Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.

We identified 15 kindreds including 29 individuals affected with ARC syndrome. First, we excluded linkage to the candidate genes ATP8B1 and ABCB11 (ref. 10), which are implicated in other disorders that cause neonatal cholestasis with low gGT activity. We then carried out a genome-wide linkage scan using the Affymetrix 10K SNP chip [11][12][13][14] in seven affected individuals from six consanguineous kindreds with ARC. This scan identified eight regions of extended homozygosity shared by all affected individuals. We analyzed these regions further by typing microsatellite markers in 64 individuals from 14 consanguineous families ( Fig. 1 and Supplementary Fig.

Bleeding problems are associated with defects in platelet ␣-granules, yet little is known about how these granules are formed and released. Mutations affecting VPS33B, a novel Sec1/Munc18 protein, have recently been linked to arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome. We have characterized platelets from patients with ARC syndrome and observed reduced aggregation with arachidonate and adenosine diphosphate (ADP). Structural abnormalities seen in ARC platelets included increased platelet size, a pale appearance in blood films, elevated numbers of ␦-granules, and completely absent ␣-granules. Soluble and membrane-bound ␣-granule proteins were significantly decreased or undetectable in ARC platelets, suggesting that both the releasable protein pools and membrane components of ␣-granules were absent. The role of VPS33B in platelet granule biogenesis was evaluated by immunofluorescence microscopy in normal human megakaryocytes. VPS33B colocalized appreciably with markers of ␣-granules, moderately with late endosomes/lysosomes, minimally with ␦-granules/lysosomes, and not with cis-Golgi complexes. VPS33B protein expression determined by immunoblotting confirmed the presence of VPS33B in control fibroblasts but not in ARC fibroblasts, and in normal megakaryocytes but not in platelets. We conclude that like other Sec1/Munc18 proteins, VPS33B is involved in intracellular vesicle trafficking, being essential for the development of platelet ␣-granules but not for granule secretion. IntroductionCongenital platelet disorders involving abnormalities in ␣ and/or dense (␦) granules are an important cause of inherited bleeding disorders. A number of genes have been linked to the ␦-granule defects associated with the Hermansky-Pudlak and ChediakHigashi syndromes, 1-6 and 16 genes have been identified in mice that regulate vesicle trafficking to platelet ␦-granules and melanosomes; some of these genes encode known vesicle trafficking proteins whereas others encode components of BLOC (biogenesis of lysosome-related organelles complexes) protein complexes. 3,7 Much less is known about the genes or proteins involved in ␣-granule defects, although some transcription factors and cellsurface glycoproteins have been implicated. For example, a family with X-linked macrothrombocytopenia and reduced ␣-granules was found to have an aspartate-to-glycine mutation in the transcription factor GATA1, 8 and hemizygous loss of the FLI1 transcription factor causes the Paris-Trousseau syndrome, characterized by abnormal megakaryocytes and giant ␣-granules. 9,10 In mice, loss of transcription factor NF-E2 expression produces abnormal megakaryocytes with absent ␣-granules, 11 and hematopoietic zinc finger (Hzf)-deficient mice have megakaryocytes and platelets with reduced ␣-granules and ␣-granule proteins. 12 Glycoprotein (GP) Ib␤-deficient mouse platelets contain abnormally large ␣-granules, 13 and giant ␣-granules have also been observed in platelets from a patient with Bernard-Soulier syndrome. 14 A deficiency of both platel...