While genome-wide association studies (GWAS) have identified germline variants influencing the risk of developing colorectal cancer (CRC), there has been limited examination of the possible role of ...inherited variation as a determinant of patient outcome.
We performed a GWAS for overall survival (OS) in 1926 patients with advanced CRC from the COIN and COIN-B clinical trials. For single nucleotide polymorphisms (SNPs) showing an association with OS (P < 1.0 × 10−5), we conducted sensitivity analyses based on the time from diagnosis to death and sought independent replications in 5675 patients from the Study of Colorectal Cancer in Scotland (SOCCS) and 16,964 patients from the International Survival Analysis in Colorectal cancer Consortium (ISACC). We analysed the Human Protein Atlas to determine if ERBB4 expression was associated with survival in 438 patients with colon adenocarcinomas.
The most significant SNP associated with OS was rs79612564 in ERBB4 (hazard ratio HR = 1.24, 95% confidence interval CI = 1.16–1.32, P = 1.9 × 10−7). SNPs at 17 loci had suggestive associations for OS and all had similar effects on the time from diagnosis to death. No lead SNPs were independently replicated in the meta-analysis of all patients from SOCCS and ISACC. However, rs79612564 was significant in stage-IV patients from SOCCS (P = 2.1 × 10−2) but not ISACC (P = 0.89) and SOCCS combined with COIN and COIN-B attained genome-wide significance (P = 1.7 × 10−8). Patients with high ERBB4 expression in their colon adenocarcinomas had worse survival (HR = 1.50, 95% CI = 1.1–1.9, P = 4.6 × 10−2).
Genetic and expression data support a potential role for rs79612564 in the receptor tyrosine kinase ERBB4 as a predictive biomarker of survival.
•A genome-wide search for biomarkers of survival in 1926 patients with advanced CRC.•Seventeen potential prognostic variants with replication of rs79612564 in ERBB4.•A median decrease in life expectancy of ∼40 days per allele carried.•Patients with high ERBB4 expression in colon tumours had worse survival.•Potential use for rs79612564 and/or ERBB4 as a prognostic biomarker.
ABSTRACT
Inherited factors account for around one third of all colorectal cancers (CRCs) and include rare high penetrance mutations in APC, MSH2, MSH6, and POLE. Here, we sought novel ...tumor‐suppressor genes that predispose to CRC by exome resequencing 50 sporadic patients with advanced CRC (18 diagnosed ≤35 years of age) at a mean coverage of 30×. To help identify potentially pathogenic alleles, we initially sought rare or novel germline truncating mutations in 1,138 genes that were likely to play a role in colorectal tumorigenesis. In total, 32 such mutations were identified and confirmed, and included an insertion in APC and a deletion in POLE, thereby validating our approach for identifying disease alleles. We sought somatic mutations in the corresponding genes in the CRCs of the patients harboring the germline lesions and found biallelic inactivation of FANCM, LAMB4, PTCHD3, LAMC3, and TREX2, potentially implicating these genes as tumor suppressors. We also identified a patient who carried a germline truncating mutation in NOTCH3, part of the Notch signaling cascade that maintains intestinal homeostasis. Our whole exome analyses provided further gene lists to facilitate the identification of potential predisposition alleles.
We exomeresequenced 50 sporadic patients with advanced CRC. To identify predisposition alleles, we sought rare/novel germline truncating mutations in 1138 genes considered likely to play a role in colorectal tumorigenesis. Thirty‐two such mutations were identified, including an insertion in APC, thereby validating our approach. We sought somatic mutations in the corresponding genes in the CRCs of the patients harbouring the germline lesions and found biallelic inactivation of FANCM, LAMB4, PTCHD3, LAMC3 and TREX2, implicating their potential role in CRC‐predisposition.
809 deep IODP Hole U1473A at Atlantis Bank, SWIR, is 2.2 km from 1,508‐m Hole 735B and 1.4 from 158‐m Hole 1105A. With mapping, it provides the first 3‐D view of the upper levels of a 660‐km2 lower ...crustal batholith. It is laterally and vertically zoned, representing a complex interplay of cyclic intrusion, and ongoing deformation, with kilometer‐scale upward and lateral migration of interstial melt. Transform wall dives over the gabbro‐peridotite contact found only evolved gabbro intruded directly into the mantle near the transform. There was no high‐level melt lens, rather the gabbros crystallized at depth, and then emplaced into the zone of diking by diapiric rise of a crystal mush followed by crystal‐plastic deformation and faulting. The residues to mass balance the crust to a parent melt composition lie at depth below the center of the massif—likely near the crust‐mantle boundary. Thus, basalts erupted to the seafloor from >1,550 mbsf. By contrast, the Mid‐Atlantic Ridge lower crust drilled at 23°N and at Atlantis Massif experienced little high‐temperature deformation and limited late‐stage melt transport. They contain primitive cumulates and represent direct intrusion, storage, and crystallization of parental MORB in thinner crust below the dike‐gabbro transition. The strong asymmetric spreading of the SWIR to the south was due to fault capture, with the northern rift valley wall faults cutoff by a detachment fault that extended across most of the zone of intrusion. This caused rapid migration of the plate boundary to the north, while the large majority of the lower crust to spread south unroofing Atlantis Bank and uplifting it into the rift mountains.
Key Points
No evidence of a high‐level melt lens with gabbros intruded at depth, then emplaced to high levels by crystal mush diapirism, plastic deformation, and faulting
Diving over the crust‐mantle boundary on the transform wall found no primitive cumulates, and evolved gabbro was intruded directly into the mantle at the transform
Primitive cumulates needed to mass balance MORB must lie at depth near the crust‐mantle boundary, while the few diabase dikes encountered intrude the gabbro
Attending to a stimulus enhances the sensitivity of perceptual decisions. However, it remains unclear how perceptual sensitivity varies according to whether a feature is expected or unexpected. Here, ...observers made fine discrimination judgments about the orientation of visual gratings embedded in low spatial-frequency noise, and psychophysical reverse correlation was used to estimate decision 'kernels' that revealed how visual features influenced choices. Orthogonal cues alerted subjects to which of two spatial locations was likely to be probed (spatial attention cue) and which of two oriented gratings was likely to occur (feature expectation cue). When an expected (relative to unexpected) feature occurred, decision kernels shifted away from the category boundary, allowing observers to capitalize on more informative, "off-channel" stimulus features. By contrast, the spatial attention cue had a multiplicative influence on decision kernels, consistent with an increase in response gain. Feature expectation thus heightens sensitivity to the most informative visual features, independent of selective attention.
Sensory experience influences the establishment of neural connectivity through molecular mechanisms that remain unclear. Here, we employ single-nucleus RNA sequencing to investigate the contribution ...of sensory-driven gene expression to synaptic refinement in the dorsal lateral geniculate nucleus of the thalamus, a region of the brain that processes visual information. We find that visual experience induces the expression of the cytokine receptor Fn14 in excitatory thalamocortical neurons. By combining electrophysiological and structural techniques, we show that Fn14 is dispensable for early phases of refinement mediated by spontaneous activity but that Fn14 is essential for refinement during a later, experience-dependent period of development. Refinement deficits in mice lacking Fn14 are associated with functionally weaker and structurally smaller retinogeniculate inputs, indicating that Fn14 mediates both functional and anatomical rearrangements in response to sensory experience. These findings identify Fn14 as a molecular link between sensory-driven gene expression and vision-sensitive refinement in the brain.
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•Visual stimulation induces a unique gene program in excitatory neurons of the dLGN•Fn14 is the most inducible molecule specific to the excitatory population•Vision-sensitive refinement is impaired in mice lacking Fn14•Changes in synaptic morphology accompany physiological deficits in mice lacking Fn14
Visual experience promotes the synaptic refinement of the retinogeniculate circuit by inducing the expression of the cytokine receptor Fn14 in excitatory neurons of the dorsal lateral geniculate nucleus of the thalamus.
Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ...ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
When hydrothermal activity ceases at black-smoker chimneys on mid-ocean ridges, populations of associated invertebrates hosting chemoautotrophic endosymbionts decline and then disappear, but the ...chimneys can persist on the seabed as relicts. Suspension-feeding brisingid seastars colonize hydrothermally inactive (relict) chimneys on the East Pacific Rise (EPR), though their distribution relative to available hard substrata and proximity to hydrothermal activity is poorly documented. In this study, brisingid abundance on sulfide and basalt substrata was assessed along an ∼3,700 m ROV
Jason II
transect at the summit of Pito Seamount (SE Pacific; ∼2,275 m). Brisingids were non-randomly distributed, with highest densities (up to ∼300 m
–2
) on relict sulfides chimneys near active black smokers. Brisingids were relatively uncommon on basalt substrata, and absent on black smokers. We infer that both relict sulfide structures and proximity to black smokers play key roles in the maintenance of dense brisingid populations on Pito Seamount and in similar environments on the EPR. Our observations suggest that experimental introduction of “artificial” relict chimneys providing microtopographic relief could test whether such an approach might mitigate potential impacts of mineral extraction on populations of suspension-feeding invertebrates.
Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC ...risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10−10 and rs6687758, OR = 1.09, P = 2.27 × 10−9), 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10−8), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10−10 and rs7136702, OR = 1.06, P = 4.02 × 10−8) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10−10). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Repair of oxidative damage to DNA bases is essential to prevent mutations and cell death. Endonuclease III is the major DNA glycosylase activity in Escherichia coli that catalyzes the excision of ...pyrimidines damaged by ring opening or ring saturation, and it also possesses an associated lyase activity that incises the DNA backbone adjacent to apurinic/apyrimidinic sites. During analysis of the area adjacent to the human tuberous sclerosis gene (TSC2) in chromosome region 16p13.3, we identified a gene, OCTS3, that encodes a 1-kb transcript. Analysis of OCTS3 cDNA clones revealed an open reading frame encoding a predicted protein of 34.3 kDa that shares extensive sequence similarity with E. coli endonuclease III and a related enzyme from Schizosaccharomyces pombe, including a conserved active site region and an iron/sulfur domain. The product of the OCTS3 gene was therefore designated hNTH1 (human endonuclease III homolog 1). The hNTH1 protein was overexpressed in E. coli and purified to apparent homogeneity. The recombinant protein had spectral properties indicative of the presence of an iron/sulfur cluster, and exhibited DNA glycosylase activity on double-stranded polydeoxyribonucleotides containing urea and thymine glycol residues, as well as an apurinic/apyrimidinic lyase activity. Our data indicate that hNTH1 is a structural and functional homolog of E. coli endonuclease III, and that this class of enzymes, for repair of oxidatively damaged pyrimidines in DNA, is highly conserved in evolution from microorganisms to human cells.
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