Stromal Genes Add Prognostic Information to Proliferation and Histoclinical Markers: A Basis for the Next Generation of Breast Cancer Gene Signatures

BACKGROUND: First-generation gene signatures that identify breast cancer patients at risk of recurrence are confined to estrogen-positive cases and are driven by genes involved in the cell cycle and proliferation. Previously we induced sets of stromal genes that are prognostic for both estrogen-positive and estrogen-negative samples. Creating risk-management tools that incorporate these stromal signatures, along with existing proliferation-based signatures and established clinicopathological measures such as lymph node status and tumor size, should better identify women at greatest risk for metastasis and death. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the strength and independence of the stromal and proliferation factors in estrogen-positive and estrogen-negative patients we constructed multivariate Cox proportional hazards models along with tree-based partitions of cancer cases for four breast cancer cohorts. Two sets of stromal genes, one consisting of DCN and FBLN1, and the other containing LAMA2, add substantial prognostic value to the proliferation signal and to clinical measures. For estrogen receptor-positive patients, the stromal-decorin set adds prognostic value independent of proliferation for three of the four datasets. For estrogen receptor-negative patients, the stromal-laminin set significantly adds prognostic value in two datasets, and marginally in a third. The stromal sets are most prognostic for the unselected population studies and may depend on the age distribution of the cohorts. CONCLUSION: The addition of stromal genes would measurably improve the performance of proliferation-based first-generation gene signatures, especially for older women. Incorporating indicators of the state of stromal cell types would mark a conceptual shift from epithelial-centric risk assessment to assessment based on the multiple cell types in the cancer-altered tissue

Modeling double strand break susceptibility to interrogate structural variation in cancer

Abstract Background Structural variants (SVs) are known to play important roles in a variety of cancers, but their origins and functional consequences are still poorly understood. Many SVs are thought to emerge from errors in the repair processes following DNA double strand breaks (DSBs). Results We used experimentally quantified DSB frequencies in cell lines with matched chromatin and sequence features to derive the first quantitative genome-wide models of DSB susceptibility. These models are accurate and provide novel insights into the mutational mechanisms generating DSBs. Models trained in one cell type can be successfully applied to others, but a substantial proportion of DSBs appear to reflect cell type-specific processes. Using model predictions as a proxy for susceptibility to DSBs in tumors, many SV-enriched regions appear to be poorly explained by selectively neutral mutational bias alone. A substantial number of these regions show unexpectedly high SV breakpoint frequencies given their predicted susceptibility to mutation and are therefore credible targets of positive selection in tumors. These putatively positively selected SV hotspots are enriched for genes previously shown to be oncogenic. In contrast, several hundred regions across the genome show unexpectedly low levels of SVs, given their relatively high susceptibility to mutation. These novel coldspot regions appear to be subject to purifying selection in tumors and are enriched for active promoters and enhancers. Conclusions We conclude that models of DSB susceptibility offer a rigorous approach to the inference of SVs putatively subject to selection in tumors

Do Two Machine-Learning Based Prognostic Signatures for Breast Cancer Capture the Same Biological Processes?

The fact that there is very little if any overlap between the genes of different prognostic signatures for early-discovery breast cancer is well documented. The reasons for this apparent discrepancy have been explained by the limits of simple machine-learning identification and ranking techniques, and the biological relevance and meaning of the prognostic gene lists was questioned. Subsequently, proponents of the prognostic gene lists claimed that different lists do capture similar underlying biological processes and pathways. The present study places under scrutiny the validity of this claim, for two important gene lists that are at the focus of current large-scale validation efforts. We performed careful enrichment analysis, controlling the effects of multiple testing in a manner which takes into account the nested dependent structure of gene ontologies. In contradiction to several previous publications, we find that the only biological process or pathway for which statistically significant concordance can be claimed is cell proliferation, a process whose relevance and prognostic value was well known long before gene expression profiling. We found that the claims reported by others, of wider concordance between the biological processes captured by the two prognostic signatures studied, were found either to be lacking statistical rigor or were in fact based on addressing some other question

Forming conjectures within a spreadsheet environment

This paper is concerned with the use of spreadsheets within mathematical investigational tasks. Considering the learning of both children and pre-service teaching students, it examines how mathematical phenomena can be seen as a function of the pedagogical media through which they are encountered. In particular, it shows how pedagogical apparatus influence patterns of social interaction, and how this interaction shapes the mathematical ideas that are engaged with. Notions of conjecture, along with the particular faculty of the spreadsheet setting, are considered with regard to the facilitation of mathematical thinking. Employing an interpretive perspective, a key focus is on how alternative pedagogical media and associated discursive networks influence the way that students form and test informal conjectures

Research on Teaching and Learning Probability

This book summarizes the vast amount of research related to teaching and learning probability that has been conducted for more than 50 years in a variety of disciplines. It begins with a synthesis of the most important probability interpretations throughout history: intuitive, classical, frequentist, subjective, logical propensity and axiomatic views. It discusses their possible applications, philosophical problems, as well as their potential and the level of interest they enjoy at different educational levels. Next, the book describes the main features of probabilistic thinking and reasoning, including the contrast to classical logic, probability language features, the role of intuitions, as well as paradoxes and the relevance of modeling. It presents an analysis of the differences between conditioning and causation, the variability expression in data as a sum of random and causal variations, as well as those of probabilistic versus statistical thinking. This is followed by an analysis of probability’s role and main presence in school curricula and an outline of the central expectations in recent curricular guidelines at the primary, secondary and high school level in several countries. This book classifies and discusses in detail the three different research periods on students’ and people’s intuitions and difficulties concerning probability: early research focused on cognitive development, a period of heuristics and biases programs, and the current period marked by a multitude of foci, approaches and theoretical frameworks

Manifestations neurologiques de la maladie de Behçet [Neurological manifestations of Behçet's disease]

National audienceNeurological manifestations of Behçet's disease (BD) occur in 5.3 to more than 50% of patients. They are divided into two major forms: "parenchymal" lesions, which include mainly meningoencephalitis as opposed to "extra-parenchymal" lesions (i.e. cerebral venous thrombosis and arterial aneurysms). Myelitis or peripheral neuropathy is exceptional. The neuro-Behçet syndrome (NBS) should be considered in the setting of neurological manifestations, particularly headache and pyramidal signs, in a young man diagnosed with BD. However, its recognition may be difficult when neurological manifestations are the presenting features of BD (one third of cases), and requires a thorough knowledge of clinical manifestations and morphological lesions. Thus, parenchymal NB lesions classically exhibit inflammatory characteristics on MRI and are located at the meso-diencephalic junction and in the brainstem, rarely with a supratentorial extension. Meningitis is not systematically associated, and may be absent in about 30% of cases. The pathogenesis of these lesions is incompletely understood, but inflammatory infiltrates include mainly neutrophils and activated T cells (mainly Th17). Differential diagnoses include infectious diseases (herpes, listeria, tuberculosis), and inflammatory diseases (i.e. multiple sclerosis and sarcoidosis). A prompt recognition of NBS should lead to initiate adequate therapies in order to limit the risk of sequelae, relapses or death.Les manifestations neurologiques de la maladie de Behçet (MB) sont retrouvées chez 5,3 à plus de 50 % des patients selon les séries. Elles sont séparées en deux grands types d'atteintes : les formes " parenchymateuses ", regroupant les atteintes intracérébrales (méningo-encéphalites), par opposition aux formes " extra-parenchymateuses ", incluant les thromboses veineuses cérébrales et les anévrismes artériels. Les atteintes médullaires et les atteintes périphériques sont exceptionnelles. Un syndrome de neuro-Behçet (NB) doit être évoqué devant la survenue de troubles neurologiques, en particulier des céphalées et une atteinte pyramidale, chez un homme jeune suivi pour une MB. Néanmoins, sa reconnaissance est difficile lors des formes inaugurales (un tiers des cas), et nécessite une connaissance des lésions morphologiques. Ainsi, les lésions de NB parenchymateux sont classiquement inflammatoires en IRM et situées à la jonction méso-diencéphalique, ainsi que dans le tronc cérébral, avec rarement une extension sus-tentorielle. Une méningite associée n'est pas systématique, absente dans environ 30 % des cas. La physiopathologie de ces lésions est imparfaitement connue, mais l'infiltrat inflammatoire est majoritairement constitué de polynucléaires neutrophiles et de lymphocytes T activés (notamment de type Th17). Les principaux diagnostics différentiels concernent les pathologies infectieuses (herpès, listériose, tuberculose), et inflammatoires (sclérose en plaques, sarcoïdose) qui doivent être systématiquement évoquées. Le traitement du NB doit être initié dès son diagnostic afin d'en limiter le risque de séquelles, de rechute ou de décès