Genetical genomics: spotlight on QTL hotspots

No abstract available

Continuation of Lorlatinib in ALK-Positive NSCLC Beyond Progressive Disease

INTRODUCTION: Lorlatinib, a potent, selective third-generation ALK tyrosine kinase inhibitor (TKI), exhibited overall and intracranial antitumor activity in patients with ALK-positive NSCLC. METHODS: Retrospective analyses in the ongoing phase 2 trial (NCT01970865) investigated the clinical benefit of continuing lorlatinib beyond progressive disease (LBPD). Patients with previous crizotinib treatment as the only ALK TKI were group A (n = 28); those with at least one previous second-generation ALK TKIs were group B (n = 74). LBPD was defined as greater than 3 weeks of lorlatinib treatment after investigator-assessed progressive disease. Only patients with the best overall response of complete or partial response or stable disease were included. RESULTS: There were no major differences in baseline characteristics between groups. The median duration of treatment for patients who continued LBPD was 32.4 months (group A) and 16.4 months (group B) versus 12.5 months (group A) and 7.7 months (group B) for patients who did not continue LBPD. The median overall survival in group A was not reached (NR) in patients who continued LBPD versus 24.4 months (95% confidence interval [CI]: 12.1-NR); group B\u27s median was 26.5 months (95% CI: 18.7-35.5) in patients who continued LBPD versus 14.7 months (95% CI: 9.3-38.5) in patients who did not continue LBPD. The median overall survival postprogression for groups A and B was NR (95% CI: 21.4-NR) and 14.6 months (95% CI: 11.2-19.2) in patients who continued LBPD and 8.0 months (95% CI: 1.5-NR) versus 5.3 months (95% CI: 2.8-14.3) in patients who did not continue LBPD. CONCLUSIONS: Continuing LBPD is a viable treatment strategy for select patients with ALK-positive NSCLC who progressed on lorlatinib

Capturing expert uncertainty in spatial cumulative impact assessments

Abstract Understanding the spatial distribution of human impacts on marine environments is necessary for maintaining healthy ecosystems and supporting ‘blue economies’. Realistic assessments of impact must consider the cumulative impacts of multiple, coincident threats and the differing vulnerabilities of ecosystems to these threats. Expert knowledge is often used to assess impact in marine ecosystems because empirical data are lacking; however, this introduces uncertainty into the results. As part of a spatial cumulative impact assessment for Spencer Gulf, South Australia, we asked experts to estimate score ranges (best-case, most-likely and worst-case), which accounted for their uncertainty about the effect of 32 threats on eight ecosystems. Expert scores were combined with data on the spatial pattern and intensity of threats to generate cumulative impact maps based on each of the three scoring scenarios, as well as simulations and maps of uncertainty. We compared our method, which explicitly accounts for the experts’ knowledge-based uncertainty, with other approaches and found that it provides smaller uncertainty bounds, leading to more constrained assessment results. Collecting these additional data on experts’ knowledge-based uncertainty provides transparency and simplifies interpretation of the outputs from spatial cumulative impact assessments, facilitating their application for sustainable resource management and conservation

Germline Susceptibility to Colorectal Cancer Due to Base-Excision Repair Gene Defects

DNA repair is a key process in the maintenance of genome integrity. Here, we present a large, systematically collected population-based association study (2,239 cases; 1,845 controls) that explores the contribution to colorectal cancer incidence of inherited defects in base-excision repair (BER) genes. We show that biallelic MUTYH defects impart a 93-fold (95% CI 42–213) excess risk of colorectal cancer, which accounts for 0.8% of cases aged <55 years and 0.54% of the entire cohort. Penetrance for homozygous carriers was almost complete by age 60 years. Significantly more biallelic carriers had coexisting adenomatous polyps. However, notably, 36% of biallelic carriers had no polyps. Three patients with heterozygous MUTYH defects carried monoallelic mutations in other BER genes (OGG1 and MTH1). Recessive inheritance accounted for the elevated risk for those aged <55 years. However, there was also a 1.68-fold (95% CI 1.07–2.95) excess risk for heterozygous carriers aged >55 years, with a population attributable risk in this age group of 0.93% (95% CI 0%–2.0%). These data provide the strongest evidence to date for a causative role of BER defects in colorectal cancer etiology and show, to our knowledge for the first time, that heterozygous MUTYH mutations predispose to colorectal cancer later in life. These findings have clinical relevance for BER gene testing for patients with colorectal cancer and for genetic counseling of their relatives

Spencer gulf marine ecosystem map layers

This file set includes:<div><br><div><b>Two raster datasets of marine ecosystems</b> in Spencer Gulf produced for a cumulative impact assessment. There is one raster for the benthic ecosystems and one for the pelagic ecosystem. For each of the rasters there is an associated projection file with the same name.</div><div><br></div><div><b>Two tiff files</b> of the ecosystem maps (illustrating what they look like when plotted)</div><div><br></div><div><b>A metadata text file</b> with details of the spatial data layers and their projection - as well as sources of further information.</div><div><br></div></div

Spencer Gulf threat activity spatial layers

This file set includes:<div><br></div><div><b>32 raster spatial data layers </b>(scaled to be between 0 and 1) for 32 human activities that were considered as potential threats to marine ecosystems in a cumulative impact assessment of Spencer Gulf in South Australia. The treats are mostly human activities (such as fishing and coastal development), but also include climate change. Each raster data layer has an associated projection file with the same filename. </div><div><div><br></div><div><b>32 tiff images</b> showing plots of each threat mapped across the Spencer Gulf study area (illustrating what the data look like when plotted).<br></div><div><br></div><div><b>A metadata excel file </b>with details about each threat layer, including data sources and native resolution, as well as details on abbreviations used.</div><div><br></div><div><b>A metadata (read me) text file</b> with information about the spatial data files and the projections - as well as sources of further information.</div><div><br></div></div

eQTL Hotspots Reported in Selected Genetical Genomics Studies.

<p>The numbers are based on the statistical procedure and threshold used in the original publication, which can vary widely between papers. Where results based on multiple thresholds were reported, we included the most conservative one in the table.</p><p>N.A., not reported in the original paper. FDR, false discovery rate.</p