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In 2012, 260\u00a0000 CGA cases (age\u2010standardised rate (ASR); 3.3\/100\u00a0000) and 691\u00a0000 NCGA cases (ASR; 8.8\/100\u00a0000) were reported worldwide. Compared with women, men had greater rates for both the subsites, especially for CGA. Recently, four molecular subtypes of GC have been proposed by the Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG); however, these classifications do not take into account predisposing germline variants and their possible interaction with somatic alterations in carcinogenesis. The etiology of adenocarcinoma of the cardia and the gastroesophageal junction (GEJ) is not known. It is thought that CGA is distinct from adenocarcinomas located in the esophagus or distal stomach, both epidemiologically and biologically. Moreover, CGA is often identified in the advanced stage having a poor prognosis. Therefore, understanding the risk and the role of predisposing factors in etiology of CGA can inform clinical practice and counseling for risk reduction. In this paper, we showed that GC family history, lifestyle, demographics, gastroesophageal reflux disease, <jats:italic>Helicobacter pylori<\/jats:italic> infection, and multiple genetic and epigenetic risk factors as well as several predisposing conditions may underlie susceptibility to CGA. However, several genome\u2010wide association studies (GWASs) should be conducted to identify novel high\u2010penetrance genes and pathways as well as causal germline variants predisposing to CGA. They must include different ethnic groups, especially from high\u2010incidence countries for CGA, because some risk loci are ancestry\u2010specific. In parallel, statistical methods can be developed to identify cancer predisposition genes (CPGs) from tumor sequencing data. It is also necessary to find novel long noncoding RNAs related to the risk of CGA. Taken altogether, new cancer risk prediction models, including all genetic and nongenetic factors influencing risk, should be developed to facilitate risk assessment, disease prevention, and early diagnosis and intervention of CGA in the future.<\/jats:p>","DOI":"10.1002\/cam4.2497","type":"journal-article","created":{"date-parts":[[2019,8,26]],"date-time":"2019-08-26T01:43:00Z","timestamp":1566783780000},"page":"6114-6126","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":102,"title":["Risk factors predisposing to cardia gastric adenocarcinoma: Insights and new perspectives"],"prefix":"10.1002","volume":"8","author":[{"given":"Esmat","family":"Abdi","sequence":"first","affiliation":[{"name":"Department of Biology Faculty of Sciences University of Mohaghegh Ardabili Ardabil 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