Genome profiling of ERBB2-amplified breast cancers

<p>Abstract</p> <p>Background</p> <p>Around 20% of breast cancers (BC) show <it>ERBB2 </it>gene amplification and overexpression of the ERBB2 tyrosine kinase receptor. They are associated with a poor prognosis but can benefit from targeted therapy. A better knowledge of these BCs, genomically and biologically heterogeneous, may help understand their behavior and design new therapeutic strategies.</p> <p>Methods</p> <p>We defined the high resolution genome and gene expression profiles of 54 <it>ERBB2</it>-amplified BCs using 244K oligonucleotide array-comparative genomic hybridization and whole-genome DNA microarrays. Expression of ERBB2, phosphorylated ERBB2, EGFR, IGF1R and FOXA1 proteins was assessed by immunohistochemistry to evaluate the functional ERBB2 status and identify co-expressions.</p> <p>Results</p> <p>First, we identified the <it>ERBB2</it>-<it>C17orf37</it>-<it>GRB7 </it>genomic segment as the minimal common 17q12-q21 amplicon, and <it>CRKRS </it>and <it>IKZF3 </it>as the most frequent centromeric and telomeric amplicon borders, respectively. Second, GISTIC analysis identified 17 other genome regions affected by copy number aberration (CNA) (amplifications, gains, losses). The expression of 37 genes of these regions was deregulated. Third, two types of heterogeneity were observed in <it>ERBB2</it>-amplified BCs. The genomic profiles of estrogen receptor-postive (ER+) and negative (ER-) <it>ERBB2</it>-amplified BCs were different. The WNT/β-catenin signaling pathway was involved in ER- <it>ERBB2</it>-amplified BCs, and <it>PVT1 </it>and <it>TRPS1 </it>were candidate oncogenes associated with ER+ <it>ERBB2</it>-amplified BCs. The size of the <it>ERBB2 </it>amplicon was different in inflammatory (IBC) and non-inflammatory BCs. <it>ERBB2</it>-amplified IBCs were characterized by the downregulated and upregulated mRNA expression of ten and two genes in proportion to CNA, respectively. IHC results showed (i) a linear relationship between <it>ERBB2 </it>gene amplification and its gene and protein expressions with a good correlation between ERBB2 expression and phosphorylation status; (ii) a potential signaling cross-talk between EGFR or IGF1R and ERBB2, which could influence response of <it>ERBB2</it>-positive BCs to inhibitors. FOXA1 was frequently coexpressed with ERBB2 but its expression did not impact on the outcome of patients with <it>ERBB2</it>-amplified tumors.</p> <p>Conclusion</p> <p>We have shown that ER+ and ER- <it>ERBB2</it>-amplified BCs are different, distinguished <it>ERBB2 </it>amplicons in IBC and non-IBC, and identified genomic features that may be useful in the design of alternative therapeutical strategies.</p

Fire Regime, Climate, and Vegetation in the Sierras de Córdoba, Argentina

Wildfires are a primary disturbance in the Sierras de Córdoba, Argentina, with approximately 2 152 000 ha burned between 1993 and 2012. However, little is known about the spatial and temporal patterns of fires and their relationship with climate and vegetation in this area. Such information is of great value for fire risk assessment and the development of strategies for fire management. Our main objective was to analyze fire activity in four sierran ranges, assessing which weather and climate conditions were mostly related to fire activity, and which land cover types were mostly burned. We used a fire database of mid-high spatial resolution and a land cover map derived from Landsat imagery. Fire regimes were different among the different sierran ranges. The Sierras Chicas range was the most affected by fires, with the largest number of fire events, burned area, and fire frequency. Although large fires represented 3% to 5% of fire events, they accounted for 60% to 86% of total burned area in different sierran ranges. Sierras of lower elevation had a winter seasonality of fires, while sierras of higher elevation had a winter-spring or spring fire seasonality. The number of fire events was positively correlated with preceding periods that were wetter than normal, while the burned area was mainly associated with midterm weather conditions. Fires occurred mainly in grasslands and shrublands, but the area of burned forests was important, too. Our results will be useful to determine the times and conditions in which fire risk is highest, and also to identify where preventive efforts should be focused.Los incendios constituyen uno de los principales disturbios en las Sierras de Córdoba, Argentina, acumulando aproximadamente 2152000 ha quemadas entre 1993 y 2012. Sin embargo, poco se conoce acerca de los patrones espaciales y temporales del fuego y su relación con el clima y la vegetación del lugar. Esta información es de gran valor para la evaluación del riesgo de incendios y para la implementación de estrategias de manejo del fuego. Nuestro objetivo fue analizar los incendios en cuatro sistemas serranos, evaluando las condiciones meteorológicas y climáticas que favorecen la ocurrencia de incendios y los tipos de vegetación que más se queman. Utilizamos una base de datos de incendios de resolución espacial media-alta y un mapa de cubiertas de suelo obtenido a partir de imágenes Landsat. Los regímenes de fuego fueron diferentes en los distintos sistemas serranos. Las Sierras Chicas fueron las más afectadas por el fuego, presentando el mayor número de eventos, área quemada y frecuencia de incendios. Los grandes incendios representaron entre 3% y 5% de los incendios, sin embargo,quemaron entre 60% y 86% del área quemada total en los diferentes sistemas serranos. Las sierras de menor altitud presentaron una estacionalidad de incendios invernal, mientras que las sierras de mayor altitud presentaron una estacionalidad inverno-primaveral o primaveral. El número de incendios se correlacionó positivamente con periodos precedentes de mayor humedad, mientras que el área quemada se correlacionó con las condiciones meteorológicas ocurrentes en el mediano plazo. Los incendios ocurrieron principalmente en áreas de pastizal y arbustal, aunque la superficie de bosques quemados fue importante también. Nuestros resultados serán de utilidad para determinar los momentos y condiciones de mayor riesgo de incendios y también para identificar las áreas donde se deben concentrar los esfuerzos preventivosInstituto de Recursos BiológicosFil: Argañaraz, Juan Pablo. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Cordoba. Instituto de Diversidad y Ecologia Animal; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; ArgentinaFil: Gavier Pizarro, Gregorio Ignacio. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Recursos Biológicos; ArgentinaFil: Zak, Marcelo Román. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Geografia; ArgentinaFil: Bellis, Laura Marisa. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Cordoba. Instituto de Diversidad y Ecologia Animal; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Diversidad y Ecología Animal; Argentin