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

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Responses of oaks and tanoaks to the sudden oak death pathogen after 8 y of monitoring in two coastal California forests

Sudden oak death, caused by Phytophthora ramorum, is widely established in mesic forests of coastal central and northern California. In 2000, we placed 18 plots in two Marin County sites to monitor disease progression in coast live oaks (Quercus agrifolia), California black oaks (Q. kelloggii), and tanoaks (Lithocarpus densiflorus), the species that are most consistently killed by the pathogen in these areas. Through early 2008, the numbers of newly infected trees increased for all species. The infection rate for trees that were asymptomatic in 2000 was 5.0% y-1 for coast live oaks, 4.1% y-1 for black oaks and 10.0% y-1 for tanoaks. Mortality rates were 3.1% y-1 for coast live oaks, 2.4% y-1 for black oaks, and 5.4% y-1 for tanoaks. Mortality not attributed to P. ramorum was 0.54% y-1 for coast live oaks, and 0.75% y-1 for tanoaks. Weibull survival models of trees that were asymptomatic in 2000 provided overall median survival times of 13.7 y for coast live oaks, 13.8 y for black oaks, and 8.8 y for tanoaks. Survival of infected (bleeding) trees declined to 9.7 y for coast live oaks, 6.2 y for black oaks, and 5.8 y for tanoaks. Ambrosia beetle attacks on bleeding trees further reduced modeled survival times by 65-80%, reaffirming the earlier finding that beetle attacks on bleeding cankers considerably reduce survival. Across all plots, the modeled time for 90% of trees that were asymptomatic in 2000 to become infected is 36.5 y for coast live oaks and 15.4 y for tanoaks. There was a trend toward higher infection rates as tree diameter increased. Greater than 90% of living coast live oaks that failed during the study had extensive beetle tunneling at the site of the break. Disease intensity in coast live oaks at the plot level was positively associated with bay laurel (Umbellularia californica) basal area and negatively associated with Pacific madrone (Arbutus menziesii) basal area. This study demonstrates the use of survival modeling to characterize the effects of epidemic disease on different species and to project the future of forests infected with tree pathogens. © 2010 Elsevier B.V

Impact of a dermatology wiki website on dermatology education

Background: The Dermatology Education Wiki (dermwiki) website serves as a resource platform for medical students and residents. The readily accessible interface provides dermatology articles, survival guides, didactic lectures, and links to faculty talks as well as research opportunities.Objective: To assess medical student and resident satisfaction with the dermwiki website.Methods: Fourth-year medical students taking a dermatology elective were provided with a temporary password to access relevant dermwiki information. A satisfaction survey was created to assess whether medical students found the website helpful. Second- and third-year dermatology residents were also surveyed to compare satisfaction scores prior to and after the introduction of the dermwiki website. End-of-rotation medical student exam scores were tabulated and compared to the average scores from years prior to the development of the dermwiki website.Results: Medical students rated the dermatology elective with the dermwiki website higher than rotations without a wiki (8.12 vs 7.31). Students planning to go into dermatology were more satisfied with the dermwiki website, reported accessing the website more frequently (11 times vs 9.5 times), and reported more time spent studying (12.2 hours vs 6.7 hours) than students not going into dermatology. End-of-rotation medical student exam scores did not differ from those prior to the development of the demwiki website. Ten second- and third-year dermatology residents unanimously stated that they were more satisfied with the program after the institution of the dermwiki website.Conclusions: Overall, addition of the dermwiki website to the dermatology elective curriculum has improved medical student and resident satisfaction scores. The improvement is greater among students planning to enter the field of dermatology. This study serves as a model for the incorporation of internet-based interactive tools to transform and supplement the learning environment

Sudden oak death in California: Disease progression in oaks and tanoaks

Sudden oak death (SOD), caused by Phytophthora ramorum, is killing oaks and tanoaks in the Coast Ranges of California, from Monterey County to Humboldt County. In March 2000, 20 disease progression plots were established in Marin County, California, to characterize the progress of disease symptoms, and to determine the fidelity of the association of three or more bark and ambrosia beetle species (Coleoptera: Scolytidae) with diseased oaks and tanoaks. Symptoms of sudden oak death and signs of associated organisms were recorded from coast live oaks (Quercus agrifolia), California black oaks (Q. kelloggii), valley oaks (Q. lobata), and tanoaks (Lithocarpus densiflorus), four times per year, from March 2000 through March 2003. Symptoms and signs in Q. agrifolia progressed from bleeding, to infestation by scolytid beetles, to the development of fruiting structures of the fungus Hypoxylon thouarsianum. Mortality of symptomatic trees increased from 2000 to 2003 as follows: Q. agrifolia (n = 668), 5.8-17.4%; Q. kelloggii (n = 53), 3.8-9.4%; and L. densiflorus (n = 164), 8.3-22.2%. All 31 Q. lobata remained asymptomatic. From 2000 to 2003, bleeding trees were 25.0-23.6% of living Q. agrifolia, 15.5-25.0% of Q. kelloggii, and 39.0-62.4% of L. densiflorus. Scolytid beetles colonized more than 95% of the living symptomatic Q. agrifolia that subsequently died. Same-symptom cohorts were followed from March 2000 through March 2003. In the asymptomatic Q. agrifolia cohort, 12.0% developed bleeding by 2003. For the bleeding only cohort, 22.7% of Q. agrifolia died, but 73.5% of the beetle-colonized bleeding cohort died. Bleeding developed in 40.9% of the initially asymptomatic L. densiflorus cohort. By 2003, 24.6% of the initially bleeding L. densiflorus cohort had died. Both Weibull and Cox Proportional Hazards regression were used to model cohort survival. The median survival time estimated by Weibull regression models declined rapidly by disease category (asymptomatic, bleeding only, bleeding with beetles), from 29 to 2.7 years for Q. agrifolia, and from 12.6 to 2.9 years for L. densiflorus. By 2003, structural bole failure had occurred in 21.5% of the Q. agrifolia that were bleeding in 2000, 93% of which had ambrosia beetle tunnels at the breakage point. For both Q. agrifolia and L. densiflorus, health failure analysis modeled by Weibull regression found a greater probability of developing sudden oak death for trees with larger stem diameters. Beetles were also positively correlated with larger diameter bleeding Q. agrifolia. © 2005 Elsevier B.V. All rights reserved