Evidence for PTGER4, PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level

Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 × 10-04) and on chromosome 8q24 at rs2585176 (P = 1.09 × 10-09). On chromosome 5p13 we found cis-eQTL effects with an upregulation of PTGER4 expression in GC risk allele carrier (P = 9.27 × 10-11). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 × 10-47). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 × 10-09). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Decreased plasma levels of nitric oxide derivatives in obstructive sleep apnoea: response to CPAP therapy

BACKGROUND—Reduced endothelium dependent vasodilation has been reported in patients with obstructive sleep apnoea (OSA) but direct measurements of the most potent naturally occurring vasodilator, nitric oxide (NO) or its derivatives (nitrate and nitrite, NO(x)), have not yet been performed in these patients.
METHODS—In 21 patients with OSA of mean (SE) age 54 (2) years, body mass index (BMI) 30.9 (1.1) kg/m(2), and apnoea-hypopnoea index (AHI) 37 (4)/h, NO(x) levels were measured in peripheral venous blood samples by chemiluminescence. Blood samples were obtained before and after two nights of continuous positive airway pressure (CPAP) and after 5.5 (1.5) months of follow up. Thirteen age matched, healthy volunteers and 18 patients without OSA but with a similar spectrum of comorbidity served as controls (control groups 1 and 2).
RESULTS—Before CPAP NO(x) levels were 21.7 (1.5) µM in patients with OSA compared with 42.6 (2.2) µM and 36.7 (1.7) µM in control groups 1 and 2, respectively (p<0.01 for each comparison). NO(x) concentrations increased to 32.1 (2.7) µM after two nights of CPAP and remained constant at 32.9 (2.3) µM at follow up (p<0.01 compared with levels before CPAP).
CONCLUSIONS—Plasma NO(x) levels are reduced in OSA and can be increased by short and long term CPAP therapy. Although the precise mechanism underlying this observation remains to be clarified, it may have important implications for the development of cardiovascular disease in patients with OSA and for the life saving effect of CPAP.


O187 ANASTOMOTIC TECHNIQUES AND ASSOCIATED MORBIDITY IN TOTAL MINIMALLY-INVASIVE TRANSTHORACIC ESOPHAGECTOMY – RESULTS FROM THE ESOBENCHMARK DATABASE

Abstract Background Total minimally-invasive transthoracic esophagectomy (ttMIE) faces increasing application in surgical treatment of esophageal cancer. For esophago-gastric reconstruction, different anastomotic techniques are currently used, but their impact on postoperative anastomotic leakage and morbidity has not been investigated. The aim of this retrospective multicenter analysis was to describe anastomotic techniques used for ttMIE and to analyze the associated morbidity. Patients and Methods Patients were selected from a basic dataset, collected over a 5-year period from 13 international surgical high-volume centers. Endpoints were anastomotic leakage rate and postoperative morbidity in correlation to anastomotic techniques, measured by the CD classification and the Comprehensive Complication Index® (CCI). Results Five anastomotic techniques were identified in 966 patients after ttMIE: Intrathoracic end-to-side circular-stapled technique in 427 patients (double-stapling n=90, purse-string n=337), intrathoracic (n=109) or cervical (n=255) side-to-side linear-stapled, and cervical end-to-side hand-sewn (n=175). Leakage rates were similar in intrathoracic and cervical anastomoses (15.9% vs. 17.2%, P=0.601), but overall complications (56.7%% vs. 63.7%, P=0.029) and median 90-day CCI (21 (IQR 0-36) vs. 29 (IQR 0-40), P=0.019) favored intrathoracic reconstructions. Leakage rates after intrathoracic end-to-side double-stapling (23.3%) and cervical end-to-side hand-sewn (25.1%) techniques were significantly higher compared with intrathoracic side-to-side linear (15.6%), end-to-side purse-string (13.9%) and cervical side-to-side linear-stapled esophago-gastrostomies (11.8%) (P&lt;0.001). Multivariable analysis confirmed anastomotic technique as independent predictor of leakage after ttMIE. Conclusion Results of this analysis present the current status of the technical evolution of ttMIE with anastomotic leakage as predominant surgical complication. However, technique-related morbidity requires cautious interpretation considering the long learning curve of this complex surgical procedure. </jats:sec