Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

2014 Rural Clinical School Training and Support Program Snapshot survey

Introduction: The Rural Clinical Training and Support (RCTS) program is an Australian Government initiative to address the shortage of medical practitioners within rural and remote Australia. There is a large amount of published information about the RCTS program and rural medical student cohorts who have undertaken short- and long-term rotations. However, very little is known about the academic and professional staff involved in the program, a knowledge gap that may impact workforce and succession planning. To address this, the Federation of Rural Australian Medical Educators (FRAME) initiated the pilot 2014 RCTS Snapshot survey to obtain data on the current RCTS workforce. Results: The estimated total RCTS workforce was 970. A total of 413 responses were received and 316 (40.9%) complete responses analysed. The majority of respondents were female (71%), the 40-60-year age group was predominant (28%), and professional staff constituted the majority (62%). The below 40-year age group had more professionals than academics (21% vs 12%) and more than 62% of academics were aged above 50 years. Notably, there were no academics aged less than 30 years. The percentage of professional staff with a rural background was higher (62%) than that of academics with a rural background (42%). However, more than 70% of academics had previous exposure to a rural area as an adult and 32% had an exposure as a part of university or the TAFE (technical and further education) system. More than half (62%) of RCTS academics were aged more than 50 years and thus approaching retirement age. The implementation of a FRAME-sponsored leadership and succession program was considered by most staff (84%) as one strategy that could be used to prevent a future shortage of academics. Lifestyle reasons for working at an RCS were common to both academic (54%) and professional (63%) staff. A passion for rural health and building capacity within the rural health workforce were other central themes to emerge from the qualitative data. Uncertainty around contract renewal and future funding were dominant themes to emerge from respondents regarding their future employment intentions within the RCTS program. Conclusions; This study has provided valuable insights into the professional and academic staff's views and aspirations about the RCTS program. These data on the current RCTS workforce provide a benchmark to which future surveys of the workforce can be compared to monitor trends in turnover or predict future shortages due to cohort ageing

Benchmarking Successional Progress in a Quantitative Food Web

<div><p>Central to ecology and ecosystem management, succession theory aims to mechanistically explain and predict the assembly and development of ecological communities. Yet processes at lower hierarchical levels, e.g. at the species and functional group level, are rarely mechanistically linked to the under-investigated system-level processes which drive changes in ecosystem properties and functioning and are comparable across ecosystems. As a model system for secondary succession, seasonal plankton succession during the growing season is readily observable and largely driven autogenically. We used a long-term dataset from large, deep Lake Constance comprising biomasses, auto- and heterotrophic production, food quality, functional diversity, and mass-balanced food webs of the energy and nutrient flows between functional guilds of plankton and partly fish. Extracting population- and system-level indices from this dataset, we tested current hypotheses about the directionality of successional progress which are rooted in ecosystem theory, the metabolic theory of ecology, quantitative food web theory, thermodynamics, and information theory. Our results indicate that successional progress in Lake Constance is quantifiable, passing through predictable stages. Mean body mass, functional diversity, predator-prey weight ratios, trophic positions, system residence times of carbon and nutrients, and the complexity of the energy flow patterns increased during succession. In contrast, both the mass-specific metabolic activity and the system export decreased, while the succession rate exhibited a bimodal pattern. The weighted connectance introduced here represents a suitable index for assessing the evenness and interconnectedness of energy flows during succession. Diverging from earlier predictions, ascendency and eco-exergy did not increase during succession. Linking aspects of functional diversity to metabolic theory and food web complexity, we reconcile previously disjoint bodies of ecological theory to form a complete picture of successional progress within a pelagic food web. This comprehensive synthesis may be used as a benchmark for quantifying successional progress in other ecosystems.</p></div