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Meric-Bernstam F.,University of Houston | Meric-Bernstam F.,The Surgical Center | Frampton G.M.,Foundation Medicine | Yelensky R.,Foundation Medicine | And 17 more authors.
Molecular Cancer Therapeutics | Year: 2014

There is growing interest in delivering genomically informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 3,320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copynumber alterations (CNA), and select rearrangements were assessed in 74 tumors from 43 patients (36 primary and 38 recurrence/metastases). Alterations potentially targetable with established or investigational therapeutics were considered "actionable." Alterations were detected in 55 genes (mean 3.95 alterations/sample, range 1-12), including mutations in PIK3CA, TP53, ARID1A, PTEN, AKT1, NF1, FBXW7, and FGFR3 and amplifications in MCL1, CCND1, FGFR1,MYC, IGF1R,MDM2,MDM4, AKT3, CDK4, and AKT2. In 33 matched primary and recurrent tumors, 97 of 112 (86.6%) somatic mutations were concordant. Of identified CNAs, 136 of 159 (85.5%) were concordant: 37 (23.3%) were concordant, but below the reporting threshold in one of the matched samples, and 23 (14.5%) discordant. There was an increased frequency ofCDK4/MDM2amplifications in recurrences, as well as gains and losses of other actionable alterations. Forty of 43 (93%) patients had actionable alterations that could inform targeted treatment options. In conclusion, deep genomic profiling of cancer-related genes reveals potentially actionable alterations in most patients with breast cancer. Overall there was high concordance between primary and recurrent tumors. Analysis of recurrent tumors before treatment may provide additional insights, as both gains and losses of targets are observed. © 2014 American Association for Cancer Research. Source

Martinez-Cadenas C.,University of Castellon | Lopez S.,University of the Basque Country | Ribas G.,INCLIVA Biomedical Research Institute | Flores C.,University Hospital Ns Of Candelaria | And 14 more authors.
Molecular Biology and Evolution | Year: 2013

In humans, the geographical apportionment of the coding diversity of the pigmentary locus melanocortin-1 receptor (MC1R) is, unusually, higher in Eurasians than in Africans. This atypical observation has been interpreted as the result of purifying selection due to functional constraint on MC1R in high UV-B radiation environments. By analyzing 3,142 human MC1R alleles from different regions of Spain in the context of additional haplotypic information from the 1000 Genomes (1000G) Project data, we show that purifying selection is also strong in southern Europe, but not so in northern Europe. Furthermore, we show that purifying and positive selection act simultaneously on MC1R. Thus, at least in Spain, regions at opposite ends of the incident UV-B radiation distribution show significantly different frequencies for the melanoma-risk allele V60L (a mutation also associated to red hair and fair skin and even blonde hair), with higher frequency of V60L at those regions of lower incident UV-B radiation. Besides, using the 1000G south European data, we show that the V60L haplogroup is also characterized by an extended haplotype homozygosity (EHH) pattern indicative of positive selection. We, thus, provide evidence for an adaptive value of human skin depigmentation in Europe and illustrate how an adaptive process can simultaneously help to maintain a disease-risk allele. In addition, our data support the hypothesis proposed by Jablonski and Chaplin (Human skin pigmentation as an adaptation to UVB radiation. Proc Natl Acad Sci USA. 2010;107:8962-8968), which posits that habitation of middle latitudes involved the evolution of partially depigmented phenotypes that are still capable of suitable tanning. © 2013 The Author. Source

Martinez-Arroyo A.M.,University of Valencia | Martinez-Arroyo A.M.,INCLIVA Biomedical Research Institute | Medrano J.V.,University of Valencia | Medrano J.V.,Fundacion Institute Investigacion Sanitaria La Fe | And 5 more authors.
Current Opinion in Genetics and Development | Year: 2014

Current knowledge about mammalian germ line development is mainly based on the mouse model and little is known about how this fundamental process occurs in humans. This review summarizes our current knowledge of genetic and epigenetic germ line development in mammals, mainly focusing on primordial germ cell (PGC) specification events, comparing the differences between mouse and human models. We also emphasize the knowledge derived from the most successful strategies used to generate germ cell-like cells in vitro in both models and major obstacles to obtaining bona fide in vitro-derived gametes are considered. © 2014 Elsevier Ltd. Source

Garrido-Gomez T.,Instituto Universitario | Garrido-Gomez T.,INCLIVA Biomedical Research Institute | Quinonero A.,Instituto Universitario | Antunez O.,University of Valencia | And 7 more authors.
Human Reproduction | Year: 2014

STUDY QUESTION Are there any proteomic differences between receptive (R) and non-receptive (NR) endometrial receptivity array (ERA)-diagnosed endometria obtained on the same day of a hormonal replacement therapy (HRT) treatment cycle? SUMMARY ANSWER There is a different proteomic signature between R and NR ERA-diagnosed endometrium obtained on the same day of HRT cycles. WHAT IS KNOWN ALREADY The human endometrial transcriptome has been extensively investigated in the last decade resulting in the development of a new diagnostic test based on the transcriptomic signature of the window of implantation (WOI). Much less is known about the proteomics derived from the transcripts present during the WOI. STUDY DESIGN, SIZE, AND DURATION This study was a basic proteomic analysis of human endometrial biopsies taken from twelve IVF patients. PARTICIPANTS/ MATERIALS, SETTING, AND METHODS Human endometrial biopsies were collected during HRT cycles after 5 days of progesterone (P) administration, and diagnosed as receptive (R; n = 6) or non-receptive (NR; n = 6) by the ERA test. Endometrial proteins were extracted, labelled and separated using differential in-gel electrophoresis (DIGE). Proteins were identified using mass spectrometry, followed up by in silico analysis. Validation studies using western blots and immunolocalization were performed for the progesterone receptor membrane component 1 (PGRMC1) and annexin A6 (ANXA6) proteins. MAIN RESULTS AND THE ROLE OF CHANCE DIGE analysis followed by protein identification by MALDI-MS and database searches revealed 24 differentially expressed proteins in R versus NR samples. In silico analysis showed two pathways which were significantly different between R and NR samples. Expression of PGRMC1 and ANXA6 was validated and localized by western blots and immunohistochemistry. These results highlight these proteins as key targets likely to be important in the comprehension of human endometrial receptivity. LIMITATIONS, REASONS FOR CAUTION This was mainly a descriptive study with no functional studies on the proteins found. We also used a low number of human endometrial samples for the DIGE analysis. WIDER IMPLICATIONS OF THE FINDINGS This study identified the proteomic profile associated with receptive or non-receptive human endometria. Our findings suggest that although histological dating indicates a putative 'receptive' status within the WOI, a different transcriptomic and proteomic profile is observed in these samples. We should move towards using more personalized WOIs, where identification of the correct endometrial receptivity status, and consequently the success of IVF, relies on individual molecular signatures rather than traditional endometrial dating. STUDY FUNDING/COMPETING INTEREST(S) F.D.'s participation in this work was supported by the Spanish Ministry of Economy and Competitiveness, through the Miguel Servet Programme (CP13/00075) co-founded by FEDER. The project was also supported by a grant from the Spanish Ministry of Economy and Competitiveness, through the FIS Programme (PI12/00450). The authors have no financial/commercial conflicts of interest to declare. © 2014 The Author. Source

Peiro-Chova L.,INCLIVA Biomedical Research Institute | Pena-Chilet M.,INCLIVA Biomedical Research Institute | Lopez-Guerrero J.A.,Fundacion Instituto Valenciano Of Oncologia | Garcia-Gimenez J.L.,University of Valencia | And 7 more authors.
Virchows Archiv | Year: 2013

Degradation of tissue samples limits performing RNA-based molecular studies, but little is known about the potential usefulness of samples of compromised quality for studies focused on miRNAs. In this work we analyze a series of cryopreserved tissue samples (n = 14), frozen samples that underwent a severe thawing process (n = 10), and their paired formalin-fixed paraffin-embedded (FFPE) tissue samples (n = 24) from patients with breast cancer obtained during primary surgical resection and collected in 2011. Quality and integrity analyses of the total and small fraction of RNA were carried out. Recovery of specific RNA molecules (miRNAs hsa-miR-21, hsa-miR-125b, and hsa-miR-191; snoRNA RNU6B; and mRNAs GAPDH and HPRT1) was also analyzed by quantitative RT-PCR. Our results suggest that visualisation of the small RNA electrophoretic profiles obtained using the Agilent 2100 bioanalyzer makes it possible to differentiate between the three groups of samples (optimally frozen, thawed, and FFPE). We demonstrate that specific miRNA molecules can be similarly recovered from different tissue sample sources, which supports their high degree of stability. We conclude that miRNAs are robustly detected irrespective of the quality of the tissue sample. In this regard, a word of caution should be raised before degraded samples are discarded: although prior quality assessment of the biological material to be analyzed is recommended, our work demonstrates that degraded tissue samples are also suitable for miRNA studies. © 2013 Springer-Verlag Berlin Heidelberg. Source

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