Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

Background: Esophageal adenocarcinoma (EA) is one of the fastest rising cancers in western countries. Barrett’s Esophagus (BE) is the premalignant precursor of EA. However, only a subset of BE patients develop EA, which complicates the clinical management in the absence of valid predictors. Genetic risk factors for BE and EA are incompletely understood. This study aimed to identify novel genetic risk factors for BE and EA.Methods: Within an international consortium of groups involved in the genetics of BE/EA, we performed the first meta-analysis of all genome-wide association studies (GWAS) available, involving 6,167 BE patients, 4,112 EA patients, and 17,159 representative controls, all of European ancestry, genotyped on Illumina high-density SNP-arrays, collected from four separate studies within North America, Europe, and Australia. Meta-analysis was conducted using the fixed-effects inverse variance-weighting approach. We used the standard genome-wide significant threshold of 5×10-8 for this study. We also conducted an association analysis following reweighting of loci using an approach that investigates annotation enrichment among the genome-wide significant loci. The entire GWAS-data set was also analyzed using bioinformatics approaches including functional annotation databases as well as gene-based and pathway-based methods in order to identify pathophysiologically relevant cellular pathways.Findings: We identified eight new associated risk loci for BE and EA, within or near the CFTR (rs17451754, P=4·8×10-10), MSRA (rs17749155, P=5·2×10-10), BLK (rs10108511, P=2·1×10-9), KHDRBS2 (rs62423175, P=3·0×10-9), TPPP/CEP72 (rs9918259, P=3·2×10-9), TMOD1 (rs7852462, P=1·5×10-8), SATB2 (rs139606545, P=2·0×10-8), and HTR3C/ABCC5 genes (rs9823696, P=1·6×10-8). A further novel risk locus at LPA (rs12207195, posteriori probability=0·925) was identified after re-weighting using significantly enriched annotations. This study thereby doubled the number of known risk loci. The strongest disease pathways identified (P<10-6) belong to muscle cell differentiation and to mesenchyme development/differentiation, which fit with current pathophysiological BE/EA concepts. To our knowledge, this study identified for the first time an EA-specific association (rs9823696, P=1·6×10-8) near HTR3C/ABCC5 which is independent of BE development (P=0·45).Interpretation: The identified disease loci and pathways reveal new insights into the etiology of BE and EA. Furthermore, the EA-specific association at HTR3C/ABCC5 may constitute a novel genetic marker for the prediction of transition from BE to EA. Mutations in CFTR, one of the new risk loci identified in this study, cause cystic fibrosis (CF), the most common recessive disorder in Europeans. Gastroesophageal reflux (GER) belongs to the phenotypic CF-spectrum and represents the main risk factor for BE/EA. Thus, the CFTR locus may trigger a common GER-mediated pathophysiology.

Beyond the ‘Tomlinson Trap’: Analysing the Effectiveness of Section 1 of the Compensation Act 2006

One of the intentions underpinning section 1 of the Compensation Act 2006 was to provide reassurance to individual volunteers, and voluntary organisations, involved in what the provision called ‘desirable activities’ and including sport. The perception was that such volunteers, motivated by an apprehension about their increased vulnerability to negligence liability, and as driven by a fear of a wider societal compensation culture, were engaging excessively in risk-averse behaviour to the detriment of such socially desirable activities. Academic commentary on section 1 of the Compensation Act 2006 has largely regarded the provision as unnecessary and doing little more than restating existing common law practice. This article argues otherwise and, on critically reviewing the emerging jurisprudence, posits the alternative view that section 1, in practice, affords an enhanced level of protection and safeguarding for individuals undertaking functions in connection with a desirable activity. Nonetheless, the occasionally idiosyncratic judicial interpretation given to term ‘desirable activity’, potentially compounded by recent enactment of the Social Action, Responsibility and Heroism Act 2015, remains problematic. Two points of interest will be used to inform this debate. First, an analysis of the then House of Lords’ decision in Tomlinson and its celebrated ‘balancing exercise’ when assessing reasonableness in the context of negligence liability. Second, a fuller analysis of the application of section 1 in the specific context of negligence actions relating to the coaching of sport where it is argued that the, albeit limited, jurisprudence might support the practical utility of a heightened evidential threshold of gross negligence.

Michael Schratz / Johanna F. Schwarz / Tanja Westfall-Greiter: Lernen als bildende Erfahrung, Vignetten in der Praxisforschung, Mit einem Vorwort von Käte Meyer-Drawe und Beiträgen von Horst Rumpf, Carol Ann Tomlinson, Mike Rose u.a. Innsbruck: Studienverlag 2012 [Rezension]

Rezension von: Michael Schratz / Johanna F. Schwarz / Tanja Westfall-Greiter: Lernen als bildende Erfahrung, Vignetten in der Praxisforschung, Mit einem Vorwort von Käte Meyer-Drawe und Beiträgen von Horst Rumpf, Carol Ann Tomlinson, Mike Rose u.a., Innsbruck: Studienverlag 2012 (161 S.; ISBN 978-3706551182)