EZH2 and BMI1 inversely correlate with prognosis and TP53 mutation in breast cancer

Introduction PolycombGroup (PcG) proteins maintain gene repression through histone modifications and have been implicated in stem cell regulation and cancer. EZH2 is part of Polycomb Repressive Complex 2 (PRC2) and trimethylates H3K27. This histone mark recruits the BMI1-containing PRC1 that silences the genes marked by PRC2. Based on their role in stem cells, EZH2 and BMI1 have been predicted to contribute to a poor outcome for cancer patients. Methods We have analysed the expression of EZH2 and BMI1 in a well-characterised dataset of 295 human breast cancer samples. Results Interestingly, although EZH2 overexpression correlates with a poor prognosis in breast cancer, BMI1 overexpression correlates with a good outcome. Although this may reflect transformation of different cell types, we also observed a functional difference. The PcG-target genes INK4A and ARF are not expressed in tumours with high BMI1, but they are expressed in tumours with EZH2 overexpression. ARF expression results in tumour protein P53 (TP53) activation, and we found a significantly higher proportion of TP53 mutations in tumours with high EZH2. This may explain why tumours with high EZH2 respond poorly to therapy, in contrast to tumours with high BMI1. Conclusions Overall, our data highlight that whereas EZH2 and BMI1 may function in a 'linear' pathway in normal development, their overexpression has different functional consequences for breast tumourigenesi

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Involvement in and Views on Social Responsibility of Gauteng Members of the South African Society of Physiotherapy: A Cross-sectional Survey

How do physiotherapists in Gauteng Province,who are members of the South African Society of Physiotherapy(SASP), view social responsibility?A cross-sectional survey was conducted after ethics approval.All 1 098 Gauteng members of the SASP were invited via a thirdpartye-mail to reach the a priori minimum sample size of 97. Theweb-based questionnaire was developed from literature, an earlierSASP survey and a position paper of the American Physical TherapyAssociation (APTA). Five experts validated the instrument.The Likert scale scores indicating agreement with indicatorsof social responsibility were totalled to form a composite socialresponsibility score. The chi-square test for independence was used to determine associations between the categorisedcomposite social responsibility score and categorical variables. Mean difference of continuous variables betweenthe categorised core for two groups were tested using the two-sample t-test. All variables with a P-value less than0.05 were included in the logistic regression analysis to investigate predictors of the necessity of social responsibility.The survey was completed by 163 participants. Of the sample, 96.9% viewed social responsibility as important.Subjects agreed most with “advocating for the health needs of society” (74,2%) and the least with “political activism”(6.1%). Compulsory community service positively influenced 74.6%.Most physiotherapists in the study viewed social responsibility as important and were involved in volunteering.There is scope to broaden the understanding among physiotherapists of what social responsibility entails

Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis

Cellular senescence has been theorized to oppose neoplastic transformation triggered by activation of oncogenic pathways in vitro, but the relevance of senescence in vivo has not been established. The PTEN and p53 tumour suppressors are among the most commonly inactivated or mutated genes in human cancer including prostate cancer. Although they are functionally distinct, reciprocal cooperation has been proposed, as PTEN is thought to regulate p53 stability, and p53 to enhance PTEN transcription. Here we show that conditional inactivation of Trp53 in the mouse prostate fails to produce a tumour phenotype, whereas complete Pten inactivation in the prostate triggers non-lethal invasive prostate cancer after long latency. Strikingly, combined inactivation of Pten and Trp53 elicits invasive prostate cancer as early as 2 weeks after puberty and is invariably lethal by 7 months of age. Importantly, acute Pten inactivation induces growth arrest through the p53-dependent cellular senescence pathway both in vitro and in vivo, which can be fully rescued by combined loss of Trp53. Furthermore, we detected evidence of cellular senescence in specimens from early-stage human prostate cancer. Our results demonstrate the relevance of cellular senescence in restricting tumorigenesis in vivo and support a model for cooperative tumour suppression in which p53 is an essential failsafe protein of Pten-deficient tumours

BRD7 is a candidate tumour suppressor gene required for p53 function

10.1038/ncb2038Nature Cell Biology124380-389NCBI

Deglacial Upwelling, Productivity and CO\u3csub\u3e2\u3c/sub\u3e Outgassing in the North Pacific Ocean

The interplay between ocean circulation and biological productivity affects atmospheric CO2 levels and marine oxygen concentrations. During the warming of the last deglaciation, the North Pacific experienced a peak in productivity and widespread hypoxia, with changes in circulation, iron supply and light limitation all proposed as potential drivers. Here we use the boron-isotope composition of planktic foraminifera from a sediment core in the western North Pacific to reconstruct pH and dissolved CO2 concentrations from 24,000 to 8,000 years ago. We find that the productivity peak during the Bølling–Allerød warm interval, 14,700 to 12,900 years ago, was associated with a decrease in near-surface pH and an increase in pCO2, and must therefore have been driven by increased supply of nutrient- and CO2-rich waters. In a climate model ensemble (PMIP3), the presence of large ice sheets over North America results in high rates of wind-driven upwelling within the subpolar North Pacific. We suggest that this process, combined with collapse of North Pacific Intermediate Water formation at the onset of the Bølling–Allerød, led to high rates of upwelling of water rich in nutrients and CO2, and supported the peak in productivity. The respiration of this organic matter, along with poor ventilation, probably caused the regional hypoxia. We suggest that CO2 outgassing from the North Pacific helped to maintain high atmospheric CO2 concentrations during the Bølling–Allerød and contributed to the deglacial CO2 rise