Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Planktic foraminifera-based sea-surface temperature record in the Tasman Sea and history of the Subtropical Front around New Zealand, over the last one million years

Planktic foraminiferal assemblages in a composite section from two cores (MD06-2989/2986) off the west coast of New Zealand's South Island (42-43.5 degrees S) provide a 1 myr (MIS 31-1) sea-surface temperature (SST) record (similar to 3-4 kyr resolution) in the Tasman Sea. A significant overall faunal change occurred near the end of the midPleistocene Climate Transition (MPT) at similar to 600 ka (MIS 15). Mean annual SSTs were estimated using the Artificial Neural Network (ANN) method. Glacial-interglacial (G-I) cycles in the MPT had similar to 9 degrees C SST range, whereas in the post-MPT SST range was similar to 6-7 degrees C. The SST and faunal changes imply that the Subtropical Front (STF) migrated similar to 6 degrees in latitude to lie just north of the sites in MPT glacials (MIS 28-16), but only migrated 3-5 degrees north in postMPT glacials. These G-I latitudinal migrations of the STF west of New Zealand contrast with the situation east of New Zealand, where migrations of both the STF and Subantarctic Front were prevented by the Chatham Rise and Campbell Plateau. Subtropical Water is inferred to have only flowed around the south of New Zealand (as it does today) during MIS 11 and the Late Pleistocene-Holocene (MIS 5-1). (C) 2011 Elsevier By. All rights reserved

The Norfolk Ridge: A Proximal Record of the Tonga‐Kermadec Subduction Initiation

Norfolk Ridge bounds the northeastern edge of the continent of Zealandia and is proximal to where Cenozoic Tonga-Kermadec subduction initiation occurred. We present and analyze new seismic reflection, bathymetric and rock data from Norfolk Ridge that show it is composed of a thick sedimentary succession and that it was formed and acquired its present-day ridge physiography and architecture during Eocene to Oligocene uplift, emergence and erosion. Contemporaneous subsidence of the adjacent New Caledonia Trough shaped the western slope of Norfolk Ridge and was accompanied by volcanism. Neogene extension along the eastern slope of Norfolk Ridge led to the opening of the Norfolk Basin. Our observations reveal little or no contractional deformation, in contrast to observations elsewhere in Zealandia, and are hence significant for understanding the mechanics of subduction initiation. We suggest that subduction nucleated north of Norfolk Ridge and propagated rapidly along the ridge during the period 40-35 Ma, giving it a linear and narrow shape. Slab roll-back following subduction initiation may have preserved the ridge and created its eastern flank. Our observations suggest that pre-existing structures, which were likely inherited from Cretaceous Gondwana subduction, were well-oriented to propagate rupture and create self-sustaining subduction. Key Points We present new marine geophysical and geological data of Norfolk Ridge located along the northeastern edge of the Zealandia continent We show that the ridge is not inherited from Cretaceous rifting that led to isolation of Zealandia but from the TECTA Cenozoic tectonic event Analysis of the structure and evolution of Norfolk Ridge underpins our understanding of tectonic processes of subduction initiation Plain Language Summary Plate tectonic theory established and proved that the surface of Earth is composed of rigid moving plates, but it remains unclear how and why these plates sometimes re-configure their boundaries and motions. Subduction zones are places where two plates converge and one plunges deep into the Earth beneath the other one. As the plate sinks, it drags the rest of the plate with it and acts as an engine that “pulls” the plate and drives horizontal motion. This is what drives the dynamics of plate tectonics. How are subduction zones created? This remains an open question, but we know from geological observations that new subduction zones do get created: more than half of all active subduction zones were created after the dinosaurs died out 65 million years ago. We present new observations from northern Zealandia (a submerged continent between New Zealand and New Caledonia) that document how one of the largest subduction zones on Earth, the Tonga-Kermadec system, started

Sea surface temperature reconstruction for the Southwest Pacific Ocean

Paleoceanographic archives derived from 17 marine sediment cores reconstruct the response of the Southwest Pacific Ocean to the peak interglacial, Marine Isotope Stage (MIS) 5e (ca. 125 ka). Paleo-Sea Surface Temperature (SST) estimates were obtained from the Random Forest model-an ensemble decision tree tool-applied to core-top planktonic foraminiferal faunas calibrated to modern SSTs. The reconstructed geographic pattern of the SST anomaly (maximum SST between 120 and 132 ka minus mean modern SST) seems to indicate how MIS 5e conditions were generally warmer in the Southwest Pacific, especially in the western Tasman Sea where a strengthened East Australian Current (EAC) likely extended subtropical influence to ca. 45°S off Tasmania. In contrast, the eastern Tasman Sea may have had a modest cooling except around 45°S. The observed pattern resembles that developing under the present warming trend in the region. An increase in wind stress curl over the modern South Pacific is hypothesized to have spun-up the South Pacific Subtropical Gyre, with concurrent increase in subtropical flow in the western boundary currents that include the EAC. However, warmer temperatures along the Subtropical Front and Campbell Plateau to the south suggest that the relative influence of the boundary inflows to eastern New Zealand may have differed in MIS 5e, and these currents may have followed different paths compared to today

Diversity of TMPRSS2-ERG fusion transcripts in the human prostate.

TMPRSS2-ERG gene fusions have recently been reported to be present in a high proportion of human prostate cancers. In the current study, we show that great diversity exists in the precise structure of TMPRSS2-ERG hybrid transcripts found in human prostates. Fourteen distinct hybrid transcripts are characterized, each containing different combinations of sequences from the TMPRSS2 and ERG genes. The transcripts include two that are predicted to encode a normal full-length ERG protein, six that encode N-terminal truncated ERG proteins and one that encodes a TMPRSS2-ERG fusion protein. Interestingly, distinct patterns of hybrid transcripts were found in samples taken from separate regions of individual cancer-containing prostates, suggesting that TMPRSS2-ERG gene fusions may be arising independently in different regions of a single prostate

Site U1351

128 page(s