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.

Moral Emotions in Palliative Care: Empirical Insights from Austria and Canada

Research aims: Moral emotions as one specific group of emotions play a vital role in delivering palliative care as e.g. ethical issues and moral distress belong to daily routine.
Moral emotions are oriented to the welfare of other persons or the society as a whole. To better understand moral emotions in Palliative Care the aims of the presented study are to ana- lyze care situations from Austria and Canada in different care settings and identify families of moral emotions on one hand and describe influencing contextual factors on the other hand. Methods: Within a qualitative study design a reanalysis of Austrian narratives on ethical issues and Canadian narra- tives on moral distress were conducted. Data in Austria encompass 36 narratives that were generated through qual- itative questionnaires in nursing homes. Canadian data are based on qualitative interviews with home care palliative specialists and encompass 47 critical incidents. The reanal- ysis of data was conducted with narrative analysis. Results: Preliminary results show that moral emotions in palliative care can be found in families around “empathy and relatedness”, “sadness, isolation and bereavement”, “anger, frustration and powerlessness”, “guilt and shame” and “being touched and feel close”. Contextual factors influencing moral emotions can be summarized as “suffer- ing and decline of client”, “expectations and dynamics of family”, “structural conflicts and power issues” and “lack of resources and information”.
Conclusion: The diversity of moral emotions reflects the everyday experiences in palliative care. It became obvious that most of the moral emotions that have been expressed appear to be interconnected within a bundle of other emo- tions. Contextual factors influencing moral emotions in pal- liative care are relatively independent of care settings. In Palliative Care moral emotions and their contextual factors constitute an important source of insight for reflection in organizational ethics.