The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer

We have identified a human homolog of the bacterial MutS and S. cerevisiae MSH proteins, called hMSH2. Expression of hMSH2 in E. coli causes a dominant mutator phenotype, suggesting that hMSH2, like other divergent MutS homologs, interferes with the normal bacterial mismatch repair pathway. hMSH2 maps to human chromosome 2p22-21 near a locus implicated in hereditary nonpolyposis colon cancer (HNPCC). A T to C transition mutation has been detected in the -6 position of a splice acceptor site in sporadic colon tumors and in affected individuals of two small HNPCC kindreds. These data and reports indicating that S. cerevisiae msh2 mutations cause an instability of dinucleotide repeats like those associated with HNPCC suggest that hMSH2 is the HNPCC gene

Epigenetic and oncogenic regulation of SLC16A7 (MCT2) results in protein over-expression, impacting on signalling and cellular phenotypes in prostate cancer

Felisbino S. received a fellowship from the Sao Paulo Research Foundation (FAPESP) ref. 2013/08830-2 and 2013/06802-1. Anne Y Warren research time funded by: Cambridge Biomedical Research Centre.Monocarboxylate Transporter 2 (MCT2) is a major pyruvate transporter encoded by the SLC16A7 gene. Recent studies pointed to a consistent overexpression of MCT2 in prostate cancer (PCa) suggesting MCT2 as a putative biomarker and molecular target. Despite the importance of this observation the mechanisms involved in MCT2 regulation are unknown. Through an integrative analysis we have discovered that selective demethylation of an internal SLC16A7/MCT2 promoter is a recurrent event in independent PCa cohorts. This demethylation is associated with expression of isoforms differing only in 5'-UTR translational control motifs, providing one contributing mechanism for MCT2 protein overexpression in PCa. Genes co-expressed with SLC16A7/MCT2 also clustered in oncogenic-related pathways and effectors of these signalling pathways were found to bind at the SLC16A7/MCT2 gene locus. Finally, MCT2 knock-down attenuated the growth of PCa cells. The present study unveils an unexpected epigenetic regulation of SLC16A7/MCT2 isoforms and identifies a link between SLC16A7/MCT2, Androgen Receptor (AR), ETS-related gene (ERG) and other oncogenic pathways in PCa. These results underscore the importance of combining data from epigenetic, transcriptomic and protein level changes to allow more comprehensive insights into the mechanisms underlying protein expression, that in our case provide additional weight to MCT2 as a candidate biomarker and molecular target in PCa.Publisher PDFPeer reviewe

HES5 silencing is an early and recurrent change in prostate tumourigenesis.

Prostate cancer is the most common cancer in men, resulting in over 10 000 deaths/year in the UK. Sequencing and copy number analysis of primary tumours has revealed heterogeneity within tumours and an absence of recurrent founder mutations, consistent with non-genetic disease initiating events. Using methylation profiling in a series of multi-focal prostate tumours, we identify promoter methylation of the transcription factor HES5 as an early event in prostate tumourigenesis. We confirm that this epigenetic alteration occurs in 86-97% of cases in two independent prostate cancer cohorts (n=49 and n=39 tumour-normal pairs). Treatment of prostate cancer cells with the demethylating agent 5-aza-2'-deoxycytidine increased HES5 expression and downregulated its transcriptional target HES6, consistent with functional silencing of the HES5 gene in prostate cancer. Finally, we identify and test a transcriptional module involving the AR, ERG, HES1 and HES6 and propose a model for the impact of HES5 silencing on tumourigenesis as a starting point for future functional studies.The authors are grateful to study volunteers for their participation and staff at the Welcome Trust Clinical Research Facility, Addenbrooke’s Clinical Research Centre, Cambridge. They also thank the NIHR Cambridge Biomedical Research Centre, the DOH HTA (ProtecT grant), and the NCRI/MRC (ProMPT grant) for help with the bio-repository, The University of Cambridge, Hutchison Whampoa Limited and Cancer Research UK for funding. They are grateful to the CRUK Cambridge Institute Genomics and Bioinformatics Core Facilities. Cross-validation of HES5 methylation includes the use of data generated by the TCGA Research Network.This is the final version of the article. It was originally published in the Endocrine-Related Cancer, April 1, 2015 22 131-144 doi: 10.1530/ERC-14-0454

The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer.

The androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa). Therefore, understanding how ARs regulate the human transcriptome is of paramount importance. The early effects of castration on human PCa have not previously been studied 27 patients medically castrated with degarelix 7 d before radical prostatectomy. We used mass spectrometry, immunohistochemistry, and gene expression array (validated by reverse transcription-polymerase chain reaction) to compare resected tumour with matched, controlled, untreated PCa tissue. All patients had levels of serum androgen, with reduced levels of intraprostatic androgen at prostatectomy. We observed differential expression of known androgen-regulated genes (TMPRSS2, KLK3, CAMKK2, FKBP5). We identified 749 genes downregulated and 908 genes upregulated following castration. AR regulation of α-methylacyl-CoA racemase expression and three other genes (FAM129A, RAB27A, and KIAA0101) was confirmed. Upregulation of oestrogen receptor 1 (ESR1) expression was observed in malignant epithelia and was associated with differential expression of ESR1-regulated genes and correlated with proliferation (Ki-67 expression).We thank CRUK, The NIHR, The Academy of Medical Sciences(RG:63397) and the National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (ProMPT) collaborative (G0500966/75466), Hutchison Whampoa Limited, the Human Research Tissue Bank (Addenbrooke’s Hospital, supported by the NIHR Cambridge BRC), and Cancer Research UK

nIFTy galaxy cluster simulations – II. Radiative models

We have simulated the formation of a massive galaxy cluster (M$_{200}^{\rm crit}$ = 1.1$\times$10$^{15}h^{-1}M_{\odot}$) in a $\Lambda$CDM universe using 10 different codes (RAMSES, 2 incarnations of AREPO and 7 of GADGET), modeling hydrodynamics with full radiative subgrid physics. These codes include Smoothed-Particle Hydrodynamics (SPH), spanning traditional and advanced SPH schemes, adaptive mesh and moving mesh codes. Our goal is to study the consistency between simulated clusters modeled with different radiative physical implementations - such as cooling, star formation and AGN feedback. We compare images of the cluster at $z=0$, global properties such as mass, and radial profiles of various dynamical and thermodynamical quantities. We find that, with respect to non-radiative simulations, dark matter is more centrally concentrated, the extent not simply depending on the presence/absence of AGN feedback. The scatter in global quantities is substantially higher than for non-radiative runs. Intriguingly, adding radiative physics seems to have washed away the marked code-based differences present in the entropy profile seen for non-radiative simulations in Sembolini et al. (2015): radiative physics + classic SPH can produce entropy cores. Furthermore, the inclusion/absence of AGN feedback is not the dividing line -as in the case of describing the stellar content- for whether a code produces an unrealistic temperature inversion and a falling central entropy profile. However, AGN feedback does strongly affect the overall stellar distribution, limiting the effect of overcooling and reducing sensibly the stellar fraction.Comment: 20 pages, 13 figures, submitted to MNRA

nIFTy galaxy cluster simulations - IV. Quantifying the influence of baryons on halo properties

Building on the initial results of the nIFTy simulated galaxy cluster comparison, we compare and contrast the impact of baryonic physics with a single massive galaxy cluster, run with 11 state-of-the-art codes, spanning adaptive mesh, moving mesh, classic and modern smoothed particle hydrodynamics (SPH) approaches. For each code represented we have a dark-matteronly (DM) and non-radiative (NR) version of the cluster, as well as a full physics (FP) version for a subset of the codes. We compare both radial mass and kinematic profiles, as well as global measures of the cluster (e.g. concentration, spin, shape), in the NR and FP runs with that in the DM runs. Our analysis reveals good consistency (<≈ 20 per cent) between global properties of the cluster predicted by different codes when integrated quantities are measured within the virial radius R200. However, we see larger differences for quantities within R2500, especially in the FP runs. The radial profiles reveal a diversity, especially in the cluster centre, between the NR runs, which can be understood straightforwardly from the division of codes into classic SPH and non-classic SPH (including the modern SPH, adaptive and moving mesh codes); and between the FP runs, which can also be understood broadly from the division of codes into those that include active galactic nucleus feedback and those that do not. The variation with respect to the median is much larger in the FP runs with different baryonic physics prescriptions than in the NR runs with different hydrodynamics solvers

Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression

Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease