universidad Autónoma de Madrid, EspañaInstituto Geológico y Minero de España, EspañaDepartamento de Edafología, Universidad Politécnica de Madrid, EspañaUnidad Docente de Geología, Universidad de Alcalá, Españ