Identification of Genetic Risk Variants for the Development of Gastric Adenocarcinoma

Abstract

Gastric cancer (GC) is a clinically heterogeneous and one of the most common malignant tumour entities affecting the human gastrointestinal tract with a multifactorial aetiology. Beside environmental risk factors, also genetic risk variants contribute to the development of GC. Their identification and functional interpretation using genome-wide association studies (GWAS) already resulted in valuable insights into the pathophysiology and genetic architecture of the disease. However, up to today, these studies were almost exclusively conducted in the Asian population and relevant sub-classifications like the tumour location (cardia and non-cardia) and the histological tumour types (diffuse and intestinal) were often not considered.<br /> The aim of this study was to characterize the genetic risk architecture of GC in the European population according to subtypes and to estimate their genetic overlap with known risk factors and other tumour entities. To this end, we collected the largest European sample of GC cases. In addition, we collected gastric corpus and antrum mucosa biopsies from healthy donors to conduct expression quantitative trait loci (eQTL) and transcriptome-wide association study (TWAS) analyses. These samples built the basis for the, to date, largest European GWAS meta-analysis, comprising 5.816 patients and 10.999 controls, and the largest gastric mucosa transcriptome datasets, including 361 samples from the corpus and 342 samples from the antrum.<br /> The GWAS resulted in the identification and replication of nine GC risk loci. Stratification for the tumour location revealed that all but one locus contributed specifically to the risk of non-cardia GC, showing no association to cardia GC. Furthermore, two loci specifically contributed to the risk of developing tumours of the intestinal type and three loci showed a pronounced effect for the risk of developing diffuse type GC. This finding highlights the heterogeneous pathophysiology of GC and exemplifies the need for the identification and stratification of clinical relevant subtypes.<br /> The gastric mucosa based TWAS and eQTL analysis provided evidence for the prioritization of the gene MUC1 at chromosome 1q22, ANKRD50 at chromosome 4q28, PTGER4 at chromosome 5p13, PSCA at chromosome 8q24 and ABO at chromosome 9q34 as risk conferring genes. In line with the prioritization of ABO, we found that the blood group O exerts protective effects for non-cardia and diffuse GC, while blood group A increases risk for both GC subtypes. <br /> Furthermore, NEGR1 at chromosome 1p31, ALK at chromosome 2q23, KLF6 at chromosome 10p15 and HNF1B at chromosome 17q12 are promising candidate genes at the respective risk loci.<br /> On the polygenic level, linkage disequilibrium score regression (LDSC) revealed a positive correlation of GC with obesity, smoking and alcohol consumption related traits, whereas a higher education and socioeconomic status have protective effects. For the first time, these findings confirm the results of observational studies on a genetic level.<br /> As cardia GC is suspected to represent a separate tumour entity, being more closely related to oesophageal adenocarcinoma (OAC), the genetic correlation between both entities was examined utilizing polygenic risk score analysis and a large European in-house OAC GWAS dataset. The analysis revealed that cardia GC and OAC are genetically homogenous at the polygenic level and can be discriminated from non-cardia GC. This finding was further supported by the identification of additional shared risk loci, after meta-analysing cardia GC subtype and OAC.<br /> All in all, the presented GWAS meta-analysis and follow-up studies provided new insights into the pathophysiology of GC at the single variant and polygenic level. The results indicate that GC is genetically heterogeneous in respect to location and histopathology. Moreover, the findings point to common molecular mechanisms underlying cardia GC and OAC.