Mammographic Breast Density and Common Genetic Variants in Breast Cancer Risk Prediction

Introduction

Known prediction models for breast cancer can potentially by improved by the addition of mammographic density and common genetic variants identified in genome-wide associations studies known to be associated with risk of the disease. We evaluated the benefit of including mammographic density and the cumulative effect of genetic variants in breast cancer risk prediction among women in a Singapore population.

Methods

We estimated the risk of breast cancer using a prospective cohort of 24,161 women aged 50 to 64 from Singapore with available mammograms and known risk factors for breast cancer who were recruited between 1994 and 1997. We measured mammographic density using the medio-lateral oblique views of both breasts. Each woman’s genotype for 75 SNPs was simulated based on the genotype frequency obtained from the Breast Cancer Association Consortium data and the cumulative effect was summarized by a genetic risk score (GRS). Any improvement in the performance of our proposed prediction model versus one containing only variables from the Gail model was assessed by changes in receiver-operating characteristic and predictive values.

Results

During 17 years of follow-up, 680 breast cancer cases were diagnosed. The multivariate-adjusted hazard ratios (95% confidence intervals) were 1.60 (1.22–2.10), 2.20 (1.65–2.92), 2.33 (1.71–3.20), 2.12 (1.43–3.14), and 3.27 (2.24–4.76) for the corresponding mammographic density categories: 11-20cm², 21-30cm², 31-40cm², 41-50cm², 51-60cm², and 1.10 (1.03–1.16) for GRS. At the predicted absolute 10-year risk thresholds of 2.5% and 3.0%, a model with mammographic density and GRS could correctly identify 0.9% and 0.5% more women who would develop the disease compared to a model using only the Gail variables, respectively.

Conclusion

Mammographic density and common genetic variants can improve the discriminatory power of an established breast cancer risk prediction model among females in Singapore.     

The Structure of Treponema pallidum Tp0751 (Pallilysin) Reveals a Non-canonical Lipocalin Fold That Mediates Adhesion to Extracellular Matrix Components and Interactions with Host Cells

Syphilis is a chronic disease caused by the bacterium Treponema pallidum subsp. pallidum. Treponema pallidum disseminates widely throughout the host and extravasates from the vasculature, a process that is at least partially dependent upon the ability of T. pallidum to interact with host extracellular matrix (ECM) components. Defining the molecular basis for the interaction between T. pallidum and the host is complicated by the intractability of T. pallidum to in vitro culturing and genetic manipulation. Correspondingly, few T. pallidum proteins have been identified that interact directly with host components. Of these, Tp0751 (also known as pallilysin) displays a propensity to interact with the ECM, although the underlying mechanism of these interactions remains unknown. Towards establishing the molecular mechanism of Tp0751-host ECM attachment, we first determined the crystal structure of Tp0751 to a resolution of 2.15 Å using selenomethionine phasing. Structural analysis revealed an eight-stranded beta-barrel with a profile of short conserved regions consistent with a non-canonical lipocalin fold. Using a library of native and scrambled peptides representing the full Tp0751 sequence, we next identified a subset of peptides that showed statistically significant and dose-dependent interactions with the ECM components fibrinogen, fibronectin, collagen I, and collagen IV. Intriguingly, each ECM-interacting peptide mapped to the lipocalin domain. To assess the potential of these ECM-coordinating peptides to inhibit adhesion of bacteria to host cells, we engineered an adherence-deficient strain of the spirochete Borrelia burgdorferi to heterologously express Tp0751. This engineered strain displayed Tp0751 on its surface and exhibited a Tp0751-dependent gain-of-function in adhering to human umbilical vein endothelial cells that was inhibited in the presence of one of the ECM-interacting peptides (p10). Overall, these data provide the first structural insight into the mechanisms of Tp0751-host interactions, which are dependent on the protein’s lipocalin fold.     

A Mutual Interest? Ethnography in Anthropology and Cultural Studies

Anthropology and cultural studies share a concern with ethnographic method. Cultural studies increasingly uses ethnography in its analyses of popular culture as it seeks to balance earlier preoccupations with text. Where cultural studies diverges from anthropology is in its encompassment within an oppositional paradigm which embeds a political agenda deep in its ethnographic work. This paper uses the area of media to explore the ways in which ethnography has been adopted and developed in cultural studies. Ethnographic focus has shifted interest in media from the text to the reception of media products. At the same time, the oppositional legacy from cultural studies' earliest days has tended to produce rather romanticised findings of a subaltern audience using media products to resist dominant cultural and political structures. It is suggested that anthropology should pay attention to cultural studies use of ethnographic method, first taking seriously the ground of popular culture as a challenge for anthropologists' more extended use of ethnography. But second, we should pay attention to the problem silences in cultural studies' ethnographies—silences like racism in audiences—since these may well have at least part of their basis in the method itself.     

The role of peripheral endemism in species diversification: evidence from the coral reef fish genus Anampses (Family: Labridae)

We examined how peripherally isolated endemic species may have contributed to the biodiversity of the Indo-Australian Archipelago biodiversity hotspot by reconstructing the evolutionary history of the wrasse genus Anampses. We identified three alternate models of diversification: the vicariance-based 'successive division' model, and the dispersal-based 'successive colonisation' and 'peripheral budding' models. The genus was well suited for this study given its relatively high proportion (42%) of endemic species, its reasonably low diversity (12 species), which permitted complete taxon sampling, and its widespread tropical Indo-Pacific distribution. Monophyly of the genus was strongly supported by three phylogenetic analyses: maximum parsimony, maximum likelihood, and Bayesian inference based on mitochondrial CO1 and 12S rRNA and nuclear S7 sequences. Estimates of species divergence times from fossil-calibrated Bayesian inference suggest that Anampses arose in the mid-Eocene and subsequently diversified throughout the Miocene. Evolutionary relationships within the genus, combined with limited spatial and temporal concordance among endemics, offer support for all three alternate models of diversification. Our findings emphasise the importance of peripherally isolated locations in creating and maintaining endemic species and their contribution to the biodiversity of the Indo-Australian Archipelago.     

Characterization of Chasmoendolithic Community in Miers Valley,McMurdo Dry Valleys,Antarctica

The Antarctic Dry Valleys are unable to support higher plant and animal life and so microbial communities dominate biotic ecosystem processes. Soil communities are well characterized, but rocky surfaces have also emerged as a significant microbial habitat. Here, we identify extensive colonization of weathered granite on a landscape scale by chasmoendolithic microbial communities. A transect across north-facing and south-facing slopes plus valley floor moraines revealed 30–100 % of available substrate was colonized up to an altitude of 800 m. Communities were assessed at a multidomain level and were clearly distinct from those in surrounding soils and other rock-inhabiting cryptoendolithic and hypolithic communities. All colonized rocks were dominated by the cyanobacterial genus Leptolyngbya (Oscillatoriales), with heterotrophic bacteria, archaea, algae, and fungi also identified. Striking patterns in community distribution were evident with regard to microclimate as determined by aspect. Notably, a shift in cyanobacterial assemblages from Chroococcidiopsis-like phylotypes (Pleurocapsales) on colder–drier slopes, to Synechococcus-like phylotypes (Chroococcales) on warmer–wetter slopes. Greater relative abundance of known desiccation-tolerant bacterial taxa occurred on colder–drier slopes. Archaeal phylotypes indicated halotolerant taxa and also taxa possibly derived from nearby volcanic sources. Among the eukaryotes, the lichen photobiont Trebouxia (Chlorophyta) was ubiquitous, but known lichen-forming fungi were not recovered. Instead, fungal assemblages were dominated by ascomycetous yeasts. We conclude that chasmoendoliths likely constitute a significant geobiological phenomenon at lower elevations in granite-dominated Antarctic Dry Valley systems.