High Throughput Interrogation of Somatic Mutations in High Grade Serous Cancer of the Ovary

BACKGROUND:Epithelial ovarian cancer is the most lethal of all gynecologic malignancies, and high grade serous ovarian cancer (HGSC) is the most common subtype of ovarian cancer. The objective of this study was to determine the frequency and types of point somatic mutations in HGSC using a mutation detection protocol called OncoMap that employs mass spectrometric-based genotyping technology. METHODOLOGY/PRINCIPAL FINDINGS:The Center for Cancer Genome Discovery (CCGD) Program at the Dana-Farber Cancer Institute (DFCI) has adapted a high-throughput genotyping platform to determine the mutation status of a large panel of known cancer genes. The mutation detection protocol, termed OncoMap has been expanded to detect more than 1000 mutations in 112 oncogenes in formalin-fixed paraffin-embedded (FFPE) tissue samples. We performed OncoMap on a set of 203 FFPE advanced staged HGSC specimens. We isolated genomic DNA from these samples, and after a battery of quality assurance tests, ran each of these samples on the OncoMap v3 platform. 56% (113/203) tumor samples harbored candidate mutations. Sixty-five samples had single mutations (32%) while the remaining samples had ≥ 2 mutations (24%). 196 candidate mutation calls were made in 50 genes. The most common somatic oncogene mutations were found in EGFR, KRAS, PDGRFα, KIT, and PIK3CA. Other mutations found in additional genes were found at lower frequencies (<3%). CONCLUSIONS/SIGNIFICANCE:Sequenom analysis using OncoMap on DNA extracted from FFPE ovarian cancer samples is feasible and leads to the detection of potentially druggable mutations. Screening HGSC for somatic mutations in oncogenes may lead to additional therapies for this patient population

Low adherent cancer cell subpopulations are enriched in tumorigenic and metastatic epithelial-to-mesenchymal transition-induced cancer stem-like cells

Cancer stem cells are responsible for tumor progression, metastasis, therapy resistance and cancer recurrence, doing their identification and isolation of special relevance. Here we show that low adherent breast and colon cancer cells subpopulations have stem-like properties. Our results demonstrate that trypsin-sensitive (TS) breast and colon cancer cells subpopulations show increased ALDH activity, higher ability to exclude Hoechst 33342, enlarged proportion of cells with a cancer stem-like cell phenotype and are enriched in sphere- and colony-forming cells in vitro. Further studies in MDA-MB-231 breast cancer cells reveal that TS subpopulation expresses higher levels of SLUG, SNAIL, VIMENTIN and N-CADHERIN while show a lack of expression of E-CADHERIN and CLAUDIN, being this profile characteristic of the epithelial-to-mesenchymal transition (EMT). The TS subpopulation shows CXCL10, BMI-1 and OCT4 upregulation, differing also in the expression of several miRNAs involved in EMT and/or cell self-renewal such as miR-34a-5p, miR-34c-5p, miR-21-5p, miR-93-5p and miR-100-5p. Furthermore, in vivo studies in immunocompromised mice demonstrate that MDA-MB-231 TS cells form more and bigger xenograft tumors with shorter latency and have higher metastatic potential. In conclusion, this work presents a new, non-aggressive, easy, inexpensive and reproducible methodology to isolate prospectively cancer stem-like cells for subsequent biological and preclinical studies.Ministry of Economy and Competitiveness, Instituto de Salud Carlos III (FEDER funds) PI10/02295 PI10/02149Fundacion Progreso y Salud, Consejeria de Salud, Junta de Andalucia (Ministry of Health, Government of Andalucia) PI-0533-2014Consejeria Economia, Innovacion, Ciencia y Empleo, Junta de Andalucia (Ministry of Economy, Innovation, Science and Employment, Government of Andalucia) CTS-656

Compilaci on de un corpus paralelo espa~nol{ingl es alineado a nivel de oraciones

Una de las l neas de investigaci on del Procesamiento de Lenguaje Natural se enfoca en automatizar la alineaci on de textos paralelos. La utilidad que presenta los textos paralelos alineados es que muestran de manera explicita la relaci on que existe entre los elementos de un texto en un idioma y los elementos del mismo texto traducido en otro idioma. En este trabajo de tesis, se plantea un m etodo para la alineaci on de textos paralelos a nivel de oraciones escritos en los idiomas espa~nol e ingl es, el cu al utiliza informaci on l exica y estad stica bajo un enfoque de programaci on din amica. El m etodo utiliza la informaci on l exica contenida en un diccionario biling ue espa~nol{ingl es de prop osito general restringido (incompleto), as como, la longitud de la oraci on medida en t erminos de palabras y en t erminos de caracteres. El m etodo propuesto se prob o en un corpus de textos literarios no balanceados (textos en los que la frecuencia de aparici on de alineaciones m ultiples, omisiones e inserciones es mayor), en el que report o una efectividad superior al 90 %. Se compararon los resultados obtenidos por el m etodo propuesto contra los obtenidos por el sistema Vanilla aligner (utiliza un enfoque estad stico) utilizando el mismo corpus y se encontr o que el m etodo desarrollado es superior, particularmente en los casos de alineaciones multiples, omisiones e inserciones. Por los resultados obtenidos se observa que el uso de la informaci on l exica contenida en un diccionario biling ue de uso general e informaci on estad stica en el m etodo propuesto, hacen de este un m etodo robusto para realizar la alineaci on a nivel de oraciones en textos que no presentan una traducci on t ecnica con respecto a m etodos solamente estad sticos

Brain Complete Response to Cabozantinib prior to Radiation Therapy in Metastatic Renal Cell Carcinoma

Cabozantinib represents an established vascular endothelial growth factor- (VEGF-) tyrosine kinase inhibitor (TKI) in the treatment paradigm of metastatic renal cell carcinoma (mRCC). Its activity in mRCC patients with brain metastases (BMs) has been largely underreported in prospective clinical trials. We present the unique case of a heavily pretreated mRCC patient with BMs who achieved a brain complete response to cabozantinib prior to receiving radiation therapy. We end with a literature review and discussion of the biologic rationale and growing evidence supporting the intracranial activity of cabozantinib