Discussion
In a large prospective pooled analysis in the ACC, we confirmed that family history of gastric cancer is associated with increased risk of gastric cancer in the Asian population. While we did not observe a statistically significant difference, the magnitude of association was more pronounced among individuals who were born later years, or diagnosed with gastric cancer at a younger age. We found no difference in risk among histological subtypes of gastric cancer. Although not statistically different from other associations, in males, having a family history of gastric cancer among brothers was most strongly associated with gastric cancer, followed by those affected fathers and mothers, compared to those without affected family members. In females, a significant positive association was only observed in those with affected mothers. Similar to incidence, we confirmed positive associations between family history of gastric cancer and gastric cancer mortality.
Previous studies have suggested that gastric cancer exhibits a greater tendency toward familial clustering and a higher predisposition to the disease than other cancers [
18].
Approximately 10% of gastric cancers display a familial aggregation [19] but only less than 3% of gastric cancer arise from hereditary gastric cancers [20]. Familial diffuse gastric cancer and hereditary diffuse gastric cancer are the most recognizable, familial gastric cancer caused by APC, CDH1, and CTNNA1 gene mutations, respectively [21]. Still, the frequency of hereditary diffuse gastric cancer is rare (incidence 0.3%–3.1% in South Korea and Japan) and does not account for a large proportion of familial clustering [22, 23]. Interestingly, according to the results of a recent investigation into germline variants in nine cancer genes and their association with gastric cancer risk, it appears that the role of hereditary factors in contributing to the likelihood of developing gastric cancer may be greater than previously thought [24]. In addition to genetic factors, family-shared environmental factors may play an important role by interacting with low penetrance genes.
Several studies reported that H. pylori infection and precancerous tissue changes (such as atrophy and intestinal metaplasia) are more common in children and siblings of patients with gastric cancer [9, 25, 26]. Notably, a randomized trial in South Korea reported that among persons with
H. pylori infection who had a family history of gastric cancer in first-degree relatives,
H. pylorieradication treatment reduced the risk of gastric cancer [
26]. Moreover, an individual’s dietary sodium intake and preference for salty foods may be influenced by their family environment [
27]. Consuming a diet high in salt may increase the likelihood of contracting an
H. pylori infection, and even worse, it can enhance the ability of
H. pylori to promote the development of gastric cancer by boosting cagA expression [
28], or directly damage the mucosal barrier [
29].
Although the difference was statistically not significant, we observed that the association between family history of gastric cancer was more prominent in individuals diagnosed with non-cardia gastric cancers than in cardia gastric cancers [30, 31]. The stronger association in non-cardia gastric cancers have been observed in several studies in Asia [
31] and also in other parts of the world [
11,
32]. The reason for this difference is not entirely clear, but several factors may be involved. One possible explanation is that non-cardia gastric cancer and cardia gastric cancer may have different risk factors.
Non-cardia gastric cancer is more strongly associated with chronic gastritis and H. pylori infection, while cardia gastric cancer is more strongly linked to obesity and gastroesophageal reflux disease [33, 34]. Another possible explanation is that the genetic factors contributing to the development of non-cardia gastric cancer may differ from those contributing to cardia gastric cancer. Studies have identified several genetic variants differentially associated with an increased risk of gastric cancer by anatomical subsite [
35]. A combination of various environmental risks with genetic predisposition may synergistically affect one subsite than the other [
24].
Due to the sex-specific differences in the incidence of gastric cancer, with males having twice the incidence of females, and potential behavioral risk factors such as alcohol consumption and smoking varying accordingly [36], we stratified our analyses by sex. We observed no sex differences in the association between family history of gastric cancer and risk of gastric cancer in the current study. Several earlier case–control studies reported higher association in females compared to males, which may reflect sex differences in recall bias in reporting the family history [
37,
38,
39]. Our findings are consistent with recent studies from a large consortium of gastric cancer studies from 17 studies from 11 countries (5946 cases) [
11], and a meta-analysis [
32]. However, further research is needed to fully understand the underlying mechanisms behind these non-differential associations by sex despite the differences in the exposure and the outcome.
Individuals enrolled at a younger age had a stronger association between family history of gastric cancer and the risk of developing the disease than those enrolled later. In addition, the association was more pronounced among those diagnosed with gastric cancer at a younger age and born later. There are several potential explanations for these results, one possibility is that these individuals may have a stronger genetic predisposition to gastric cancer, which is compounded by a common environment shared within the family [
40,
41].
Early-onset cancer, familial aggregation of cancer, and diagnosis of multiple primary tumors are all indicative of an inherited cancer predisposition [
42,
43]. Gastric cancer is typically diagnosed after age 60, but when it occurs before age 50, there is often a familial predisposition [
44,
45]. This suggests that genetic factors may play a stronger role in the development of gastric cancer at a younger age. Another factor that could contribute to the more substantial genetic component in young individuals with gastric cancer is the interaction between genetic factors and additional risk factors accumulated over time. Unhealthy lifestyle habits or dietary patterns may interact with genetic predispositions to increase cancer risk [
46]. Finally, younger individuals may be more likely to undergo regular screenings and have a higher awareness of the diseases when they have close family members who have been diagnosed with gastric cancer [
47,
48].
In this study, our findings confirm that a family history of gastric cancer is associated with an elevated risk of gastric cancer within the Asian population. While the incidence rate of gastric cancer among individuals with a family history is higher in Asia compared to Europe or North America, the frequency of hereditary diffuse gastric cancer relative to the overall incidence of familial gastric carcinogenesis is lower in Asia [
49]. In addition, due to several gene-association researches indicating potential differences among different geographical regions and ethnicities, consideration will be given to the possibility of variations in this association between Asians and Westerners [
50,
51,
52,
53]. However, several case–controls studies and a prospective study in Western populations also reported positive association between family history and gastric cancer [
54,
55,
56,
57,
58]. Future research is warranted to further explore the possible differences in the association in different regions and race/ethnic groups.