Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

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

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

Predicting the effect of local and global environmental change on shorebirds: a case study on the Exe estuary, U.K.

We used an individual-based model to assess site quality and to predict the effect of local (i.e. disturbance from a cycle path) and global (i.e. climate change) environmental change on the survival of six species of overwintering shorebirds on the Exe estuary, U.K. We also compare site quality on the Exe estuary with three other estuary Special Protection Areas (SPAs) and compare our predictions for the effects of climate change with predictions made for another southern U.K. estuary, Poole Harbour. Prey biomass densities in the Exe estuary were high for all six shorebirds, being as high as or higher than those found on other estuary SPAs. Simulations of increased levels of disturbance from a proposed cycle path along the side of the estuary predicted that disturbance of upper mudflat areas was unlikely to affect shorebird survival but that increased disturbance of nearby fields would reduce curlew survival. Shorebirds on the Exe estuary were far less seriously affected than those in Poole Harbour by reductions in mean daily temperatures, loss of terrestrial habitats and simulated sea-level rise. We conclude that the Exe estuary is a high quality estuary and that the shorebird populations modelled were less susceptible to climate change than those in Poole Harbour

Differential survival in adult Eurasian oystercatchers Haematopus ostralegus

I explored the fitness implications of individual and sex differences in foraging strategy in the Eurasian oystercatcher Haematopus ostralegus by monitoring the survival of individually colour-ringed birds of known sex and known feeding specialisation. Over the period of this study, adult female annual and overwinter survival was significantly lower than adult male survival. However, contrary to previous findings, no differences in survival were found between birds of different feeding specialisations. Lower female survival was not due to sex differences in feeding specialisation. Possible mechanisms for sex differences in survival and the survival implications of different feeding specialisations are discussed. I conclude that sex differences in survival may be due to differences in social status. I also suggest that worm/clam feeders and mussel-stabbers, feeding specialisations previously associated with lower survival rates, may have benefited more than mussel-hammerers from milder winter temperatures in recent years

Modelling the effect of environmental change on shorebirds: A case study on Poole Harbour, UK

An individuals-based model, MORPH, was used to assess the quality of Poole Harbour, UK, for five overwintering shorebirds: dunlin Calidris alpina, redshank Tringa totanus, black-tailed godwit Limosa limosa, oystercatcher Haematopus ostralegus and curlew Numenius arquata. Site quality, and the effect of environmental change, was measured as predicted overwinter survival. Dunlin had the highest prey biomass densities and were the least likely to be affected by reductions in their food supply, lower temperatures or loss of terrestrial habitats. Black-tailed godwits and curlew had the lowest prey biomass densities and were the most likely to be affected by reductions in their food supply, lower temperatures and loss of terrestrial habitats. All five shorebird species were seriously affected by simulated sea-level rise. Conservation issues identified for the Poole Harbour SPA were the relatively low densities of larger size classes of polychaete worms, the importance of maintaining and managing surrounding terrestrial habitats and the effect of sea-level rise on the length of time for which intertidal food supplies are availabl

Benefits to shorebirds from invasion of a non-native shellfish

Introductions of non-native species are seen as major threats to ecosystem function and biodiversity. However, invasions of aquatic habitats by non-native species are known to benefit generalist consumers that exhibit dietary switches and prey upon the exotic species in addition to or in preference to native ones. There is, however, little knowledge concerning the population-level implications of such dietary changes. Here, we show that the introduction of the Manila clam Tapes philippinarum into European coastal waters has presented the Eurasian oystercatcher Haematopus ostralegus ostralegus with a new food resource and resulted in a previously unknown predator–prey interaction between these species. We demonstrate, with an individuals-based simulation model, that the presence of this non-native shellfish, even at the current low density, has reduced the predicted over-winter mortality of oystercatchers at one recently invaded site. Further increases in clam population density are predicted to have even more pronounced effects on the density dependence of oystercatcher over-winter mortality. These results suggest that if the Manila clam were to spread around European coastal waters, a process which is likely to be facilitated by global warming, this could have considerable benefits for many shellfish-eating shorebird populations