Altered Form Research Articles

PRÍONS E DOENÇAS PRIÔNICAS: UMA REVISÃO

The name príon is given to an altered form of a protein present at the surface of neurons. Prions are remarkable for been able to induct their normal counterpart to assume the pathological configuration on a kind of chain reaction, with the possibility of trasmission between subjects and even through different species. Prions can cause a series of neurodegenerative disorders affecting humans (Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, kuru), and animals such cattle (bovine spongiform encephalopathy or “mad cow disease”), deer (chronic wasting disease) and sheep (scrapie). This article is a non-systematic review, obtained on PubMed, SciELO and Google Scholar databases, with the aim to give a general view about the nature of prions, followed by a brief discussion of the human diseases caused by prions.

Canadian Literature and the Temporality of Dying Colonialism

This article historicizes cultural appropriation in Canadian literature today by examining key texts from the critiques of cultural appropriation in Canadian culture in the 1990s. Appropriation is contextualized in relation to a modernist temporality that constructs an Other outside of modernity and to the temporality in Frantz Fanon’s A Dying Colonialism, a temporality in which the colonized is liberated but the colonizer is still “choked” and not yet rehabilitated. Reading appropriation through its cultural historical context in relation to modernist art and conceptual art, the practice of appropriation emerges as an extension of colonial practices and as an extractivist economy. Countering this, I point to the Indigenous concept of “cultural belongings” as a form of critique and alterity that counters the logic of cultural appropriation.

Innovative screening test for the early detection of sickle cell anemia

In this study, the capability of thermogravimetry in conjuction with a multivariate statistical analysis, was investigated for the screening of Sickle Cell Anemia (SCA), a hereditary disorder of hemoglobin characterized by severe hemolytic anemia with different severe clinical manifestations.SCA results from a mutation in the sixth codon of the beta globin gene, which results in the substitution of glutamic acid for valine and leads to the production of an altered form of hemoglobin, hemoglobin S (HbS). People with this disorder have atypical hemoglobin molecules which tend to aggregate together and form filaments inside the red blood cells. These deformed red blood cells called half-moon or sickle, are rigid and unable to flow inside the small vessels, creating occlusions of the small circulation. Systematic screening for SCA is not a common practice, and diagnosis is usually made when a severe complication occurs. An early and rapid diagnosis is important for patients in order to prevent and treat the painful episodes that can occur when sickled red blood cells, which are stiff and inflexible, get stuck in small blood vessels.A novel test was developed using whole blood samples from patients with congenital defects and analyzed by the TG7 thermobalance (PerkinElmer) without any pretreatment. The resulting TG and DTG curves of blood samples were compared to those typical of healthy individuals and results demonstrated a different thermal behaviour of the anemic patients with respect to healthy individuals as result of the different amounts of water content and corpuscular fraction. The multivariate statistical analysis performed by chemometrics allowed a quick identification of differences between the two population and provided a model of prediction in patients with heterogeneous congenital hematological disorders. The predictive ability of the model was tested by processing patient affected by SCA and with a confirmed diagnosis obtained by the molecular analysis. The model provided for a sensitivity and an accuracy of a 100% and an error of prediction of about 0.1%.

When the Window Cracks: Transparency and the Fractured Self in Depersonalisation

There has recently been a resurgence of philosophical and scientific interest in the foundations of self-consciousness, with particular focus on its altered, anomalous forms. This paper looks at the altered forms of self-awareness in Depersonalization Disorder (DPD), a condition in which people feel detached from their self, their body and the world (Derealisation). Building upon the phenomenological distinction between reflective and pre-reflective self-consciousness, we argue that DPD may alter the transparency of basic embodied forms of pre-reflective self-consciousness, as well as the capacity to flexibly modulate and switch between the reflective and pre-reflective facets of self-awareness. Empirical evidence will be invoked in support of the idea that impaired processing of bodily signals is characteristic of the condition. We provide first-hand subjective reports describing the experience of self-detachment or fracture between an observing and an observed self. This split is compared with similar self-detachment phenomena reported in certain Buddhist-derived meditative practices. We suggest that these alterations and changes may reveal the underlying and tacit transparency that characterises the embodied and basic pre-reflective forms of self-consciousness, in the same way that a crack in a transparent glass may indicate the presence of an unnoticed window.

Housing Tenure Outcomes of Children and Owner Occupants: A Literature Review

This paper reviews relevant literature pertaining to three key themes that have emerged in the housing tenure debates, specifically renting versus buying. These three themes have been identified as the educational outcomes of children, well-being outcomes and wealth outcomes. These themes while important to the consumer, have far reaching implications in policy and social services, dictating a significant portion of a person’s quality of life. Through this literature review I take a thematic approach to examine the identified themes in detail, to understand their shortcomings, outcomes and come to a conclusion on the most beneficial form of housing tenure and recommendations for future research. While it was found in almost every examined case that home ownership is generally the best form of housing tenure when it comes to positive outcomes of the aforementioned themes. It was further concluded that these outcomes may be a mere correlation of examined variables and not an intrinsic cause of the beneficial outcomes. These findings support the need for future research into the causation of degrees of benefit from different forms of housing tenure and subsequent alteration to policy to reflect the trajectory toward the best outcomes of occupiers.

Abstract A17: Pan-solid tumor comparison of variant detection in paired liquid and tissue biopsies

Abstract Comprehensive genomic profiling (CGP) of circulating tumor DNA (ctDNA) provides an opportunity to noninvasively monitor a patient’s tumor burden via liquid biopsy. Liquid biopsies can assess a patient’s mutational landscape through time and provide information on treatment response and relapse. It has become increasingly common to have paired genomic data analysis between liquid and tissue biopsies from the same patient. However, the impact of clinical, temporal, and biologic factors on percentage of positive agreement (PPA) of variant detection between these biopsies is unclear. For our study, we leveraged two databases containing CGP data from paired liquid and tissue biopsy specimens tested by Foundation Medicine (FMI): the FMI database (>1700 paired samples) and the Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB). The CGDB is a subset of the FMI database linked with the Flatiron Health nationwide de-identified EHR-derived database, which includes demographic, treatment, and clinical outcomes information (>500 paired samples). We report pan-solid tumor and per-indication prevalence and PPA for variants commonly assayed in both liquid and tissue tests. We found that PPA depended on the tumor DNA concentration in plasma and tissue biopsies, as well as the amount of time between tests. We also investigated the effect of treatments administered in the time between liquid and tissue tests on the detected variants and observed some well-described resistance alterations at a higher frequency in liquid samples, including a higher prevalence of ESR1 point mutations in breast cancer, more EGFR T790M alterations in lung cancer, and frequent KRAS Q61H alterations in colorectal cancer. Liquid biopsies can also contain DNA shed from multiple metastatic sites. We observed evidence of this in the form of polyclonal resistance alterations, which may also account for differences in PPA over time. Our findings indicate that while PPA is generally high between samples, it may be influenced by factors such as intervening therapies, resistance, therapy efficacy, and polyclonality of liquid samples. Citation Format: Zoe June F. Assaf, Smruthy Sivakumar, Dexter X. Jin, Sophia L. Maund, Svetlana Lyalina, Guneet Walia, Ethan S. Sokol, Sally E. Trabucco. Pan-solid tumor comparison of variant detection in paired liquid and tissue biopsies [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A17.

Self-Stigma Toward Nonsuicidal Self-Injury: An Examination of Implicit and Explicit Attitudes.

Evidence suggests that individuals without a history of nonsuicidal self-injury (NSSI) are likely to view NSSI as a stigmatized behavior. However, there is limited evidence evaluating the presence of self-stigma among individuals who have engaged in NSSI. We recruited a university sample (n=351) and employed implicit and explicit measures to examine the degree of stigmatization toward those with NSSI scarring, as compared to nonintentional disfigurement (i.e., accidental scarring) and to tattoos (i.e., a culturally sanctioned form of intentional tissue alteration). We examined the extent to which bias is related to indicators of NSSI severity among those with a history of NSSI. We provide evidence that negative biases toward NSSI may represent the effects of self-stigma. However, findings suggest that biases were generally attenuated among participants with a history of NSSI as compared to those without. Participants who had lower levels of NSSI explicit bias were more likely to have a history of more severe engagement in NSSI; however, no significant relationships were found between implicit bias and NSSI severity indicators. We present a theoretical rationale for attenuated biases among individuals with a history of NSSI and discuss implications of this research for NSSI recovery.

Roentgenographic analysis of lumbar lordotic dimensions among indigenes of Delta State

The spinal column of humans possesses strategically placed concave and convex curves which work in harmony to give an upright posture. The inwardly concave curvature in the lumbar region of the spine is known as the lordosis and it plays a very important role in the formation of the posture of humans. Analysis of the human lordosis is of great importance as it has been shown to be a major factor in the onset of low back pain, and is of great importance in spinal reconstructive surgery, through which some form of repair can be done to the spinal column that has undergone some form of alteration. The present study was carried out to analyse the lumbar lordotic dimensions among indigenes of Delta State. The aim of the study was to find out the average lordotic angle, vertebral body height and intervertebral disc height for the male and female population. The study was also aimed at finding the range for the normal lordotic angles as well as the correlations between these dimensions and the age of an individual. A regression equation was also formulated with which the lordotic angle of an individual can be estimated given the age of that individual. The sample size was 384 individuals (204 males and 180 females) with an age range of 20-60 years. The male population had a mean angle of 59.33±2.45° and the females had a lower mean value of 53.33±2.61°. The study showed males had higher mean values for lumbar vertebra height and intervertebral disc height. A steady increase in the height of the lumbar vertebra and intervertebral disc from the first to the last was observed in this study. This study also showed that a weak negative correlation existed between the age of an individual and the lordotic angle and the vertebral height. Correlations between the age and intervertebral disc height showed a weak positive correlation. A regression formula was derived for estimating the lordotic angle of an individual given the age. This study will be of great importance to medical practitioners and forensic anthropologists in spinal reconstructive surgery and forensic human identification by gender and age.
 Keywords: Lumbar Spine. Lordosis, Lordotic Angle, Correlation, Regression.

Effect of a SO2 Rich Atmosphere on Tempera Paint Mock-Ups. Part 2: Accelerated Aging of Azurite- and Malachite-Based Paints

In order to improve our knowledge of the weathering response of tempera paints exposed to an industrial atmosphere, azurite- and malachite-based paint mock-ups prepared with either rabbit glue or egg yolk binders were artificially aged in an SO2 rich atmosphere. The aim was to identify the different alteration mechanisms and forms of degradation in the paints by observing their physical (color, gloss, reflectance, and roughness), mineralogical, chemical, and micro-textural characteristics. Superficial physical changes were evaluated by stereomicroscopy, spectrophotometry, gloss measurement, hyperspectral imaging, and roughness measurements. Chemical and mineralogical changes were evaluated by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy with microanalysis (SEM-EDS), which was also used to evaluate the micro-texture of the paints. The differences between the fresh temperas were due mainly to the binder (egg yolk or rabbit glue) used in the paint mixture, which also played a crucial role in the different deterioration patterns in the artificially aged paint mock-ups. Thus, the egg yolk-based paints remained physically quite intact after SO2 exposure, although they suffered more significant chemical degradation, above all in the form of copious precipitation of Cu and Ca-rich sulfate salts and the subsequent yellowing of the egg yolk binder. The SO2 aged rabbit glue-based mock-ups showed microscopically important crack formation and binder loss and fewer sulfated salts precipitated on the surface of the paints.

Carbon black-benzo(a)pyrene complex-induced apoptosis and autophagy blockage in rat alveolar macrophages

Cooking of foods and the burning of biomass and fossil fuels in stoves are the main sources of cooking fumes, with carbon black and polycyclic aromatic hydrocarbons as main components. The toxicity of carbon black and polycyclic aromatic hydrocarbons has been well studied individually, but the combined toxicity is much less understood. Carbon black can adsorb benzo(a)pyrene to form a complex which displays an altered physical form which in this study has been constructed to simulate particles in the cooking fumes and explore the combined toxic effect on rat alveolar macrophages. The complex-induced cell apoptosis and blocked cell autophagy flux compared with both individually. The mechanism of toxicity may be by intracellular reactive oxygen species generation, impairing the mitochondrial membrane potential and activating apoptosis signaling pathways.

Chromatin and Cytoskeletal Tethering Determine Nuclear Morphology in Progerin-Expressing Cells

The nuclear morphology of eukaryotic cells is determined by the interplay between the lamina forming the nuclear skeleton, the chromatin inside the nucleus, and the coupling with the cytoskeleton. Nuclear alterations are often associated with pathological conditions as in Hutchinson-Gilford progeria syndrome, in which a mutation in the lamin A gene yields an altered form of the protein, named progerin, and an aberrant nuclear shape. Here, we introduce an inducible cellular model of Hutchinson-Gilford progeria syndrome in HeLa cells in which increased progerin expression leads to alterations in the coupling of the lamin shell with cytoskeletal or chromatin tethers as well as with polycomb group proteins. Furthermore, our experiments show that progerin expression leads to enhanced nuclear shape fluctuations in response to cytoskeletal activity. To interpret the experimental results, we introduce a computational model of the cell nucleus that explicitly includes chromatin fibers, the nuclear shell, and coupling with the cytoskeleton. The model allows us to investigate how the geometrical organization of the chromatin-lamin tether affects nuclear morphology and shape fluctuations. In sum, our findings highlight the crucial role played by lamin-chromatin and lamin-cytoskeletal alterations in determining nuclear shape morphology and in affecting cellular functions and gene regulation.

Congenital diabetes mellitus.

Congenital diabetes mellitus is a rare disorder characterized by hyperglycemia that occurs shortly after birth. We define "Diabetes of Infancy" if hyperglycemia onset before 6 months of life. From the clinical point of view, we distinguish two main types of diabetes of infancy: transient (TNDM), which remits spontaneously, and permanent (PNDM), which requires lifelong treatment. TNDM may relapse later in life. About 50% of cases are transient (TNDM) and 50% permanent. Clinical manifestations include severe intrauterine growth retardation, hyperglycemia and dehydration. A wide range of different associated clinical signs including facial dysmorphism, deafness and neurological, cardiac, kidney or urinary tract anomalies are reported. Developmental delay and learning difficulties may also be observed. In this paper we review all the causes of congenital diabetes and all genes and syndromes involved in this pathology. The discovery of the pathogenesis of most forms of congenital diabetes has made it possible to adapt the therapy to the diagnosis and in the forms of alteration of the potassium channels of the pancreatic Beta cells the switch from insulin to glibenclamide per os has greatly improved the quality of life. Congenital diabetes, although it is a very rare form, has been at the must of research in recent years especially for pathogenesis and pharmacogenetics. The most striking difference compared to the more frequent autoimmune diabetes in children (type 1 diabetes) is the possibility of treatment with hypoglycemic agents and the apparent lower frequency of chronic complications.

Variants in the Hippo Signaling Pathway are Associated with Craniofacial Skeletal Form and BMI

Childhood obesity rates in the United States have demonstrated a marked increase since the late 20th century. Current research has suggested that obesity can cause increases in bone density and an acceleration of skeletal growth. While studies have shown that obesity may be associated with altered craniofacial form, the mechanism and associated factors through which this interaction operates remains poorly understood. This study explores a potential link between obesity and craniofacial skeletal form as a function of the Hippo signaling pathway, an important regulator of organ size, tissue development, and craniofacial development.Lateral cephalograms from a sample of n=64 patients between the ages 7 to 17 were obtained from the Midwestern University Multispecialty Clinic. BMI percentile was computed for all children in the study following CDC guidelines (normal weight n=37, overweight n=9, obese n=18). 45 2D landmarks were registered via Generalized Procrustes Analysis (GPA) in order to facilitate a geometric morphometric (GM) analysis. Healthy Eating Index (HEI) scores obtained from Block Food Frequency Questionnaire (FFQ) surveys were used to control for the effects of diet in all subsequent analyses. Shape residuals were submitted to Principal Components Analysis (PCA) and Canonical Variate Analysis (CVA) to identify which aspects of skeletal form differentiate individual phenotypes based on BMI. Finally, associations between these phenotypes and 23 single nucleotide polymorphisms (SNPs) in seven genes within the Hippo signaling pathway were explored.Principal Components (PCs) accounting for at least 1% of facial shape variation were examined in order to determine components that differentiate between normal and obese groups. Based on this, suggestive/significant differences were found in PC 8 (p=0.056) and PC12 (p=0.012) based on BMI category. PC 8 (accounting for 3.6% of the total shape variation) indicates that chin projection, nose length, and mandibular morphology differentiate between normal and obese children. SNPs in TEAD3 (p=0.04) and FAT4 (p = 0.02) were significantly associated with shape variation along PC8. PC 12 (2.6% of the total shape variation) showed significant variation in chin projection and decreased incisor size in the obese group relative to the normal weight group. Additionally, a SNP within LATS2 (p = 0.04) was significantly correlated with shape variation along PC12. Finally, results from the CVA identified two components with CV2 indicating a significant relationship with LEF1 (p= 0.02). CV2 demonstrates increased facial projection in individuals with obesity.Across all analyses, we found a consistent pattern in mandibular length, facial projection, and incisor size that differentiated between normal and obese individuals. SNPs within key genes in the Hippo signaling pathway were associated with these phenotypes, indicating a potential causative relationship. Future studies will explore this relationship further.

After council communism: the post-war rediscovery of the council tradition

ABSTRACT This article traces a discontinuous tradition of council thought from the Dutch and German council communist tendencies of the 1920s to its re-emergence in the writings of three important mid-twentieth-century political theorists: Cornelius Castoriadis, Claude Lefort, and Hannah Arendt. It connects an intellectual history of the council concept in post-war Europe with a political history of the small revolutionary groups that fostered council-related political activity during this era. It claims that, as the experience of the European council movements began to be interpreted within a new political context, this gave rise to several radically altered forms of council thought. In this more subjectivist and praxis-oriented tradition, the councils became a utopian placeholder for theorists to explore their particular interests in human creativity (Castoriadis), self-limiting power (Lefort), and political freedom (Arendt). This analysis develops our understanding of the continuities and ruptures of the council tradition within political thought.

DNMT1 promotes cell proliferation via methylating hMLH1 and hMSH2 promoters in EGFR-mutated non-small cell lung cancer.

Aberrant DNA methylation is a common form of epigenetic alterations and it has been proved to be closely related to many cancers, while its role in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is not clear. This study focuses on the role of DNA methyltransferase 1 (DNMT1) in EGFR-mutated NSCLC pathogenesis. First, the expression of DNMT1 was up-regulated, while the expressions of human mutL homolog 1(hMLH1) and human mutS homolog 2 (hMSH2) were down-regulated in EGFR-mutated NSCLC patients and cell line HCC827. The results of the correlation analysis showed that DNMT1 expression was inversely correlated with the expressions of hMLH1 and hMSH2. Then, we found that DNMT1 enhanced the promoter methylation levels of hMLH1 and hMSH2, thus suppressing their expressions. DNMT1 knockdown inhibited the proliferation of HCC827 cells, while both hMLH1 knockdown and hMSH2 knockdown could eliminate its inhibitory effect on cell proliferation. In xenograft mouse models, lentiviral vector-sh-DNMT1 could significantly reduce tumor volumes, confirmed that DNMT1 inhibited tumor cell proliferation in vivo. In conclusion, DNMT1 suppressed the expressions of hMLH1 and hMSH2 via elevating their promoter methylation, thus promoting cell proliferation in EGFR-mutated NSCLC.

Function and Features of the Modification Permit in Turkish Zoning and Building Law

Construction of buildings, which has a special place in social life, and the changes made to them in the form of repair, alteration and addition are not only subjects of engineering, but also subjects of legal regulations. There may be modification requirements such as repairs, alterations or additions for various reasons in the buildings whose construction process is ongoing or for which the use permit has been obtained after the construction process has been completed. Building modifications are generally subject to a modification permit. Modification permits have an extremely important function in Turkish zoning and building law in terms of their relationship with the main building permit. Some modifications are not subject to a permit. A functional criterion is needed to distinguish between modifications that are subject to a permit and those that are not. For example, in buildings with permits (especially for pergolas and porches) there have been disputes about whether additions or the closing of balconies should be subject to a permit. A criterion can be drawn from the general philosophy of the Zoning and Building Act. This criterion can be defined as: among the repairs, changes, and additions to buildings with a permit, those in accordance with the building permit and its annexes will not require a modification permit; whereas those contrary to the building permit and its annexes will.

DEVELOPMENT OF UNIVERSITY LIBRARIES IN DIGITAL GLOBALIZATION

The article is devoted to automated information and library services in the libraries of higher educational institutions of the Republic of Kazakhstan and the capabilities of libraries included in the Republican Interuniversity Electronic Library System and highlights the ways of introducing information technologies into the work of libraries of higher educational institutions, replenishing electronic resources, entering domestic, world information resources. The main goal of the libraries of the republic is to increase information literacy, harmonious integration in the digital environment. Implementation of automated work in the library process, the implementation of library information programs. Modern libraries are looking for ways to rationally combine new technologies with altered forms of life and pave the way for the right solution and embracing global problems. Combining national information, the library plays the role of a major ideological institute, exploring and disseminating, and providing services to consumers in accordance with modern requirements.

Altered visual character and object recognition in Japanese-speaking adolescents with developmental dyslexia

Many studies have confirmed a brain dysfunction in people with developmental dyslexia (DD) in certain brain regions, including the left superior temporal gyrus and the left fusiform gyrus. However, the neurobiological substrates in Japanese-speaking people with dyslexia are not fully understood, mostly due to the uniqueness of the orthographic systems. Since a substantial part of the written Japanese includes the logographic Kanji as well as the phonographic Kana systems, the reading disability might be caused not only by a dysfunction in the phonological system, but also by a dysfunction in the visual recognition system. Previous studies reported altered hierarchical visual word form processing in the left occipitotemporal cortex; however, it remains unclear whether the altered hierarchical visual processing is language stimuli-specific. Therefore, we aimed to investigate whether (a) Japanese-speaking individuals with DD exhibit atypical hierarchical visual processing, and if so, (b) whether the altered hierarchical visual processing is language stimuli-specific or not. The present study investigated the brain activation pattern for the hierarchical component of the Kanji characters and object stimuli in typically developing (TD) adolescents and adolescents with DD using functional magnetic resonance imaging. For the Kanji characters, adolescents with DD showed a greater activation in the left occipital gyrus and right occipital fusiform gyrus, and this hyperactivity was also found for pseudo and artificial Kanji characters. These results imply reliance on an early visual system in Kanji reading in Japanese-speaking adolescents with DD. Additionally, we also investigated the brain activity for object stimuli, and adolescents with DD showed a greater activation in the bilateral occipital gyri compared with the TD adolescents. These results imply an altered hierarchical visual processing characterized by overactivation in the early visual areas, which is a not restricted to language stimulus only.

The clinicomolecular landscape of de novo versus relapsed stage IV metastatic breast cancer

Backgroundde novo metastatic breast cancer (dnMBC) is responsible for 6–10% of breast cancer presentations with increasing incidence and has remained resistant to detection by mammography screening. Recent publications hypothesized that in addition to poor screening uptake, the presentation of dnMBC may be due to its unfavourable biology which remains unknown at the molecular level. Here we investigated the tumour biology of dnMBC in the form of clinicopathology, genomic alterations and differential gene expression to create a comparative landscape of de novo versus relapsed metastatic breast cancer (rMBC). Additionally, to address the current screening limitations, we conducted a preliminary biomarker investigation for early dnMBC detection. MethodsIn this retrospective case-control study, gene expression and clinical data were accessed from the Cancer Genome Atlas (TCGA) for primary tumours of treatment-naïve patients with dnMBC (n = 17), rMBC (n = 49), and normal tissue (n = 113). The clinical and histological data were assessed categorically using Fisher's Exact-Test for significance (p < .05), or continuously using the Mann-Whitney Test (p < .05) where appropriate. The differential gene expression analysis was performed using EdgeR's negative binomial distribution model with a false discovery rate (FDR) <0.05. The resulting gene list was analysed manually for roles in metastasis as well as ontologically using STRING-DB with FDR <0.05. ResultsdnMBCs showed improved median survival vs rMBC (36 vs. 12 months). dnMBCs were more likely to be hormone receptor positive, less likely to be triple negative with lower histological lymphocytic infiltrate. In terms of genome alterations, dnMBCs had 4-fold increased PTEN mutations and poor survival with ABL2 and GATA3 alterations. Expression-wise, dnMBCs down-regulated TNFa, IL-17 signalling, and chemotaxis, while up-regulating steroid biosynthesis, cell migration, and cell adhesion. Biomarker analysis detected pre-existing and novel breast cancer biomarkers. ConclusionThe comparative tumour landscape revealed significant clinical, pathological and molecular differences between dnMBC and rMBC, indicating that dnMBC may be a separate biological entity to rMBC at the primary level with differing paths to metastasis. Additionally, we provided a list of potential serum biomarkers that may be useful in detecting dnMBC in its pre-metastatic window if such a window exists.

Genomic basis for RNA alterations in cancer

Transcript alterations often result from somatic changes in cancer genomes1. Various forms of RNA alterations have been described in cancer, including overexpression2, altered splicing3 and gene fusions4; however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relatively small cohorts of patients for whom samples have been analysed by both transcriptome and whole-genome sequencing. Here we present, to our knowledge, the most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)5. Using matched whole-genome sequencing data, we associated several categories of RNA alterations with germline and somatic DNA alterations, and identified probable genetic mechanisms. Somatic copy-number alterations were the major drivers of variations in total gene and allele-specific expression. We identified 649 associations of somatic single-nucleotide variants with gene expression in cis, of which 68.4% involved associations with flanking non-coding regions of the gene. We found 1,900 splicing alterations associated with somatic mutations, including the formation of exons within introns in proximity to Alu elements. In addition, 82% of gene fusions were associated with structural variants, including 75 of a new class, termed ‘bridged’ fusions, in which a third genomic location bridges two genes. We observed transcriptomic alteration signatures that differ between cancer types and have associations with variations in DNA mutational signatures. This compendium of RNA alterations in the genomic context provides a rich resource for identifying genes and mechanisms that are functionally implicated in cancer.