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specific structural variation across 1000 medulloblastoma genomes
Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson disease, which is exquisitely restricted to Group 4 Recurrent translocations of PVT1, including PVT1 MYC and PVT1 NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF signalling in Group 3, and NF signalling in Group 4, suggest future avenues for rational, targeted therapy.
a, The medulloblastoma genome classified by subgroup. c, Significant regions of focal SCNA identified by GISTIC2 in either pan cohort or subgroup specific analyses. The number of genes mapping to the GISTIC2 peak region (where applicable) is listed in brackets after the suspected driver gene, as is the frequency of each event.
a, GISTIC2 significance plot of amplifications (red) and deletions (blue) observed in SHH. The number of genes mapping to each significant region are included in brackets and regions enriched in SHH are shaded red. b, c, Recurrent amplifications of PPM1D (b) and PIK3C2B/MDM4 (c) are restricted to SHH. d, Fluorescence in situ hybridization (FISH) validation of MDM4 amplification. e, SHH signalling, TP53 signalling and RTK/PI3K signalling represent the core pathways genomically targeted in van cleef arpel alhambra necklace fake SHH. P values indicate the prevalence with which the respective pathway is targeted in SHH versus non SHH cases (Fisher exact test). Frequencies of focal and broad (parentheses) SCNAs are listed. f, Mutual exclusivity analysis of focal SCNAs in SHH. g, Clinical implications of SCNAs affecting MYCN, GLI2 or PTCH1 in SHH (log rank tests).
a, b, GISTIC2 plots depicting significant SCNAs in Group 3 (a) and Group 4 (b) with subgroup enriched regions shaded in yellow and green, respectively. c, Recurrent amplifications targeting type II (ACVR2A and ACVR2B) and type I (TGFBR1) activin receptors in Group 3. Frequencies of focal and broad (parentheses) SCNAs are listed. e, Enrichment map of gene sets affected by SCNAs in Group 3 versus Group 4.
a, Highly recurrent, focal, single copy gain of SNCAIP in Group 4. b, Paired end mapping verifies recurrent tandem duplication of SNCAIP in Group 4. c, Schematic representation of SNCAIP tandem duplication. d, SNCAIP is a Group 4 signature gene. Upper panel, SNCAIP expression across subgroups in a published series of 103 primary medulloblastomas. Error bars depict the minimum and maximum values, excluding outliers. Lower panel, SNCAIP ranks among the top 1% (rank, 39th out of 16,758) of highly expressed genes in Group 4. e, NMF consensus clustering of 188 expression profiled Group 4 tumours supports two transcriptionally distinct subtypes designated 4 and 4 (cophenetic coefficient = 0.9956). g, Group 4 cases harbouring SNCAIP duplication exhibit a 1.5 fold increase in SNCAIP expression. f, g, Error bars depict the minimum and maximum values, excluding outliers.
a, b, RNA Seq identifies multiple fusion transcripts driven by PVT1 in Group 3. Schematics depict the structures of verified PVT1 MYC (a) and PVT1 NDRG1 (b) fusion genes. c, Heat map of the MYC/PVT1 locus showing a subset of 13 MYC amplified Group 3 cases subsequently verified to exhibit PVT1 gene fusions (shown in d). Yellow box highlights the common breakpoint affecting the first exon/intron of PVT1, including miR 1204. d, Summary of PVT1 fusion transcripts identified in Group 3. e, f, WGS confirms complex patterns of rearrangement on chr8q24 in PVT1 fusion (+) Group 3.
a, Quantitative RT of PVT1 encoded microRNAs confirms upregulation of miR 1204 in PVT1 MYC fusion (+) Group 3 tumours. MYC balanced/fusion ( n = 4; MYC amplified/fusion ( n = 6; MYC amplified/fusion (+), n = 8. b, c, Knockdown of miR 1204 attenuates the proliferative capacity of PVT1 MYC fusion (+) MED8A medulloblastoma cells (b) but has no effect on fusion ( ONS76 cells (c). Four principal subgroups of medulloblastoma have been identified: WNT, SHH, Group 3 and Group 4 (ref. 7), and there is preliminary evidence for clinically significant subdivisions of the subgroups3, 7, 8. Rational, targeted therapies based on genetics are not currently in use for medulloblastoma, although inhibitors of the Sonic Hedgehog pathway protein Smoothened have shown early promise9. Actionable targets for WNT, Group 3 and Group 4 tumours have not been identified4, 10. Sanger sequencing of 22 medulloblastoma exomes revealed on average only 8 single nucleotide variants (SNVs) per tumour11. Some SNVs were subgroup restricted (PTCH1, CTNNB1), whereas others occurred across subgroups (TP53, MLL2). We proposed that the observed intertumoural heterogeneity might have underpowered prior attempts to discover targets for rational therapy.
The Medulloblastoma Advanced Genomics International Consortium (MAGIC) consisting of scientists and physicians from 46 cities across the globe gathered more than 1,200 medulloblastomas which were studied by SNP arrays (n = 1,239; Fig. 1a, Supplementary Fig. 1 and Supplementary Tables 1 Medulloblastoma subgroup affiliation of 827 cases was determined using a custom nanoString based RNA assay (Supplementary Fig. 2)12. Disparate patterns of broad cytogenetic gain and loss were observed across the subgroups (Fig. 1b and Supplementary Figs 3, 7, 8, 10 and 11). Analysis of the entire cohort using GISTIC2 (ref. 13) to discover significant events delineated 62 regions of recurrent SCNA (Fig. 1c, Supplementary Fig. 4 and Supplementary Tables 4 and 5); analysis by subgroup increased sensitivity such that 110 candidate SCNAs were identified, most of which are subgroup enriched (Fig. 1c and Supplementary Table 6).
a, The medulloblastoma genome classified by subgroup. c, Significant regions of focal SCNA identified by GISTIC2 in either pan cohort or subgroup specific analyses. The number of genes mapping to the GISTIC2 peak region (where applicable) is listed in brackets after the suspected driver gene, as is the frequency of each event. 1d and Supplementary Table 7). The most prevalent amplifications affected members of the MYC family with MYCN predominantly amplified in SHH and Group 4, MYC in Group 3, and MYCL1 in SHH medulloblastomas. Multiple genes/regions were exclusively amplified in SHH, including GLI2, MYCL1, PPM1D, YAP1 and MDM4 (Fig. 1d). Recurrent homozygous deletions were exceedingly rare, with only 15 detected across 1,087 tumours (Fig. 1e). Homozygous deletions targeting known tumour suppressors PTEN, PTCH1 and CDKN2A/B were the most common, all enriched in SHH cases (Fig. 1e and Supplementary Table 7). Novel homozygous deletions included KDM6A, a histone lysine demethylase deleted in Group 4. A custom nanoString CodeSet was used to verify 24 significant regions of gain across 192 MAGIC cases, resulting in a verification rate of 90.9% (Supplementary Fig. 5). We conclude that SCNAs in medulloblastoma are common, and are predominantly subgroup enriched.
WNT medulloblastoma genomes are impoverished of recurrent focal regions of SCNA, exhibiting no significant regions of deletion and only a small subset of focal gains found at comparable frequencies in non WNT tumours (Supplementary Figs 4, 6 and Supplementary Table 8). CTNNB1 mutational screening confirmed canonical exon 3 mutations in 63 out of 71 (88.7%) WNT tumours, whereas monosomy 6 was detected in 58 out of 76 (76.3%) (Supplementary Fig. 6; Supplementary Table 9). Four knock off black van cleef necklace WNT tumours (4/71; 5.6%) had neither CTNNB1 mutation nor monosomy 6, but maintained typical WNT expression signatures. Given the size of our cohort and the resolution of the platform, we conclude that there are no frequent, targetable SCNAs for WNT medulloblastoma.
SHH tumours exhibit multiple significant focal SCNAs (Fig. 2a, Supplementary Figs 12, 15, 16 and Supplementary Tables 10 and 11). SHH enriched/restricted SCNAs included amplification of GLI2 and deletion of PTCH1 (Fig. 2a, e, f)10. MYCN and CCND2 were among the most frequently amplified genes in SHH (Supplementary Table 6), but were also altered in non SHH cases. Genes upregulated in SHH tumours (that is, SHH signature genes) are significantly over represented among the genes focally amplified in SHH tumours (P = 0.001 permutation tests; Supplementary Fig. 9). Recurrent amplification of SHH signature genes has clinical implications, as amplification of downstream transcriptional targets could mediate resistance to upstream SHH pathway inhibitors14.
a, GISTIC2 significance plot of amplifications (red) and deletions (blue) observed in SHH. The number of genes mapping to each significant region are included in brackets and regions enriched in SHH are shaded red. b, c, Recurrent amplifications of PPM1D (b) and PIK3C2B/MDM4 (c) are restricted to SHH. d, Fluorescence in situ hybridization (FISH) validation of MDM4 amplification. e, SHH signalling, TP53 signalling and RTK/PI3K signalling represent the core pathways genomically targeted in SHH. P values indicate the prevalence with which the respective pathway is targeted in SHH versus non SHH cases (Fisher exact test). Frequencies of focal and broad (parentheses) SCNAs are listed. f, Mutual exclusivity analysis of focal SCNAs in SHH. g, Clinical implications of SCNAs affecting MYCN, GLI2 or PTCH1 in SHH (log rank tests).
Novel, SHH enriched SCNAs included components of TP53 signalling, including amplifications of MDM4 and PPM1D, and focal deletions of TP53 (Fig. 2a Targetable events, including amplifications of IGF signalling genes IGF1R and IRS2, PI3K genes PIK3C2G and PIK3C2B, and deletion of PTEN were restricted to SHH tumours (Fig. 2a, c, e). Importantly, focal events affecting genes in the SHH pathway were largely mutually exclusive and prognostically significant (Fig. 2f, g). Many of the recurrent, targetable SCNAs identified in SHH medulloblastoma (IGF1R, KIT, MDM4, PDGFRA, PIK3C2G, PIK2C2B and PTEN) have already been targeted with small molecules for treatment of other malignancies, which might allow rapid translation for targeted therapy of subsets of SHH patients (Supplementary Table 16). Novel SHH targets identified here are excellent candidates for combinatorial therapy with Smoothened inhibitors, to avoid the resistance encountered in both humans and mice9, 14, 15.
Group 3 and Group 4 medulloblastomas have generic names as comparatively little is known about their genetic basis, and no targets for rational therapy have been identified7. MYC amplicons are largely restricted to Group 3, whereas MYCN amplicons are seen in Group 4 and SHH tumours (Fig. 1d)3, 4. Indeed, MYC and MYCN loci comprise the most significant regions of amplification observed in Group 3 and Group 4, respectively (Fig. 3a, b, Supplementary Figs 13, 14, 17 and Supplementary Tables 12 Group 3 MYC amplicons were mutually exclusive from those affecting the known medulloblastoma oncogene OTX2 (ref. 16) and were highly prognostic (Supplementary Fig. 21)3, 16. Type II activin receptors, ACVR2A and ACVR2B and family member TGFBR1 are highly amplified in Group 3 tumours, indicating deregulation of TGF signalling as a driver event in Group 3 (Fig. 3c and Supplementary Fig. 22). The Group 3 enriched medulloblastoma oncogene OTX2 is a prominent target of TGF signalling in the developing nervous system17 and TGF pathway inhibitors CD109 (ref. 18), FKBP1A (refs 19 and 20) and SNX6 (ref. 20) are recurrently deleted in Group 3 (Fig. 3a, d). 3d). Similarly, novel deletions affecting regulators of the NF pathway, including NFKBIA (ref. 21) and USP4 (ref. 22) were identified in Group 4 (Supplementary Fig. 23), proposing that NF signalling may represent a rational Group 4 therapeutic target.
a, b, GISTIC2 plots depicting significant SCNAs in Group 3 (a) and Group 4 (b) with subgroup enriched regions shaded in yellow and green, respectively. c, Recurrent amplifications targeting type II (ACVR2A and ACVR2B) and type I (TGFBR1) activin receptors in Group 3. Frequencies of focal and broad (parentheses) SCNAs are listed. e, Enrichment map of gene sets affected by SCNAs in Group 3 versus Group 4.
Network analysis of Group 3 and Group 4 SCNAs illustrates the different pathways over represented in each subgroup. Only TGF signalling is unique to Group 3 (Fig. 3e). In contrast, cell cycle control, chromatin modification and neuronal development are all Group 4 enriched. Cumulatively, the dismal prognosis of Group 3 patients, the lack of published targets for rational therapy, and the prior targeting of TGF signalling in other diseases suggest that van cleef gold necklace copy TGF may represent an appealing target for Group 3 rational therapies (Supplementary Table 16).
Although Group 4 is the most prevalent medulloblastoma subgroup, its pathogenesis remains poorly understood. The most frequent SCNA observed in Group 4 (33/317; 10.4%) is a recurrent region of single copy gain on chr5q23.2 targeting a single gene, SNCAIP (synuclein, alpha interacting protein) (Fig. 4a and Supplementary Fig. 24). SNCAIP, encodes synphilin 1, which binds to to promote the formation of Lewy bodies in the brains of patients with Parkinson disease23, 24. Additionally, rare germline mutations of SNCAIP have been described in Parkinson families25. Large insert, mate pair, whole genome sequencing (WGS) demonstrates that SNCAIP copy number gains arise from tandem duplication of a truncated SNCAIP (lacking non coding exon 1), inserted telomeric to the germline SNCAIP allele (Fig. 4b, c and Supplementary Fig. 25). Affymetrix SNP6 array profiling of patient matched germline material confirmed that SNCAIP duplications are somatic (Supplementary Fig. 26), and subsequent whole transcriptome sequencing (RNA Seq) of select Group 4 cases (n = 5) verified that SNCAIP is the only gene expressed in the duplicated region (Supplementary Fig. 27). Analysis of published copy number profiles for 3,131 primary tumours26 and 947 cancer cell lines27 (total of 4,078 cases) revealed only four cases with apparent duplication of SNCAIP, all of which were inferred as Group 4 medulloblastomas (data not shown). We conclude that SNCAIP duplication is a somatic event highly specific to Group 4 medulloblastoma.
a, Highly recurrent, focal, single copy gain of SNCAIP in Group 4. b, Paired end mapping verifies recurrent tandem duplication of SNCAIP in Group 4. c, Schematic representation of SNCAIP tandem duplication. d, SNCAIP is a Group 4 signature gene. Upper panel, SNCAIP expression across subgroups in a published series of 103 primary medulloblastomas. Error bars depict the minimum and maximum values, excluding outliers. Lower panel, SNCAIP ranks among the top 1% (rank, 39th out of 16,758) of highly expressed genes in Group 4. e, NMF consensus clustering of 188 expression profiled Group 4 tumours supports two transcriptionally distinct subtypes designated 4 and 4 (cophenetic coefficient = 0.9956). g, Group 4 cases harbouring SNCAIP duplication exhibit a 1.5 fold increase in SNCAIP expression. f, g, Error bars depict the minimum and maximum values, excluding outliers.
Re analysis of 499 published medulloblastoma expression profiles confirmed that SNCAIP is one of the most highly upregulated Group 4 signature genes (Fig. 4d and Supplementary Fig. 28). Profiling of 188 Group 4 tumours on expression microarrays followed by consensus non negative matrix factorization (NMF) clustering delineates two subtypes of Group 4 (4 and 4 Fig. 4e and Supplementary Fig. 29). SNCAIP is more highly expressed in Group 4 than 4 (Fig. 4f), and 4 samples with tandem duplication showed approximately 1.5 fold increased expression, consistent with gene dosage (Fig. 4g and Supplementary Figs 35 and 36). Group 4 exhibits a relatively balanced genome compared to 4 (Supplementary Figs 30 and several 4 cases harbour SNCAIP duplication in conjunction with i17q and no other SCNAs (Supplementary Fig. 33). Importantly, SNCAIP duplications are mutually exclusive from other prominent SCNAs in Group 4, including MYCN and CDK6 amplifications (Supplementary Fig. 34).
Although recurrent gene fusions have recently been discovered in solid tumours, none have been reported in medulloblastoma. RNA Seq of Group 3 tumours (n = 13) identified two independent gene fusions in two different tumours (MB 182 and MB 586), both involving the 5 end of PVT1, a non coding gene frequently co amplified with MYC in Group 3 (Fig. 5a, b, Supplementary Fig. 37 and Supplementary Tables 17 and 18). Sanger sequencing confirmed a fusion transcript consisting of exons 1 and 3 of PVT1 fused to the coding sequence of MYC (exons 2 and 3) in MB 182, and a fusion involving PVT1 exon 1 fused to the 3 end of NDRG1 in MB 586 (Fig. 5a, b).
a, b, RNA Seq identifies multiple fusion transcripts driven by PVT1 in Group 3. Schematics depict the structures of verified PVT1 MYC (a) and PVT1 NDRG1 (b) fusion genes. c, Heat map of the MYC/PVT1 locus showing a subset of 13 MYC amplified Group 3 cases subsequently verified to exhibit PVT1 gene fusions (shown in d). Yellow box highlights the common breakpoint affecting the first exon/intron of PVT1, including miR 1204. d, Summary of PVT1 fusion transcripts identified in Group 3. e, f, WGS confirms complex patterns of rearrangement on chr8q24 in PVT1 fusion (+) Group 3.
Group 3 copy number data at the MYC/PVT1 locus indicated that additional samples might harbour PVT1 gene fusions (Fig. 5c). PCR with reverse transcription (RT profiling of select Group 3 cases confirmed PVT1 MYC fusions in at least 60% (12/20) of MYC amplified cases (Fig. 5d and Supplementary Table 19). Fusion transcripts included many other portions of chr8q, with up to four different genomic loci mapping to a single transcript, a pattern reminiscent of chromothripsis28, 29 (Fig. 5d). WGS performed on four MYC amplified Group 3 tumours harbouring PVT1 fusion transcripts identified a series of complex genomic rearrangements on chr8q (Fig. 5e, f, Supplementary Fig. 38 and Supplementary Tables 20 and 21). Chromosome 8 copy number profile for MB 586 (PVT1 NDRG1) derived from WGS showed that PVT1 and NDRG1 are structurally linked, as predicted by RNA Seq, and several adjacent regions of 8q24 were extensively rearranged (Fig. 5e, f and Supplementary Table 21). Monte Carlo simulation suggests that this fragmented 8q amplicon arose through chromothripsis, a process of erroneous DNA repair following a single catastrophic event in which a chromosome is shattered into many pieces (Supplementary Fig. 39). Further examination of our copy number data set revealed rare examples of chromothripsis across subgroups (Supplementary Fig. 40), with only chr8 in Group 3 demonstrating statistically significant, region specific chromothripsis (Q = 0.0004, false discovery rate (FDR) corrected Fisher exact test). Among Group 3 tumours, the occurrence of chr8q chromothripsis is correlated with deletion of chr17p (location of TP53; data not shown), in keeping with the association of loss of TP53 and chromothripsis recently described in medulloblastoma (P = 0.0199, Fisher exact test)28. Whereas the PVT1 locus has been suggested to be a genomically fragile site, we observe that the majority of MYC amplified Group 3 tumours harbour PVT1 fusions that arise through a process consistent with chromothripsis.
PVT1 is a non coding host gene for four microRNAs, miR 1204 Previous studies have implicated miR 1204 as a candidate oncogene that enhances oncogenesis in combination with MYC30, 31. PVT1 fus
Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson disease, which is exquisitely restricted to Group 4 Recurrent translocations of PVT1, including PVT1 MYC and PVT1 NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF signalling in Group 3, and NF signalling in Group 4, suggest future avenues for rational, targeted therapy.
a, The medulloblastoma genome classified by subgroup. c, Significant regions of focal SCNA identified by GISTIC2 in either pan cohort or subgroup specific analyses. The number of genes mapping to the GISTIC2 peak region (where applicable) is listed in brackets after the suspected driver gene, as is the frequency of each event.
a, GISTIC2 significance plot of amplifications (red) and deletions (blue) observed in SHH. The number of genes mapping to each significant region are included in brackets and regions enriched in SHH are shaded red. b, c, Recurrent amplifications of PPM1D (b) and PIK3C2B/MDM4 (c) are restricted to SHH. d, Fluorescence in situ hybridization (FISH) validation of MDM4 amplification. e, SHH signalling, TP53 signalling and RTK/PI3K signalling represent the core pathways genomically targeted in van cleef arpel alhambra necklace fake SHH. P values indicate the prevalence with which the respective pathway is targeted in SHH versus non SHH cases (Fisher exact test). Frequencies of focal and broad (parentheses) SCNAs are listed. f, Mutual exclusivity analysis of focal SCNAs in SHH. g, Clinical implications of SCNAs affecting MYCN, GLI2 or PTCH1 in SHH (log rank tests).
a, b, GISTIC2 plots depicting significant SCNAs in Group 3 (a) and Group 4 (b) with subgroup enriched regions shaded in yellow and green, respectively. c, Recurrent amplifications targeting type II (ACVR2A and ACVR2B) and type I (TGFBR1) activin receptors in Group 3. Frequencies of focal and broad (parentheses) SCNAs are listed. e, Enrichment map of gene sets affected by SCNAs in Group 3 versus Group 4.
a, Highly recurrent, focal, single copy gain of SNCAIP in Group 4. b, Paired end mapping verifies recurrent tandem duplication of SNCAIP in Group 4. c, Schematic representation of SNCAIP tandem duplication. d, SNCAIP is a Group 4 signature gene. Upper panel, SNCAIP expression across subgroups in a published series of 103 primary medulloblastomas. Error bars depict the minimum and maximum values, excluding outliers. Lower panel, SNCAIP ranks among the top 1% (rank, 39th out of 16,758) of highly expressed genes in Group 4. e, NMF consensus clustering of 188 expression profiled Group 4 tumours supports two transcriptionally distinct subtypes designated 4 and 4 (cophenetic coefficient = 0.9956). g, Group 4 cases harbouring SNCAIP duplication exhibit a 1.5 fold increase in SNCAIP expression. f, g, Error bars depict the minimum and maximum values, excluding outliers.
a, b, RNA Seq identifies multiple fusion transcripts driven by PVT1 in Group 3. Schematics depict the structures of verified PVT1 MYC (a) and PVT1 NDRG1 (b) fusion genes. c, Heat map of the MYC/PVT1 locus showing a subset of 13 MYC amplified Group 3 cases subsequently verified to exhibit PVT1 gene fusions (shown in d). Yellow box highlights the common breakpoint affecting the first exon/intron of PVT1, including miR 1204. d, Summary of PVT1 fusion transcripts identified in Group 3. e, f, WGS confirms complex patterns of rearrangement on chr8q24 in PVT1 fusion (+) Group 3.
a, Quantitative RT of PVT1 encoded microRNAs confirms upregulation of miR 1204 in PVT1 MYC fusion (+) Group 3 tumours. MYC balanced/fusion ( n = 4; MYC amplified/fusion ( n = 6; MYC amplified/fusion (+), n = 8. b, c, Knockdown of miR 1204 attenuates the proliferative capacity of PVT1 MYC fusion (+) MED8A medulloblastoma cells (b) but has no effect on fusion ( ONS76 cells (c). Four principal subgroups of medulloblastoma have been identified: WNT, SHH, Group 3 and Group 4 (ref. 7), and there is preliminary evidence for clinically significant subdivisions of the subgroups3, 7, 8. Rational, targeted therapies based on genetics are not currently in use for medulloblastoma, although inhibitors of the Sonic Hedgehog pathway protein Smoothened have shown early promise9. Actionable targets for WNT, Group 3 and Group 4 tumours have not been identified4, 10. Sanger sequencing of 22 medulloblastoma exomes revealed on average only 8 single nucleotide variants (SNVs) per tumour11. Some SNVs were subgroup restricted (PTCH1, CTNNB1), whereas others occurred across subgroups (TP53, MLL2). We proposed that the observed intertumoural heterogeneity might have underpowered prior attempts to discover targets for rational therapy.
The Medulloblastoma Advanced Genomics International Consortium (MAGIC) consisting of scientists and physicians from 46 cities across the globe gathered more than 1,200 medulloblastomas which were studied by SNP arrays (n = 1,239; Fig. 1a, Supplementary Fig. 1 and Supplementary Tables 1 Medulloblastoma subgroup affiliation of 827 cases was determined using a custom nanoString based RNA assay (Supplementary Fig. 2)12. Disparate patterns of broad cytogenetic gain and loss were observed across the subgroups (Fig. 1b and Supplementary Figs 3, 7, 8, 10 and 11). Analysis of the entire cohort using GISTIC2 (ref. 13) to discover significant events delineated 62 regions of recurrent SCNA (Fig. 1c, Supplementary Fig. 4 and Supplementary Tables 4 and 5); analysis by subgroup increased sensitivity such that 110 candidate SCNAs were identified, most of which are subgroup enriched (Fig. 1c and Supplementary Table 6).
a, The medulloblastoma genome classified by subgroup. c, Significant regions of focal SCNA identified by GISTIC2 in either pan cohort or subgroup specific analyses. The number of genes mapping to the GISTIC2 peak region (where applicable) is listed in brackets after the suspected driver gene, as is the frequency of each event. 1d and Supplementary Table 7). The most prevalent amplifications affected members of the MYC family with MYCN predominantly amplified in SHH and Group 4, MYC in Group 3, and MYCL1 in SHH medulloblastomas. Multiple genes/regions were exclusively amplified in SHH, including GLI2, MYCL1, PPM1D, YAP1 and MDM4 (Fig. 1d). Recurrent homozygous deletions were exceedingly rare, with only 15 detected across 1,087 tumours (Fig. 1e). Homozygous deletions targeting known tumour suppressors PTEN, PTCH1 and CDKN2A/B were the most common, all enriched in SHH cases (Fig. 1e and Supplementary Table 7). Novel homozygous deletions included KDM6A, a histone lysine demethylase deleted in Group 4. A custom nanoString CodeSet was used to verify 24 significant regions of gain across 192 MAGIC cases, resulting in a verification rate of 90.9% (Supplementary Fig. 5). We conclude that SCNAs in medulloblastoma are common, and are predominantly subgroup enriched.
WNT medulloblastoma genomes are impoverished of recurrent focal regions of SCNA, exhibiting no significant regions of deletion and only a small subset of focal gains found at comparable frequencies in non WNT tumours (Supplementary Figs 4, 6 and Supplementary Table 8). CTNNB1 mutational screening confirmed canonical exon 3 mutations in 63 out of 71 (88.7%) WNT tumours, whereas monosomy 6 was detected in 58 out of 76 (76.3%) (Supplementary Fig. 6; Supplementary Table 9). Four knock off black van cleef necklace WNT tumours (4/71; 5.6%) had neither CTNNB1 mutation nor monosomy 6, but maintained typical WNT expression signatures. Given the size of our cohort and the resolution of the platform, we conclude that there are no frequent, targetable SCNAs for WNT medulloblastoma.
SHH tumours exhibit multiple significant focal SCNAs (Fig. 2a, Supplementary Figs 12, 15, 16 and Supplementary Tables 10 and 11). SHH enriched/restricted SCNAs included amplification of GLI2 and deletion of PTCH1 (Fig. 2a, e, f)10. MYCN and CCND2 were among the most frequently amplified genes in SHH (Supplementary Table 6), but were also altered in non SHH cases. Genes upregulated in SHH tumours (that is, SHH signature genes) are significantly over represented among the genes focally amplified in SHH tumours (P = 0.001 permutation tests; Supplementary Fig. 9). Recurrent amplification of SHH signature genes has clinical implications, as amplification of downstream transcriptional targets could mediate resistance to upstream SHH pathway inhibitors14.
a, GISTIC2 significance plot of amplifications (red) and deletions (blue) observed in SHH. The number of genes mapping to each significant region are included in brackets and regions enriched in SHH are shaded red. b, c, Recurrent amplifications of PPM1D (b) and PIK3C2B/MDM4 (c) are restricted to SHH. d, Fluorescence in situ hybridization (FISH) validation of MDM4 amplification. e, SHH signalling, TP53 signalling and RTK/PI3K signalling represent the core pathways genomically targeted in SHH. P values indicate the prevalence with which the respective pathway is targeted in SHH versus non SHH cases (Fisher exact test). Frequencies of focal and broad (parentheses) SCNAs are listed. f, Mutual exclusivity analysis of focal SCNAs in SHH. g, Clinical implications of SCNAs affecting MYCN, GLI2 or PTCH1 in SHH (log rank tests).
Novel, SHH enriched SCNAs included components of TP53 signalling, including amplifications of MDM4 and PPM1D, and focal deletions of TP53 (Fig. 2a Targetable events, including amplifications of IGF signalling genes IGF1R and IRS2, PI3K genes PIK3C2G and PIK3C2B, and deletion of PTEN were restricted to SHH tumours (Fig. 2a, c, e). Importantly, focal events affecting genes in the SHH pathway were largely mutually exclusive and prognostically significant (Fig. 2f, g). Many of the recurrent, targetable SCNAs identified in SHH medulloblastoma (IGF1R, KIT, MDM4, PDGFRA, PIK3C2G, PIK2C2B and PTEN) have already been targeted with small molecules for treatment of other malignancies, which might allow rapid translation for targeted therapy of subsets of SHH patients (Supplementary Table 16). Novel SHH targets identified here are excellent candidates for combinatorial therapy with Smoothened inhibitors, to avoid the resistance encountered in both humans and mice9, 14, 15.
Group 3 and Group 4 medulloblastomas have generic names as comparatively little is known about their genetic basis, and no targets for rational therapy have been identified7. MYC amplicons are largely restricted to Group 3, whereas MYCN amplicons are seen in Group 4 and SHH tumours (Fig. 1d)3, 4. Indeed, MYC and MYCN loci comprise the most significant regions of amplification observed in Group 3 and Group 4, respectively (Fig. 3a, b, Supplementary Figs 13, 14, 17 and Supplementary Tables 12 Group 3 MYC amplicons were mutually exclusive from those affecting the known medulloblastoma oncogene OTX2 (ref. 16) and were highly prognostic (Supplementary Fig. 21)3, 16. Type II activin receptors, ACVR2A and ACVR2B and family member TGFBR1 are highly amplified in Group 3 tumours, indicating deregulation of TGF signalling as a driver event in Group 3 (Fig. 3c and Supplementary Fig. 22). The Group 3 enriched medulloblastoma oncogene OTX2 is a prominent target of TGF signalling in the developing nervous system17 and TGF pathway inhibitors CD109 (ref. 18), FKBP1A (refs 19 and 20) and SNX6 (ref. 20) are recurrently deleted in Group 3 (Fig. 3a, d). 3d). Similarly, novel deletions affecting regulators of the NF pathway, including NFKBIA (ref. 21) and USP4 (ref. 22) were identified in Group 4 (Supplementary Fig. 23), proposing that NF signalling may represent a rational Group 4 therapeutic target.
a, b, GISTIC2 plots depicting significant SCNAs in Group 3 (a) and Group 4 (b) with subgroup enriched regions shaded in yellow and green, respectively. c, Recurrent amplifications targeting type II (ACVR2A and ACVR2B) and type I (TGFBR1) activin receptors in Group 3. Frequencies of focal and broad (parentheses) SCNAs are listed. e, Enrichment map of gene sets affected by SCNAs in Group 3 versus Group 4.
Network analysis of Group 3 and Group 4 SCNAs illustrates the different pathways over represented in each subgroup. Only TGF signalling is unique to Group 3 (Fig. 3e). In contrast, cell cycle control, chromatin modification and neuronal development are all Group 4 enriched. Cumulatively, the dismal prognosis of Group 3 patients, the lack of published targets for rational therapy, and the prior targeting of TGF signalling in other diseases suggest that van cleef gold necklace copy TGF may represent an appealing target for Group 3 rational therapies (Supplementary Table 16).
Although Group 4 is the most prevalent medulloblastoma subgroup, its pathogenesis remains poorly understood. The most frequent SCNA observed in Group 4 (33/317; 10.4%) is a recurrent region of single copy gain on chr5q23.2 targeting a single gene, SNCAIP (synuclein, alpha interacting protein) (Fig. 4a and Supplementary Fig. 24). SNCAIP, encodes synphilin 1, which binds to to promote the formation of Lewy bodies in the brains of patients with Parkinson disease23, 24. Additionally, rare germline mutations of SNCAIP have been described in Parkinson families25. Large insert, mate pair, whole genome sequencing (WGS) demonstrates that SNCAIP copy number gains arise from tandem duplication of a truncated SNCAIP (lacking non coding exon 1), inserted telomeric to the germline SNCAIP allele (Fig. 4b, c and Supplementary Fig. 25). Affymetrix SNP6 array profiling of patient matched germline material confirmed that SNCAIP duplications are somatic (Supplementary Fig. 26), and subsequent whole transcriptome sequencing (RNA Seq) of select Group 4 cases (n = 5) verified that SNCAIP is the only gene expressed in the duplicated region (Supplementary Fig. 27). Analysis of published copy number profiles for 3,131 primary tumours26 and 947 cancer cell lines27 (total of 4,078 cases) revealed only four cases with apparent duplication of SNCAIP, all of which were inferred as Group 4 medulloblastomas (data not shown). We conclude that SNCAIP duplication is a somatic event highly specific to Group 4 medulloblastoma.
a, Highly recurrent, focal, single copy gain of SNCAIP in Group 4. b, Paired end mapping verifies recurrent tandem duplication of SNCAIP in Group 4. c, Schematic representation of SNCAIP tandem duplication. d, SNCAIP is a Group 4 signature gene. Upper panel, SNCAIP expression across subgroups in a published series of 103 primary medulloblastomas. Error bars depict the minimum and maximum values, excluding outliers. Lower panel, SNCAIP ranks among the top 1% (rank, 39th out of 16,758) of highly expressed genes in Group 4. e, NMF consensus clustering of 188 expression profiled Group 4 tumours supports two transcriptionally distinct subtypes designated 4 and 4 (cophenetic coefficient = 0.9956). g, Group 4 cases harbouring SNCAIP duplication exhibit a 1.5 fold increase in SNCAIP expression. f, g, Error bars depict the minimum and maximum values, excluding outliers.
Re analysis of 499 published medulloblastoma expression profiles confirmed that SNCAIP is one of the most highly upregulated Group 4 signature genes (Fig. 4d and Supplementary Fig. 28). Profiling of 188 Group 4 tumours on expression microarrays followed by consensus non negative matrix factorization (NMF) clustering delineates two subtypes of Group 4 (4 and 4 Fig. 4e and Supplementary Fig. 29). SNCAIP is more highly expressed in Group 4 than 4 (Fig. 4f), and 4 samples with tandem duplication showed approximately 1.5 fold increased expression, consistent with gene dosage (Fig. 4g and Supplementary Figs 35 and 36). Group 4 exhibits a relatively balanced genome compared to 4 (Supplementary Figs 30 and several 4 cases harbour SNCAIP duplication in conjunction with i17q and no other SCNAs (Supplementary Fig. 33). Importantly, SNCAIP duplications are mutually exclusive from other prominent SCNAs in Group 4, including MYCN and CDK6 amplifications (Supplementary Fig. 34).
Although recurrent gene fusions have recently been discovered in solid tumours, none have been reported in medulloblastoma. RNA Seq of Group 3 tumours (n = 13) identified two independent gene fusions in two different tumours (MB 182 and MB 586), both involving the 5 end of PVT1, a non coding gene frequently co amplified with MYC in Group 3 (Fig. 5a, b, Supplementary Fig. 37 and Supplementary Tables 17 and 18). Sanger sequencing confirmed a fusion transcript consisting of exons 1 and 3 of PVT1 fused to the coding sequence of MYC (exons 2 and 3) in MB 182, and a fusion involving PVT1 exon 1 fused to the 3 end of NDRG1 in MB 586 (Fig. 5a, b).
a, b, RNA Seq identifies multiple fusion transcripts driven by PVT1 in Group 3. Schematics depict the structures of verified PVT1 MYC (a) and PVT1 NDRG1 (b) fusion genes. c, Heat map of the MYC/PVT1 locus showing a subset of 13 MYC amplified Group 3 cases subsequently verified to exhibit PVT1 gene fusions (shown in d). Yellow box highlights the common breakpoint affecting the first exon/intron of PVT1, including miR 1204. d, Summary of PVT1 fusion transcripts identified in Group 3. e, f, WGS confirms complex patterns of rearrangement on chr8q24 in PVT1 fusion (+) Group 3.
Group 3 copy number data at the MYC/PVT1 locus indicated that additional samples might harbour PVT1 gene fusions (Fig. 5c). PCR with reverse transcription (RT profiling of select Group 3 cases confirmed PVT1 MYC fusions in at least 60% (12/20) of MYC amplified cases (Fig. 5d and Supplementary Table 19). Fusion transcripts included many other portions of chr8q, with up to four different genomic loci mapping to a single transcript, a pattern reminiscent of chromothripsis28, 29 (Fig. 5d). WGS performed on four MYC amplified Group 3 tumours harbouring PVT1 fusion transcripts identified a series of complex genomic rearrangements on chr8q (Fig. 5e, f, Supplementary Fig. 38 and Supplementary Tables 20 and 21). Chromosome 8 copy number profile for MB 586 (PVT1 NDRG1) derived from WGS showed that PVT1 and NDRG1 are structurally linked, as predicted by RNA Seq, and several adjacent regions of 8q24 were extensively rearranged (Fig. 5e, f and Supplementary Table 21). Monte Carlo simulation suggests that this fragmented 8q amplicon arose through chromothripsis, a process of erroneous DNA repair following a single catastrophic event in which a chromosome is shattered into many pieces (Supplementary Fig. 39). Further examination of our copy number data set revealed rare examples of chromothripsis across subgroups (Supplementary Fig. 40), with only chr8 in Group 3 demonstrating statistically significant, region specific chromothripsis (Q = 0.0004, false discovery rate (FDR) corrected Fisher exact test). Among Group 3 tumours, the occurrence of chr8q chromothripsis is correlated with deletion of chr17p (location of TP53; data not shown), in keeping with the association of loss of TP53 and chromothripsis recently described in medulloblastoma (P = 0.0199, Fisher exact test)28. Whereas the PVT1 locus has been suggested to be a genomically fragile site, we observe that the majority of MYC amplified Group 3 tumours harbour PVT1 fusions that arise through a process consistent with chromothripsis.
PVT1 is a non coding host gene for four microRNAs, miR 1204 Previous studies have implicated miR 1204 as a candidate oncogene that enhances oncogenesis in combination with MYC30, 31. PVT1 fus
Take 2 in a classic VW Camper Van
The classic VW Type 2 camper van, now made in Brazil, can be bought new in the UK. Mark Dixon put some flowers in his hair and took off
Appropriately, I was driving through Woodstock that's Woodstock in Oxfordshire, rather than New York State when it happened. A young lad in his Vauxhall made a rude gesture with his right hand as I passed. Mentally tut tutting at his appalling manners, I was several miles down the road before I realised that, far from being offensive, he was actually using one of those incomprehensible "VW" gestures with which fellow vee dub enthusiasts van cleef arpel alhambra necklace copy signal their approval. Oh, the shame!
You get a lot of that sort of thing when you drive an old VW camper van. Or, knock off van cleef heart necklace indeed, a new one if it's the classic Type 2 "Bay Window" imported by Danbury Motor Caravans.
Surfer Alex Wade was impressed by the all new, 30,000 VW California he reviewed in these pages on August 18, but still hankered for the classic Type 2 camper. In fact the Type 2 is still made in Brazil, from where Danbury ships them over to convert into camper vans for nostalgic ex hippies and anyone who likes a vehicle with a bit of character.
The big difference between older vans and the current model is that the engine is now water cooled rather than air cooled. This gives the front end a curiously 1960s East European look, but if it bothers you then Danbury can sell you a nose mounted dummy spare wheel cover drilled with dozens of vent holes. From a few feet van cleef arpel alhambra necklace fake away the cover appears solid, yet it lets enough air through for the radiator to do its job.
Inside, the vans are kitted out by Danbury to usual motorhome spec which, on this Diamond Classic model, means cooker, fridge, fold out double bed, elevating roof and chintzy fabric. That big sliding door on the side makes getting in and out a doddle, although the hefty slam you need to shut it won't win you any friends on the campsite when you get out for a pee at two in the morning.
Danbury will also convert the left hand drive vehicle to right hand drive. This isn't totally successful as the gearlever ends up close to your leg, while the steering wheel and instrument binnacle are offset to the left. In any case, right hand drive isn't really necessary since with just 80bhp on tap you won't be doing much overtaking.
Tucked away at the back of the van, the Polo engine is quiet and it's also economical I was getting 31mpg on cross country roads while the lack of power isn't such an issue: 65mph is about as fast as you'll want to go, given the van's predilection for sniffing out either verge of the carriageway if you let your concentration lapse for an instant.
The wayward handling and a frankly awful gearchange that feels as if you're stirring a thick soup, not to mention the non synchro first gear (in 2007!), mean it's hard to make a case for the Danbury being a serious alternative to a modern camper van. But that's the whole point: it's not a ''serious'' van. It is a bit of fun, and now that original 1970s Type 2s are fetching silly money the 26,359 asking price for a new Danbury to this spec isn't outrageous either.
Apparently Nick Park, the animator of Wallace and Gromit fame, has a Danbury. What's the betting that Wallace may be upgrading from his Austin A35 van in the near future?.
The classic VW Type 2 camper van, now made in Brazil, can be bought new in the UK. Mark Dixon put some flowers in his hair and took off
Appropriately, I was driving through Woodstock that's Woodstock in Oxfordshire, rather than New York State when it happened. A young lad in his Vauxhall made a rude gesture with his right hand as I passed. Mentally tut tutting at his appalling manners, I was several miles down the road before I realised that, far from being offensive, he was actually using one of those incomprehensible "VW" gestures with which fellow vee dub enthusiasts van cleef arpel alhambra necklace copy signal their approval. Oh, the shame!
You get a lot of that sort of thing when you drive an old VW camper van. Or, knock off van cleef heart necklace indeed, a new one if it's the classic Type 2 "Bay Window" imported by Danbury Motor Caravans.
Surfer Alex Wade was impressed by the all new, 30,000 VW California he reviewed in these pages on August 18, but still hankered for the classic Type 2 camper. In fact the Type 2 is still made in Brazil, from where Danbury ships them over to convert into camper vans for nostalgic ex hippies and anyone who likes a vehicle with a bit of character.
The big difference between older vans and the current model is that the engine is now water cooled rather than air cooled. This gives the front end a curiously 1960s East European look, but if it bothers you then Danbury can sell you a nose mounted dummy spare wheel cover drilled with dozens of vent holes. From a few feet van cleef arpel alhambra necklace fake away the cover appears solid, yet it lets enough air through for the radiator to do its job.
Inside, the vans are kitted out by Danbury to usual motorhome spec which, on this Diamond Classic model, means cooker, fridge, fold out double bed, elevating roof and chintzy fabric. That big sliding door on the side makes getting in and out a doddle, although the hefty slam you need to shut it won't win you any friends on the campsite when you get out for a pee at two in the morning.
Danbury will also convert the left hand drive vehicle to right hand drive. This isn't totally successful as the gearlever ends up close to your leg, while the steering wheel and instrument binnacle are offset to the left. In any case, right hand drive isn't really necessary since with just 80bhp on tap you won't be doing much overtaking.
Tucked away at the back of the van, the Polo engine is quiet and it's also economical I was getting 31mpg on cross country roads while the lack of power isn't such an issue: 65mph is about as fast as you'll want to go, given the van's predilection for sniffing out either verge of the carriageway if you let your concentration lapse for an instant.
The wayward handling and a frankly awful gearchange that feels as if you're stirring a thick soup, not to mention the non synchro first gear (in 2007!), mean it's hard to make a case for the Danbury being a serious alternative to a modern camper van. But that's the whole point: it's not a ''serious'' van. It is a bit of fun, and now that original 1970s Type 2s are fetching silly money the 26,359 asking price for a new Danbury to this spec isn't outrageous either.
Apparently Nick Park, the animator of Wallace and Gromit fame, has a Danbury. What's the betting that Wallace may be upgrading from his Austin A35 van in the near future?.
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Williams Eggleston
It's pretty hard nowadays to recapture the sense of outrage generated by photographer William Eggleston's show at the Museum of Modern Art in 1976. Critics at the time turned up their noses at Eggleston's super saturated colors, his unglamorous subjects plucked from the streets of Memphis, Tenn., and his oddball compositions which he claimed were arranged to mimic the Confederate flag. Visitors to the current Eggleston retrospective, Democratic Camera: Photographs and Video, 1961 2008, aren't likely to be riled the cartier pendant love imitation same way. The current show, organized last year by the Whitney Museum of American Art, will likely appear to contemporary eyes as simply venerable 1970s street photography: sometimes gaudy, sometimes ecstatic, but basically traditional hardly the stuff of scandal.
In Eggleston's time, some dismissed his work as being akin to cranking out snapshots of whatever came to hand. In 1976, conservative New York Times art critic Hilton Kramer wrote: "He likes trucks, cars, tricycles, unremarkable suburban houses and dreary landscapes too, and he especially likes his family and friends, who may, for all I know, be wonderful people, who appear in these pendant love cartier knock off pictures as dismal figures inhabiting a commonplace world of little visual interest."
In the art world of today, Eggleston is lauded for his eye and for his knack for capturing off kilter images, if not the importance of his larger artistic vision. Show curators Elizabeth Sussman and Thomas Weski, from the Whitney Museum and the Academy of Visual Arts in Leipzig, respectively, seem to accept Eggleston's own claims about his indifference to his subject matter his stated belief that he looks at the world as if "nothing was more important or less important." Even the show's title, Democratic Camera, suggests Eggleston is primarily a formalist, thinking about his relationship to the camera, color, and composition above all else.
Eggleston's best photos, however, won't sustain this reading. Eggleston was essentially a regionalist; his photographs are an extended riff on the artist's uneasy relationship with the ruined South and his own status as a moneyed Southern dandy on the skids. Eggleston was born in 1939 and raised on the family cotton farm in Tallahatchie County, Miss. He attended a series of universities without ever receiving a degree; since those days, he has always worn a suit and never owned a pair of bluejeans. Eggleston early on developed a sweet tooth for certain makes of expensive European cars Ferrari, Bentley, Rolls Royce which he incongruously drove around the Mississippi Delta throughout the 1970s in pursuit of women, drink, and drugs.
He was initially inspired by French photographer Henri Cartier Bresson and his notion of the decisive moment, a point at which the actions in front of the camera are distilled into one essential image, dependent largely on chance and instinct. Eggleston lamented that he necklace cartier love imitation couldn't see anything he actually liked or wanted to photograph in Tennessee certainly not equaling what Cartier Bresson found in Paris. He began to document his surroundings, anyway: commercial detritus, strange children wandering on empty roads, and bored bohemians slowly numbing themselves in living rooms and dive bars. Those subjects haunt the best of the 150 photos on view here, drawn from the past 50 years of his career.
Eggleston's preferred human subjects are often curious characters, shown in a way calculated to unsettle at times vaguely recalling some of the freakish people haunting the images of Eggleston's contemporary, Diane Arbus. Morton, Mississippi (c. 1969 70), for example, shows a silver haired gentleman slouching on the edge of a bed in a modest country bedroom. One of his hands is tucked between his legs; the other gingerly holds a revolver and touches the gun's barrel to a folded up quilt to his right. The man's mouth is agape, and his eyes appear glazed as if he is partly paralyzed, on the verge of some terrible decision, or simply remembering what he once did with this weapon, years before. Another image, Greenwood, Mississippi (1972), shows a dimly lit interior, the walls of which are plastered with graffiti. A naked man stands in the center of the room, scratching at his thinning hair; he stares intently at a cigarette that appears to have burned down almost to the filter on the dresser in the foreground. A giant tank oxygen? nitrous oxide? looms behind him.
Empty rooms in Eggleston images can be just as off putting as people as with the naked light bulb and glossy, impossibly saturated blood red ceiling in another image titled Greenwood, Mississippi (1973). It's worth remembering that up to the moment Eggleston began working with color, fine art photographs were almost universally black and white, often created with large format cameras. He didn't develop his own photographs; instead, he sent them to a laboratory to be printed with the dye transfer process a method of printing associated with advertising or commercial work, but certainly not with fine art. And Eggleston kept himself unencumbered by a tripod, preferring to meander around with a 35mm camera in order to encounter his decisive moments by chance.
Yet as much as chance plays a role in Eggleston's work, there is little that isn't deliberate in his distinctive manner of composing.
In Memphis (1969 71), Eggleston shows a woman sitting uneasily on a large curbstone. Her face sits in the exact center of the image. The decision to position her in this way produces strange repercussions: More than half of the photo is backdrop and sky; the woman, seated and staring directly at the viewer, is pushed into the bottom of the image, and one of her feet is cropped. The other appears to rest gingerly on the bottom edge of the photo. Her left hand is a blur; it appears that she necklace love cartier knock off raised her arm, perhaps in surprise, as she realized she was being photographed. A concrete post to the right of this woman is tightly wrapped with many feet of heavy chain strangely echoing the bracelet on her left arm, and offering a cheeky comment on her guarded, slightly impatient expression.
These arbitrary looking crops and unusual use of space are certainly by design, whether they were orchestrated beforehand or simply selected from an array of options later. Such affectations make the moments Eggleston captures seem all the more alien, snatched from the stream of time and made unfamiliar to us. This was Eggleston's mode: not framing timeless, balanced moments as Ansel Adams or Edward Weston might do but emphasizing the provisional, cockeyed quality of daily life as it unfolded around him.
Anyone curious about Eggleston's relationship to his subjects need look no further than Stranded in Canton (1974), the long, essentially unedited experimental video that shows Eggleston meandering through his milieu, bobbing and weaving with the lens. Scenes from this recently re edited video are shown here on four small monitors; the footage is all black and white, and much of it has been filmed with an infrared lens giving the people Eggleston captures the appearance of having huge, dark pupils and bathing everything around him in soft, glowing light.
Eggleston is clearly a strange voyeur, loping through groupings of revelers who vie for the attention of his lens. "He'd shoot with some kind of night vision lens often until the bitter end, then just fall over unconscious on the floor," said Memphis musician Bill Dickinson in a 2004 interview, describing the making of the movie. "He wasn't just at the party, he was the party."
Despite the mixed 1970s reaction to Eggleston's work, he has become an art star in the last couple of decades hence the show's including works up to 2008. He is now typically introduced as the grandfather of color photography, although he was certainly not the first fine artist to work in color, just the most highly visible. Eggleston still staggers among us, but in recent years, he has wandered far from the Delta and has received and accepted invitations to take photographs in Kyoto, Berlin, and on the sets of various movies made by a generation of Eggleston devotees.
Eggleston's Kyoto photos, dating from 2001, rely on superimposed images created by reflections, figures glimpsed through semi opaque glass, and unusual, brilliantly colored flowers and fish. Some of these pieces are reminiscent of vintage Eggleston but are at best only very competent formal exercises. Without Memphis and the texture of life in that part of the world, Eggleston's work loses its bite, its verve.
Whatever trepidation Eggleston has felt about Memphis, he has made a career for himself by turning all of the landscape around him into what now often is referred to as "Eggleston country." Yet Eggleston is a regionalist with a difference, almost postmodern in his adoption of a deliberately inelegant vocabulary for composing and framing, all within an equally artificial, heightened world of color. His decisions as a photographer speak generally to the problems of making discontinuous experiences into static images. More specifically, they speak to the problems of being in a cosmopolitan, bohemian, debauched state of mind in a rural setting on the outskirts of everywhere else you think you'd rather be.in regards to cartier bracelet plating gold screw copy Newest fashion news recommend tell you
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It's pretty hard nowadays to recapture the sense of outrage generated by photographer William Eggleston's show at the Museum of Modern Art in 1976. Critics at the time turned up their noses at Eggleston's super saturated colors, his unglamorous subjects plucked from the streets of Memphis, Tenn., and his oddball compositions which he claimed were arranged to mimic the Confederate flag. Visitors to the current Eggleston retrospective, Democratic Camera: Photographs and Video, 1961 2008, aren't likely to be riled the cartier pendant love imitation same way. The current show, organized last year by the Whitney Museum of American Art, will likely appear to contemporary eyes as simply venerable 1970s street photography: sometimes gaudy, sometimes ecstatic, but basically traditional hardly the stuff of scandal.
In Eggleston's time, some dismissed his work as being akin to cranking out snapshots of whatever came to hand. In 1976, conservative New York Times art critic Hilton Kramer wrote: "He likes trucks, cars, tricycles, unremarkable suburban houses and dreary landscapes too, and he especially likes his family and friends, who may, for all I know, be wonderful people, who appear in these pendant love cartier knock off pictures as dismal figures inhabiting a commonplace world of little visual interest."
In the art world of today, Eggleston is lauded for his eye and for his knack for capturing off kilter images, if not the importance of his larger artistic vision. Show curators Elizabeth Sussman and Thomas Weski, from the Whitney Museum and the Academy of Visual Arts in Leipzig, respectively, seem to accept Eggleston's own claims about his indifference to his subject matter his stated belief that he looks at the world as if "nothing was more important or less important." Even the show's title, Democratic Camera, suggests Eggleston is primarily a formalist, thinking about his relationship to the camera, color, and composition above all else.
Eggleston's best photos, however, won't sustain this reading. Eggleston was essentially a regionalist; his photographs are an extended riff on the artist's uneasy relationship with the ruined South and his own status as a moneyed Southern dandy on the skids. Eggleston was born in 1939 and raised on the family cotton farm in Tallahatchie County, Miss. He attended a series of universities without ever receiving a degree; since those days, he has always worn a suit and never owned a pair of bluejeans. Eggleston early on developed a sweet tooth for certain makes of expensive European cars Ferrari, Bentley, Rolls Royce which he incongruously drove around the Mississippi Delta throughout the 1970s in pursuit of women, drink, and drugs.
He was initially inspired by French photographer Henri Cartier Bresson and his notion of the decisive moment, a point at which the actions in front of the camera are distilled into one essential image, dependent largely on chance and instinct. Eggleston lamented that he necklace cartier love imitation couldn't see anything he actually liked or wanted to photograph in Tennessee certainly not equaling what Cartier Bresson found in Paris. He began to document his surroundings, anyway: commercial detritus, strange children wandering on empty roads, and bored bohemians slowly numbing themselves in living rooms and dive bars. Those subjects haunt the best of the 150 photos on view here, drawn from the past 50 years of his career.
Eggleston's preferred human subjects are often curious characters, shown in a way calculated to unsettle at times vaguely recalling some of the freakish people haunting the images of Eggleston's contemporary, Diane Arbus. Morton, Mississippi (c. 1969 70), for example, shows a silver haired gentleman slouching on the edge of a bed in a modest country bedroom. One of his hands is tucked between his legs; the other gingerly holds a revolver and touches the gun's barrel to a folded up quilt to his right. The man's mouth is agape, and his eyes appear glazed as if he is partly paralyzed, on the verge of some terrible decision, or simply remembering what he once did with this weapon, years before. Another image, Greenwood, Mississippi (1972), shows a dimly lit interior, the walls of which are plastered with graffiti. A naked man stands in the center of the room, scratching at his thinning hair; he stares intently at a cigarette that appears to have burned down almost to the filter on the dresser in the foreground. A giant tank oxygen? nitrous oxide? looms behind him.
Empty rooms in Eggleston images can be just as off putting as people as with the naked light bulb and glossy, impossibly saturated blood red ceiling in another image titled Greenwood, Mississippi (1973). It's worth remembering that up to the moment Eggleston began working with color, fine art photographs were almost universally black and white, often created with large format cameras. He didn't develop his own photographs; instead, he sent them to a laboratory to be printed with the dye transfer process a method of printing associated with advertising or commercial work, but certainly not with fine art. And Eggleston kept himself unencumbered by a tripod, preferring to meander around with a 35mm camera in order to encounter his decisive moments by chance.
Yet as much as chance plays a role in Eggleston's work, there is little that isn't deliberate in his distinctive manner of composing.
In Memphis (1969 71), Eggleston shows a woman sitting uneasily on a large curbstone. Her face sits in the exact center of the image. The decision to position her in this way produces strange repercussions: More than half of the photo is backdrop and sky; the woman, seated and staring directly at the viewer, is pushed into the bottom of the image, and one of her feet is cropped. The other appears to rest gingerly on the bottom edge of the photo. Her left hand is a blur; it appears that she necklace love cartier knock off raised her arm, perhaps in surprise, as she realized she was being photographed. A concrete post to the right of this woman is tightly wrapped with many feet of heavy chain strangely echoing the bracelet on her left arm, and offering a cheeky comment on her guarded, slightly impatient expression.
These arbitrary looking crops and unusual use of space are certainly by design, whether they were orchestrated beforehand or simply selected from an array of options later. Such affectations make the moments Eggleston captures seem all the more alien, snatched from the stream of time and made unfamiliar to us. This was Eggleston's mode: not framing timeless, balanced moments as Ansel Adams or Edward Weston might do but emphasizing the provisional, cockeyed quality of daily life as it unfolded around him.
Anyone curious about Eggleston's relationship to his subjects need look no further than Stranded in Canton (1974), the long, essentially unedited experimental video that shows Eggleston meandering through his milieu, bobbing and weaving with the lens. Scenes from this recently re edited video are shown here on four small monitors; the footage is all black and white, and much of it has been filmed with an infrared lens giving the people Eggleston captures the appearance of having huge, dark pupils and bathing everything around him in soft, glowing light.
Eggleston is clearly a strange voyeur, loping through groupings of revelers who vie for the attention of his lens. "He'd shoot with some kind of night vision lens often until the bitter end, then just fall over unconscious on the floor," said Memphis musician Bill Dickinson in a 2004 interview, describing the making of the movie. "He wasn't just at the party, he was the party."
Despite the mixed 1970s reaction to Eggleston's work, he has become an art star in the last couple of decades hence the show's including works up to 2008. He is now typically introduced as the grandfather of color photography, although he was certainly not the first fine artist to work in color, just the most highly visible. Eggleston still staggers among us, but in recent years, he has wandered far from the Delta and has received and accepted invitations to take photographs in Kyoto, Berlin, and on the sets of various movies made by a generation of Eggleston devotees.
Eggleston's Kyoto photos, dating from 2001, rely on superimposed images created by reflections, figures glimpsed through semi opaque glass, and unusual, brilliantly colored flowers and fish. Some of these pieces are reminiscent of vintage Eggleston but are at best only very competent formal exercises. Without Memphis and the texture of life in that part of the world, Eggleston's work loses its bite, its verve.
Whatever trepidation Eggleston has felt about Memphis, he has made a career for himself by turning all of the landscape around him into what now often is referred to as "Eggleston country." Yet Eggleston is a regionalist with a difference, almost postmodern in his adoption of a deliberately inelegant vocabulary for composing and framing, all within an equally artificial, heightened world of color. His decisions as a photographer speak generally to the problems of making discontinuous experiences into static images. More specifically, they speak to the problems of being in a cosmopolitan, bohemian, debauched state of mind in a rural setting on the outskirts of everywhere else you think you'd rather be.
Mindless knock off pendant cartier love vandals have torched a Twickenham children's play centre From This Is Local London
Mindless vandals have torched a Twickenham children's play centreHorrific arson attack on charitable playcentre in TwickenhamMindless vandals have torched a Twickenham children's play centreThe outdoor facilities remain closed as staff work hard to improve the damage causedMindless vandals have torched a Twickenham children's play centreUnidentified vandals torched the children's playcentre in the cartier chain for men fake early hours of the morningThe police are working with English Heritage to uncover the criminals who destroyed Marble Hill Playcentres One O'Clock Club's outdoor space and Wendy House, on Richmond Road, in the early hours of Saturday (May 13).
The voluntary run indoor play facilities and building escaped the arson attack but remained closed on Monday May 15 so staff could work on the damaged caused to the club's outdoor area.
Kevin Stinton, manager of Marble Hill Playcentres, said: "We are all very upset about the damage caused over the weekend."
Local residents and visitors took to Facebook to post comments about how horrified they are by the incident, share personal stories of time spent there and ask if there is anything they can do to help.
"We have been touched by the offers of support from the local community in light of this incident and thank them all for their kind words," the playcentres' manager added.
The centre is run by a group of local parents who set up the drop in play facility for babies and children up to five years old to enjoy a variety of activities whilst parents enjoyed a sociable environment.
Kay Lint, property manager of Marble Hill house from the English Heritage, said: "This was a shocking incident as Marble Hill playcentres is a much loved part of imitation cartier gold chain the community and the services it provides.
"As one of our key partners, English Heritage is working closely with Marble Hill playcentres and its staff to support them during this time."
The centre also offers children from five to 15 years old the chance to play on the only open access adventure playground in copy cartier gold chain the borough which was luckily unharmed by the fire.
Marble Hill is a not for profit organisation which can also cater for children with impaired mobility and give them access to play alongside peers via specially designed birds nest swings and a wheelchair accessible walkway.regarding cartier necklace red gold love copy Latest fad news suggest dynamic
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Mindless vandals have torched a Twickenham children's play centreHorrific arson attack on charitable playcentre in TwickenhamMindless vandals have torched a Twickenham children's play centreThe outdoor facilities remain closed as staff work hard to improve the damage causedMindless vandals have torched a Twickenham children's play centreUnidentified vandals torched the children's playcentre in the cartier chain for men fake early hours of the morningThe police are working with English Heritage to uncover the criminals who destroyed Marble Hill Playcentres One O'Clock Club's outdoor space and Wendy House, on Richmond Road, in the early hours of Saturday (May 13).
The voluntary run indoor play facilities and building escaped the arson attack but remained closed on Monday May 15 so staff could work on the damaged caused to the club's outdoor area.
Kevin Stinton, manager of Marble Hill Playcentres, said: "We are all very upset about the damage caused over the weekend."
Local residents and visitors took to Facebook to post comments about how horrified they are by the incident, share personal stories of time spent there and ask if there is anything they can do to help.
"We have been touched by the offers of support from the local community in light of this incident and thank them all for their kind words," the playcentres' manager added.
The centre is run by a group of local parents who set up the drop in play facility for babies and children up to five years old to enjoy a variety of activities whilst parents enjoyed a sociable environment.
Kay Lint, property manager of Marble Hill house from the English Heritage, said: "This was a shocking incident as Marble Hill playcentres is a much loved part of imitation cartier gold chain the community and the services it provides.
"As one of our key partners, English Heritage is working closely with Marble Hill playcentres and its staff to support them during this time."
The centre also offers children from five to 15 years old the chance to play on the only open access adventure playground in copy cartier gold chain the borough which was luckily unharmed by the fire.
Marble Hill is a not for profit organisation which can also cater for children with impaired mobility and give them access to play alongside peers via specially designed birds nest swings and a wheelchair accessible walkway.
GWS arent planning to review their education process despite Shane Mumfords sledge of Lance Franklin and have praised their ruckman for apologising to the Sydney superstar. Air Jordan 13 Retro Italia .Former Swan Mumford taunted Franklin in Saturdays preliminary final by reportedly saying good to see youre not on holidays this year, a reference to the forward missing the 2015 finals series because of a serious mental health issue.The Giants website posted a video of Mumford talking about his phone apology and admitting he hadnt used a good choice of words when sledging Franklin.Giants general manager of football Wayne Campbell stressed the club addressed education and welfare issues on an ongoing basis.Id like to think that we do that on a constant basis, whether thats with the whole group or the leadership group discussing things, Campbell said.A lot of the stuff that gets talked about at the leadership group and the whole group doesnt make the public domain, so we like to think that we constantly address that.I wouldnt have thought we would be addressing it just on the back of this.Campbell and midfielder Stephen Coniglio, who on Wednesday inked a two-year contract extension, praised the way Mumford had reacted to the fallout from his sledge of Franklin.His (Mumfords) mood over the last 48 hours has been great around the group, his annoying self around the club, Coniglio said.But I think the one thing as a person, the fact that he could actually apologise and speak to Lance on the phone and apologise for what he said, speaks a lot about the person he is.From a teammate and mates point of view, to play with a guy like that is fantastic and what he offers us on the field we love and what he does around the club is faultless.Campbell said you cant help but admire someone who acknowledges that he has made an error and puts his hand up, Shane did that.I think its a good way to deal with things that he gets on the phone and has a chat to Lance and they deal with it behind closed doors as best as they can and then we move on from there.Coniglio said the absence of suspended veteran forward Steve Johnson for the preliminary final was a massive loss, but stressed the wily veteran still exerted influence off the field.His actual input coming into the club, both on and off the field, his experience, his actual drive to push hard for a premiership, has been great,, Coniglio said.Unfortunately, hell miss next week, but well welcome him back with open arms the week after, if we can get there. Jordan 6 Retro Shop Online . The incident occurred at 19:56 of the second period of the Kings 4-2 road win over Edmonton on Sunday. Nolan punched Oilers forward Jesse Joensuu in the jaw in front of the Kings goal during a scrum. Air Jordan 4 Retro 2018 . -- Jacksonville wide receiver Cecil Shorts will likely be a game-time decision whether hell play Sunday in the Jaguars home game against the San Diego Chargers. http://www.airjordanretroscarpe.it/italia-jordan-4-retro-scarpe-uomo-oregon-ducks-scarpe-grigio-nere-giada-verde-50.html . The return match will take place next Wednesday. Udinese leads Fiorentina 2-1 in the other semifinal. Napoli staged a second-half comeback from two goals down after Gervinhos opener and a stunning strike from Kevin Strootman. White-hot Melbourne Victory striker Natasha Dowie has twin goals in mind as she prepares for the first Melbourne derby of the W-League season.The first order of business is becoming the first side to stop Melbourne Citys relentless charge through the league.And if she can do that, the leagues in-form striker believes she will be on track to represent England again.Dowie, 28, has three goals in as many games this season, leading the W-League goalscoring charts despite Victory languishing on the bottom of the table.On Sunday at AAMI Park, her side faces the most imposing test of their season to date when their cross-town rivalry resumes.But Dowie - whose impressive CV includes stints in England, the USA and a quarter-century of caps with the Three Lions - says Victory can spring a surprise.Fair play to City, they ran away with last year and theyre the strong favourites 100 per cent, she told AAP.But with a derby its not about form, its about who turns up on the day.I learned that playing for Liverpool. Whenever wed play Everton - always classed as the weaker team - it was never easy.Theres no point in playing tthe game if you cant get up for games like this and it would be amazing if we could turn them over and stop their unbeaten run. Air Jordan 11 Retro Italia. Off the back of a short spell with Boston Breakers, Dowie said she was hitting new heights.I feel great and Im probably in the best form Ive ever been in, she said.Id be happier if we were winning games. But on an individual note I cant be doing any more than Im doing.Dowie was the leading scorer in the 2013 English Womens Super League, but missed out on the 2013 European Championship.Her qualifying goals helped England reach the 2015 Womens World Cup but the striker was again overlooked for the Canada tournament.Still, she remains hopeful that good form over the Australian summer can help her win caps in the future.Ive been in and out of the England setup and Id be stupid to say it wasnt in my mind. Every player wants to play for their country and go to the big tournaments, she said.With my goalscoring record, I feel like I should be involved. Cheap NFL Jerseys Cheap NFL Jerseys China Cheap Jerseys From China Cheap NFL Jerseys Authentic Wholesale Jerseys China Cheap NFL Jerseys China NFL Cheap Jerseys ' ' '
RIO DE JANEIRO -- The pole vault world-record holder was banned. Skal Labissiere Jersey . The hometown favorite didnt make it through qualifying.It was all perfectly set up for Jenn Suhr to win another Olympic gold medal.It didnt happen.The American couldnt overcome a respiratory infection that left her dizzy, coughing up blood earlier in the day and throwing up twice near the pole vault area during the competition.Suhr ended up tied for seventh Friday in an event won by Ekaterini Stefanidi of Greece. Sandi Morris of the United States finished with silver and Eliza McCartney of New Zealand wound up with bronze.I feel horrible, said Suhr, who captured Olympic gold four years ago in London and silver at the 2008 Beijing Games. Im actually getting concerned. Its going on Day 10 and I feel worse today.Her next stop -- home to New York get treatment for this mysterious illness.They think its respiratory and now in the lungs. This morning I was coughing up blood, the 34-year-old Suhr said. Its getting scary.I just want to get out of here and go home and figure it out.Just when the path to another gold medal appeared wide open, too.Suhrs top competitor was supposed to be Yelena Isinbayeva, the world-record holder who has been banned from the games, along with dozens of other Russians, because of a doping investigation. Isinbayeva called it quits on Friday as she focuses on a new career in sports politics and even mulls over an offer to lead the Russian track and field team.Also missing from the field was Fabiana Murer, the Brazilian who was expected to get in the mix for a medal but didnt make it out of qualifying.Its such a crappy feeling to know youve worked four years for this and for this to happen, Suhr said. Its embarrassing, too.Early on, Suhr thought she felt OK enough to compete. While warming up, she was clearing the bar at 4.90 meters, which wouldve won this competition. It didnt carry over into the final. Stefanidi and Morris both cleared the same height -- 4.85 -- but Stefanidi had fewer misses.I was like, `Im on, Suhr said. After warmups, everything shut down. My muscles -- Ive never had them shake.Morris could tell her teammate didnt feel well.She just looked pretty dreary. I dont know how else to say it, Morris said. She just didnt look energetic. I really feel for her. Its just an unfortunate circumstance to get sick at this time. Willie Cauley-Stein Jersey . In the lead up - which seemed to begin the moment Mike Geiger blew the whistle in Houston last Thursday night - the Impact rumour mill went into overdrive. The speculation went into meltdown mode, of the golden nugget variety. Buddy Hield Kings Jersey . The team said Saturday that Lopez was hurt during its 121-120 overtime loss at Philadelphia on Friday. The Nets said they would issue another update next week after consultation with their doctors. http://www.kingsbasketballpro.com/Ben-Mclemore-Kings-Jersey/ . The quest begins with what is supposed to be an easy one, although Germany has traditionally been a stubborn opponent to Canadian teams at international tournaments.Cheap NFL Jerseys Cheap NFL Jerseys China Cheap Jerseys From China Cheap NFL Jerseys Authentic Wholesale Jerseys China Cheap NFL Jerseys China NFL Cheap Jerseys ' ' '
St. Adidas Tomas Hertl Jersey . Louis, MO (Sports Network) - The St. Louis Blues signed forward Adam Cracknell to a one-year contract on Tuesday. The 27-year-old participated in 20 games this past season, totaling two goals and four assists. He was set to become an unrestricted free agent in July. In parts of three NHL seasons, the Saskatchewan native has compiled six goals and 14 points in 46 NHL games. Adidas Joel Ward Jersey . Uniteds eighth defeat of a wretched campaign means Liverpool, which currently occupies the fourth and final Champions League place, could go nine points clear of its fierce rival by beating West Bromwich Albion on Sunday. Charlie Adam scored both of Stokes goals at Britannia Stadium either side of Robin van Persies equalizer, with a miserable day for seventh-place United capped by first-half injuries to centre halves Jonny Evans and Phil Jones that forced them off. Adidas Joe Thornton Jersey . -- If this was Aaron Gordons final home game at Arizona, and it almost certainly was, then he went out in style. http://www.sharkssportsshop.com/adidas+logan+couture+sharks+jersey . -- Jacksonville wide receiver Cecil Shorts will likely be a game-time decision whether hell play Sunday in the Jaguars home game against the San Diego Chargers. Former GWS football manager Graeme Allen reportedly told a welfare worker at the AFL club to delete an email from Lachie Whitfields girlfriend last season, telling him he would look after the drug concerns raised.It was revealed last month that Whitfield had been investigated for trying to dodge drug testers in 2015, after his then-girlfriend had expressed concerns over his behaviour and potential use of illicit substances.Its also claimed that the Giants midfielder stayed at the home of welfare manager Craig Lambert to avoid ASADA, while Allen deleted key text messages in relation to the matter.However according to Fairfax Media, Whitfields girlfriend also emailed player welfare worker Brett Hand to expresss the same concerns, only for him to be told by Allan that she was erratic and that he would deal with the issue. Adidas Patrick Marleau Jersey. Hand is not accused of any wrongdoing given he was following orders from a manager.Its also believed that Whitfield may have been concerned the illicit substances may have been laced with performance-enhancing drugs (PEDs).The penalty for avoiding tests due to concerns surrounding PEDs is a minimum four-year ban for any players or officials involved.Allan has recently been employed as the football director at Collingwood, while Lambert is now at Brisbane. Cheap NFL Jerseys Cheap NFL Jerseys China Cheap Jerseys From China Cheap NFL Jerseys Authentic Wholesale Jerseys China Cheap NFL Jerseys China NFL Cheap Jerseys ' ' '
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