A novel chordoma xenograft allows in vivo drug testing and reveals the importance of NF-kB signaling in chordoma biology
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Yuelin Zhu
PROVIDER: E-GEOD-50137 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Chordoma is a rare primary bone malignancy that arises in the skull base, spine and sacrum and originates from remnants of the notochord. These tumors are typically resistant to conventional chemotherapy, and to date there are no FDA-approved agents to treat chordoma. The lack of in vivo models of chordoma has impeded the development of new therapies for this tumor. Primary tumor from a sacral chordoma was xenografted into NOD/SCID/IL-2R γ-null mice. The xenograft is serially transplantable and was characterized by both gene expression analysis and whole genome SNP genotyping. The NIH Chemical Genomics Center performed high-throughput screening of 2,816 compounds using two established chordoma cell lines, U-CH1 and U-CH2B. The screen yielded several compounds that showed activity and two, sunitinib and bortezomib, were tested in the xenograft. Both agents slowed the growth of the xenograft tumor. Sensitivity to an inhibitor of IκB, as well as inhibition of an NF-κB gene expression signature demonstrated the importance of NF-κB signaling for chordoma growth. This serially transplantable chordoma xenograft is thus a practical model to study chordomas and perform in vivo preclinical drug testing. The copy number and allelic balance pattern of a novel human chordoma xenograft samples was determined with Illumina BeadChips.
2013-12-22 | E-GEOD-50136 | biostudies-arrayexpress
Project description:The diagnosis of myelodysplastic syndromes (MDS) remains problematic due to the subjective nature of morphological assessment. The reported high frequency of somatic mutations and increased structural variants by array-based cytogenetics have provided potential objective markers of disease however this has been complicated by reports of similar abnormalities in the healthy population. We aimed to identify distinguishing features between those with early MDS and reported healthy individuals by characterising 69 patients who, following a non-diagnostic marrow, developed progressive dysplasia or acute myeloid leukaemia (AML). Targeted sequencing and array based cytogenetics identified a driver mutation and/or structural variant in 91% (63/69) of pre-diagnostic samples with the mutational spectrum mirroring that in the MDS population. When compared with the reported healthy population the mutations detected had significantly greater median variant allele fraction (40% vs 9-10%) and occurred more commonly with additional mutations (≥2 mutations 64% vs. 8%). Furthermore mutational analysis identified a high-risk group of patients with shorter time to disease progression and poorer overall survival. The mutational features in our cohort are distinct from those seen in the healthy population and, even in the absence of definitive disease, can predict outcome. Early detection may allow consideration of intervention in poor risk patients. We performed array based cytogenetics using HumanCytoSNP-12 (Illumina) on 69 patients diagnosed with acute myeloid leukaemia or myelodysplastic syndrome who had a previously non-diagnostic sample. SNP array analysis was performed on all diagnostic samples. In those with a documented abnormality, SNP-A was performed on the corresponding pre-diagnostic sample (n=32).
2015-09-17 | E-GEOD-73074 | biostudies-arrayexpress
Project description:Chiari-like malformation (CM) is a developmental abnormality of the craniocervical junction that is common in the Griffon Bruxellois (GB) breed with an estimated prevalence of 65%. This disease is characterized by overcrowding of the neural parenchyma at the craniocervical junction and disturbance of cerebrospinal fluid (CSF) flow. The most common clinical sign is pain either as a direct consequence of CM or neuropathic pain as a consequence of secondary syringomyelia. The etiology of CM remains unknown but genetic factors play an important role. To investigate the genetic complexity of the disease, a quantitative trait locus (QTL) approach was adopted. A total of 14 quantitative skull and atlas measurements were taken and were tested for association to CM. Six traits were found to be associated to CM and were subjected to a whole-genome association study using the Illumina canine high density bead chip in 74 GB dogs (50 affected and 24 controls). Linear and mixed regression analyses were used to identify quantitative trait loci. To identify the presence of causative haplotype for Chiari-Like Malformation 80 Griffon Bruxellois dogs were genotyped using Illumina CanineHD Beadchip. This cohort consisted of 53 cases and 27 controls. Ten samples were whole genome amplified using the Qiagen Repli-g kit following the protocol. Linear and mixed regression model were used to define association between morphologic traits and genetic data. The sample traits (provided in the sample characteristics field) are described in the 'README_Traits_description.pdf' Processed data were obtained in 3 different normalization batches. The normalization batch/raw data file information is provided in the sample description field.
2014-05-19 | E-GEOD-52221 | biostudies-arrayexpress
Project description:Sakha M-bM-^@M-^S an area connecting South and Northeast Siberia M-bM-^@M-^S is significant for understanding the history of peopling of Northeast Eurasia and the Americas. Previous studies have shown a genetic contiguity between Siberia and East Asia and the key role of South Siberia in the colonization of Siberia. We report the results of a high-resolution phylogenetic analysis of 701 mtDNAs and 318 Y chromosomes from five native populations of Sakha (Yakuts, Evenks, Evens, Yukaghirs and Dolgans) and of the analysis of more than 500,000 autosomal SNPs of 758 individuals from 55 populations, including 40 previously unpublished samples from Siberia. Phylogenetically terminal clades of East Asian mtDNA haplogroups C and D and Y-chromosome haplogroups N1c, N1b and C3, constituting the core of the gene pool of the native populations from Sakha, connect Sakha and South Siberia. Analysis of autosomal SNP data confirms the genetic continuity between Sakha and South Siberia. Maternal lineages D5a2a2, C4a1c, C4a2, C5b1b and the Yakut-specific STR sub-clade of Y-chromosome haplogroup N1c can be linked to a migration of Yakut ancestors, while the paternal lineage C3c was most likely carried to Sakha by the expansion of the Tungusic people. MtDNA haplogroups Z1a1b and Z1a3, present in Yukaghirs, Evens and Dolgans, show traces of different and probably more ancient migration(s). Analysis of both haploid loci and autosomal SNP data revealed only minor genetic components shared between Sakha and the extreme Northeast Siberia. Although the major part of West Eurasian maternal and paternal lineages in Sakha could originate from recent admixture with East Europeans, mtDNA haplogroups H8, H20a and HV1a1a, as well as Y-chromosome haplogroup J, more probably reflect an ancient gene flow from West Eurasia through Central Asia and South Siberia. Our high-resolution phylogenetic dissection of mtDNA and Y-chromosome haplogroups as well as analysis of autosomal SNP data suggests that Sakha was colonized by repeated expansions from South Siberia with minor gene flow from the Lower Amur/Southern Okhotsk region and/or Kamchatka. The minor West Eurasian component in Sakha attests to both recent and ongoing admixture with East Europeans and an ancient gene flow from West Eurasia. 40 samples were analysed with the Illumina platform Human660W-Quad v1.0 and are described herein.
2013-06-26 | E-GEOD-46828 | biostudies-arrayexpress
Project description:Here we present genome-wide high-coverage genotyping data on a panel of 85 human samples from Eurasia that are used in addition to public data in studing the genomic context of a 24 kya old DNA sample from Southern Siberia that was sequenced to the avwerage depth of 1X. 85 samples were analysed with the Illumina platforms Human610-Quad v1.0, HumanHap650Yv3 (HumanHap650Yv3_A) and Human660W-Quad v1.0 Genotyping BeadChips and are described herein.
2013-11-18 | E-GEOD-50727 | biostudies-arrayexpress
Project description:Despite being located at the crossroads of Asia, genetics of the Afghanistan populations have been largely overlooked. It is currently inhabited by five major ethnic populations: Pashtun, Tajik, Hazara, Uzbek and Turkmen. Here we present autosomal from a subset of our samples, mitochondrial and Y- chromosome data from over 500 Afghan samples among these 5 ethnic groups. This Afghan data was supplemented with the same Y-chromosome analyses of samples from Iran, Kyrgyzstan, Mongolia and updated Pakistani samples (HGDP-CEPH). The data presented here was integrated into existing knowledge of pan-Eurasian genetic diversity. The pattern of genetic variation, revealed by structure-like and Principal Component analyses and Analysis of Molecular Variance indicates that the people of Afghanistan are made up of a mosaic of components representing various geographic regions of Eurasian ancestry. The absence of a major Central Asian-specific component indicates that the Hindu Kush, like the gene pool of Central Asian populations in general, is a confluence of gene flows rather than a source of distinctly autochthonous populations that have arisen in situ: a conclusion that is reinforced by the phylogeography of both haploid loci. 24 samples were analysed with the Illumina platform Human660W-Quad v1.0 Genotyping BeadChip and are described herein.
2013-11-04 | E-GEOD-51158 | biostudies-arrayexpress
Project description:Here we present genome-wide high-coverage genotyping data on a panel of 75 human samples from Western Balkan region, Europe, that are used in addition to public data in studing the genetic variation of Southern Europe that was sequenced to the avwerage depth of 1X. 70 samples were analysed with the Illumina platform Human660W-Quad v1.0 Genotyping BeadChip and are described herein.
2014-08-22 | E-GEOD-59032 | biostudies-arrayexpress
Project description:To carry out population genetics analyses of the Arctic gregion we carried out Illumina Bead-Array-based enotyping on 18 samples from Greenland. 19 samples were analysed with the Illumina platform Human660W-Quad v1.0 Genotyping BeadChip and are described herein.
2014-08-28 | E-GEOD-59546 | biostudies-arrayexpress
Project description:We genotyped 322 new samples from 38 Eurasian populations and combined it with previously published data to characterize the population structure of Turkic-speaking populations in the context of their geographic neighbors across Eurasia 322 samples were analysed with the Illumina Human610-Quad, Human660W-Quad, and HumanOmni1-Quad Genotyping BeadChips and are described herein.
2015-02-21 | E-GEOD-66157 | biostudies-arrayexpress
Project description:Medieval era encounters of nomadic groups of the Eurasian Steppe and largely sedentary East Europeans had a variety of demographic and cultural consequences. Amongst these outcomes was the emergence of the Lipka Tatars - a Slavic-speaking Sunni-Muslim ethno-religious minority residing in modern Belarus, Lithuania and Poland, whose ancestors arrived in these territories via several migration waves, mainly from the Golden Horde. Our results show that Belarusian Lipka Tatars share a substantial part of their gene pool with Europeans as indicated by their Y-chromosomal, mitochondrial DNA and autosomal variation. Nevertheless, Belarusian Lipkas still retain a strong genetic signal of their nomadic ancestry, witnessed by the presence of common Y-chromosomal and mitochondrial DNA variants as well as autosomal segments identical by descent between Lipkas and East Eurasians from temperate and northern regions. Hence, we document Lipka Tatars as a unique example of former Medieval migrants into Central Europe, who became sedentary, changed language to Slavic, yet preserved their faith and retained, both uni- and bi-parentally, a clear genetic echo of a complex population interplay throughout the Eurasian Steppe Belt, extending from Central Europe to northern China. 6 samples were analysed with the Illumina platform HumanOmniExpress-24 v1.0 BeadChip and are described herein. Please note that the submitted information does not compromise participant privacy and is in accord with the original consent in addition to all applicable laws, regulations, and institutional policies. The submitter verified that there are no privacy concerns and that our human data can be open access.
2016-08-15 | E-GEOD-82309 | biostudies-arrayexpress