The H. pylori infection rate is decreasing due to improved socioeconomic conditions and sanitation. For example, the H. pylori seroprevalence among Koreans older than 16 years of age was 59.6% and 54.4% in 2005 and in 2011, respectively [11,40], a considerable decrease from 66.9% in 1998 [41]. Additionally, in the Czech Republic, the prevalence decreased dramatically from 41.7% [42] to 23.5% [43] between 2001 and 2011.

The H. pylori infection rate is higher in subjects with than without a family history of gastric cancer [44,45]. These results were in accordance with a Korean study [16]. However, a nationwide epidemiological survey involving 10,796 Korean subjects who participated in health check-ups in 2011 reported that the H. pylori seropositive rate in subjects with a family history was not significantly different from that of subjects without a family history (55.1% vs. 54.4%) [11]. This result was similar to those reported in 1998 [41] and in 2005 [40]. Therefore, a difference in H. pylori infection rate is not responsible for the increased risk of gastric carcinogenesis in first-degree family members of gastric cancer patients.

Relatives with gastric cancer are significantly and independently more frequently colonized by H. pylori strains with higher numbers of CagA-EPIYA-C segments (OR, 4.2; 95% CI, 1.5 to 11.7) and of the most virulent genotype s1m1 vacA (OR, 2.80; 95% CI, 1.0 to 7.5) [46]. In contrast, it has been reported that H. pylori genotypes such as vacA s1 cagA might not be important determinants of the type and advanced form of gastritis in the first-degree relatives of gastric cancer patients [47]. Therefore, further comprehensive research is needed.

H. pylori infection and having a first-degree relative with gastric cancer are positively related. One study from Germany reported that subjects with both a family history and infection with a CagA-positive H. pylori strain had a more than eightfold higher risk of gastric cancer (OR, 8.2; 95% CI, 2.2 to 30.4) and a 16-fold higher risk of noncardia gastric cancer (OR, 16.0; 95% CI, 3.9 to 66.4) compared with uninfected subjects who had no family history [17]. A Korean study also showed that the relative excess risk for patients with both H. pylori infection and a family history of gastric cancer exceeded the sum of the relative excess risks for each risk factor alone: 5.32 – 1.00 > (1.58 – 1.00) + (1.33 – 1.00) [18]. A Japanese study showed that women with both a family history and H. pylori infection had a more than fivefold increased risk of gastric cancer (OR, 5.10; 95% CI, 1.58 to 16.5) compared to those without these factors [48].

The relation between a family history of the disease and the risk of gastric cancer is reduced somewhat by control of H. pylori infection. This implies that intrafamilial aggregation of gastric carcinoma may be due, at least in part, to intrafamilial clustering of H. pylori infection. However, a strong relationship between a family history and an increased risk of gastric carcinoma remained after control of H. pylori infection, suggesting that other factors, such as genetic or lifestyle factors, contribute to the familial clustering of gastric cancer.

Familial risk is a hallmark of genetic susceptibility. However, with the exception of HGDC, no genetic screening has been recommended [8]. Regarding the genetic aspect of gastric carcinogenesis, familial aggregation may be the result of a number of low-penetrant alleles acting in combination, rather than one or a few highly penetrant dominant cancer genes [7]. Several genes—such as interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), IL-6, IL-8, IL-10, Toll-like receptor 4 (TLR-4), and transforming growth factor β (TGF-β)—are suspected to affect susceptibility to H. pylori infection or to moderate local inflammation [49-51].

El-Omar et al. [49] first reported an association between the IL-1β-31C and IL-1RN 2/2 genotypes with a higher risk of chronic hypochlorhydria and gastric cancer. The presence of IL-1β-511T, IL-1RN*2/*2, TNF-α-308A, and IL-10 (haplotype ATA/ATA) was associated with a greater risk of noncardia gastric cancer in individuals infected with H. pylori [50].

Genetic factors are involved in triggering, by H. pylori infection, premalignant lesions such as intestinal metaplasia (IM). Research on the risk factors of atrophic gastritis (AG) and IM in subjects without significant gastroduodenal diseases showed that AG was related to both H. pylori infection and the presence of genes encoding virulence factors such as vacA m1 and cagA. In contrast, the risk factors for IM were H. pylori infection, smoking, age over 61 years, eating spicy food, and IL-10-592 C/A [52]. These results suggest that genetic polymorphisms are associated with IM, which increases the risk of gastric cancer 10.9-fold, compared to subjects without IM [52]. Moreover, a family history of gastric cancer is not significantly associated with the incidence of AG [53].

The results of gene-association studies differ among geographic areas and ethnicities. For instance, genetic polymorphisms in IL-1β and TNF-α are consistently related to gastric cancer among Caucasians [54,55], while the effect was inconsistent among Asian patients [56,57]. In contrast, IL-8 and TGF-β genetic polymorphisms and gastric carcinogenesis were related more consistently among Asian than Western patients [58-60]. Moreover, since most studies did not include family history as a covariate, knowledge of its influence on the linkage between inflammation-related gene polymorphisms and susceptibility to gastric cancer is limited. According to a recent comprehensive study of 123 gastric cancer patients with a family history and 639 age- and sexmatched control gastric cancer patients without a family history [38], intestinal-type gastric cancer patients with a family history spent their youth in rural areas more frequently than did those without a family history (OR, 2.0; 95% CI, 1.0 to 3.9), and fewer harbored TGFβ1-509T (OR, 0.5; 95% CI, 0.3 to 0.9). This suggested that both environmental factors and genetic polymorphisms affect the genesis of intestinal-type gastric cancer in subjects with a family history [38]. It has been reported that matrix metalloproteinase 9 gene polymorphisms are associated with a greater risk of gastric cancer in individuals with one parent or sibling with gastric cancer compared with those with no family history [61].

The hypothesis that familial aggregation of gastric cancer is attributable to low-penetrance polymorphic variants has not been validated [24]. To determine the mechanism underlying the increased susceptibility to gastric cancer among subjects with a family history of the disease, environmental factors, H. pylori infection, and the interaction between H. pylori virulence factors and genetic susceptibility must be taken into consideration. Moreover, the familial clustering of gastric cancer should be investigated in genome-wide association studies.

There is no definite consensus about which gastric cancer is ‘familial,’ other than familial gastric cancer syndrome. Although having a first-degree relative with gastric cancer is an important risk factor, the individual impact according to the number of affected relatives or the family member affected is unclear.

It is generally accepted that the risk of gastric cancer increases with an increasing number of affected relatives [23]. The risk of gastric cancer was higher in individuals with a single first-degree family member with gastric cancer (OR, 2.7; 95% CI, 1.7 to 4.3), and increased further for subjects with two or more first-degree relatives with gastric cancer (OR, 9.6; 95% CI, 1.2 to 73.4) [18]. Indeed, an Italian study reported that having two or more first-degree relatives with gastric cancer was associated with a greater risk of developing gastric cancer than a single first-degree relative (OR, 5.5; 95% CI, 3.0 to 10.2 vs. OR, 1.7; 95% CI, 1.3 to 2.1) [62]. Furthermore, a history of gastric cancer in a sibling showed a more significant association with an increased susceptibility to gastric cancer than a history of gastric cancer in a parent (sibling: OR, 2.6; 95% CI, 1.8 to 3.7; parent: OR, 1.7; 95% CI, 1.3 to 2.2) [62].

The adjusted risk of gastric cancer was higher for subjects with an affected mother than for those with an affected father (OR, 2.3 and 1.3), and increased further for subjects with both parents (OR, 3.0) or two or more siblings (OR, 8.5) affected by gastric cancer [62]. The risk of gastric cancer for subjects with a sibling with gastric cancer also increased significantly (OR, 2.4; 95% CI, 1.3 to 4.7), but the risk was less than that of subjects with an affected parent (OR, 3.3; 95% CI, 1.9 to 5.8) [18]. Although studies of the impact of affected siblings or parents on gastric cancer development have reported discrepant results, the higher risk of gastric cancer in those with affected mothers than affected fathers is consistent. A Korean study showed that the risk of gastric cancer was higher in subjects with an affected mother than an affected father (OR, 3.8; 95% CI, 1.5 to 9.6 vs. OR, 2.9; 95% CI, 1.5 to 5.6) [18]. Similarly, another Korean study reported that gastric cancer patients with a maternal history had an overall larger number of affected relatives than those with an affected father, siblings, or offspring [63]. The reason for the increased risk with a history in the maternal line is unclear. The fact that maternal dietary practices strongly influence the dietary preference and nutritional status of the offspring may contribute to the maternal familial pattern. Moreover, frequent and intimate contact between mothers with their children might increase the likelihood of transmission of H. pylori infection. Further study is needed to clarify this.

The impact of family history of gastric cancer on susceptibility to gastric cancer might differ according to gender. Nagase et al. [30] reported that family history was a stronger risk factor for females than for males (OR, 4.5 for females and 1.2 for males). This was consistent with an Italian study (OR, 2.2 for females and 1.8 for males) [62] and a Korean study (OR, 3.6 for females and 2.7 for males) [18]. Yatsuya et al. [48] also reported that a positive history of gastric cancer in one or more first-degree relatives was associated with an increased risk of the disease in females, but not in males, after controlling for H. pylori infection and other confounding variables. Since gastric cancer is a male-dominant disease worldwide, a family history might be more easily detected among female cases. This may be explained by gender differences in recall or styles of reporting the family history. Genetic factors might exert a greater influence on gastric carcinogenesis in female patients with a family history.

Subjects with a single first-degree affected relative may be different from those with two or more first-degree relatives with gastric cancer in terms of lifetime gastric cancer risk, impact of familial risk, or genetic factors. The clinicopathological characteristics of gastric cancer patients with one or two or more affected relative were compared [63]. The significant risk factors for gastric cancer in subjects with a single relative with the disease were almost identical to those in the total family history-positive subjects [63]. Only alcohol consumption was excluded from the risk factors of those in the total family history-positive subjects. However, among subjects with two or more relatives with gastric cancer, TGFβ1-509 T/T, rural residency in childhood, alcohol consumption, moderate to strong spicy food ingestion and cagA positivity were risk factors for gastric cancer [63]. Alcohol consumption was associated with a more marked increase in gastric cancer risk in the group with two or more affected relatives than in the group with a single affected relative [63]. Similarly, it has been reported that matrix metalloproteinase 9 gene polymorphisms are associated with a history of gastric cancer in multiple family members [61]. This implies that ‘gastric cancer patients with a family history’ is a heterogeneous group that requires characterization and stratification. Thus, a detailed family history assessment of cancer patients, including the number of affected first-degree relatives, is needed to increase our understanding of familial or hereditary gastric cancer and identify genetic risk factors. Selection of patients with multiple affected relatives will facilitate evaluation of familial or hereditary cancer. However, this approach has a limitation since some patients with a single affected relative could, in future, be transferred to the group with two or more affected relatives. Recently, the Japanese National Cancer Center developed a prediction model for estimating the cumulative probability of gastric cancer occurrence based on a cohort of 19,028 individuals, using demographic and clinical variables, including a family history of gastric cancer and biological information (serum anti-H. pylori immunoglobulin G titers, levels of pepsinogen I and pepsinogen II) [64]. Further prospective studies at a nationwide level are necessary to identify individuals with a family history who are at very high risk of gastric cancer.

The onset of malignancy in affected relatives of young age is generally believed to be associated with a higher risk for other family members. The National Cancer Center in Korea reported that gastric cancer patients with a parent diagnosed before 50 years of age developed gastric cancer approximately 10 years earlier than individuals without a family history of gastric cancer [65]. Interestingly, early diagnosis of gastric cancer was more frequent in patients with an affected father. That is, the mean age at diagnosis in patients with a paternal history was 54.4 ± 10.4 years, which was significantly younger than in those without a family history (58.1 ± 12.0 years, p < 0.001) [65]. However, this finding was not the case in patients who had an affected mother (57.2 ± 10.0 years) or sibling (62.2 ± 9.8 years) [65]. This result is consistent with a report that gastric cancer patients with an affected father were younger than those with an affected mother (mean age, 57.0 ± 11.4 years vs. 62.2 ± 9.2 years, p = 0.012) [63]. Gastric cancer patients with both parents affected were younger than those with one affected parent, suggesting an earlier age distribution of familial cases [63]. The early onset of gastric cancer in parents seems to be associated with the age of gastric cancer diagnosis (or onset) in their offspring.

A separate entity, ‘early onset gastric cancer,’ is defined as gastric cancer presenting at the age of ≤ 45 years. It is characterized by a poorer prognosis in young patients, a female preponderance, and more frequent occurrence of diffuse-type cancer [66-68]. Some early onset gastric cancer cases are inherited gastric cancer syndromes [66], of whom < 10% have a family history [68]. The possibility that those with certain single genetic predisposition (inherited gastric cancer syndrome) may be incorporated into general gastric cancers cases with family history was not excluded. There is a reason why detailed information including ages at diagnosis, histology of cancer and pedigree was essential to study gastric cancers with family.

Intestinal-type gastric cancer is believed to undergo multistage carcinogenesis through AG and IM [69]; thus, which may be more frequent in subjects with a family history. According to a meta-analysis of six studies, the rates of AG and IM among subjects with family history of gastric cancer were 2.2- and 1.98-fold higher, respectively, than in subjects without a family history [15]. However, a study from Iran in 2012 reported that a family history of gastric cancer was associated with an increased incidence of IM, but not AG [70]. In addition, Oh et al. [71] reported that first-degree relatives had an adjusted OR of 2.69 (95% CI, 1.1 to 6.8; p = 0.037) for antral IM in males in a multivariable regression analysis, but there was no such effect on AG. Indeed, analyses of endoscopic observations of 4,023 patients undergoing health screenings in Korea have showed that the risk factors for IM were similar to those of AG, but dairy product consumption (OR, 1.4) and a family history of gastric cancer (OR, 1.5) were associated only with IM [12]. According to a recent comprehensive study of 123 gastric cancer patients with a family history and 639 age- and sex-matched gastric cancer patients without a family gastric cancer history, the rate of IM in the body among patients < 50 years old with a family history was higher than that of the patients without a family history (p = 0.018) [38]. Therefore, IM occurs more frequently among individuals with a family history [12,15,71].

The prognosis of a gastric cancer patient with affected relatives tends to be better than that of a patient without a family history [36,72,73]. According to a report from Korea, many gastric cancer patients with a family history exhibited shallow gastric cancer infiltration [72]. The National Cancer Center in Korea reported that patients with a family history showed better prognostic outcomes, including disease-free survival rate, recurrence-free survival rate, and overall survival rate. Interestingly, a significant prognostic improvement was observed, particularly in those with stages III and IV gastric cancer [73]. While only 55.1% of gastric cancer patients without a family history were diagnosed with intestinal-type, 71.8% of family history-positive gastric cancer patients had intestinal-type gastric cancers (p = 0.015) [73]. This was consistent with an Italian report that 71.8% of gastric cancer patients with a family history had intestinal-type gastric cancer, compared to only 55.1% of patients without a family history [74]. This might explain, in part, the favorable prognosis of gastric cancer patients with a family history. However, a Japanese study reported that the prognosis of gastric cancer patients with a family history was worse than that of patients without a family history [75]. A report from Taiwan showed that prognosis was not affected by a family history of gastric cancer [76]. These discrepancies might be caused by differences in controlling confounding factors. A recent meta-analysis of five studies showed that family history can exert beneficial effects in gastric cancer patients [77]. Subjects undertake frequent health screenings due to their family history of gastric cancer [78], show good health-related behaviors, such as non-smoking, non-alcoholic drinking and consistent exercise, and frequently have microsatellite instability and mismatch repair proteins, which are associated with a good prognosis [73].

Although many individuals with a family history are concerned about their risk of developing gastric cancer, guidelines for assessment of the family history of individuals with gastric cancer have not been developed, unlike other common cancers. Fundamentally, there has been a lack of attention to the definition of familial gastric cancer, the characteristics of gastric cancer in patients with a family history and the molecular basis of gastric cancer in a family. ‘Familial’ often indicates only a positive family history, while ‘hereditary’ suggests alterations in specific genes.

To identify subjects with a family history at very high risk of gastric cancer is of particular interest. Subjects with a family history with current or past H. pylori infection, with two or more first-degree affected relatives, or who are female, are more likely to develop gastric cancer compared to subjects without these factors. Subjects with any first-degree affected relative who was diagnosed with gastric cancer prior to age 50 years may need early endoscopy screening.

While more attention to ‘familial gastric cancer’ is necessary to assess its characteristics, the presence of a family history has little influence on the methods used for prevention of gastric cancer. Dietary modifications such as consuming fresh vegetables and fruits, minimizing salty and spicy food consumption, avoidance of smoked food, and stopping smoking are recommended [79]. Eradicating H. pylori is important for first-degree relatives of gastric cancer patients, particularly those in their 20s and 30s, because it can prevent progression to IM [38,80].

The European guidelines suggest that operative link of gastritis assessment, operative link for gastric intestinal metaplasia, serum pepsinogen level, a serological H. pylori test and a family history of gastric cancer enable identification of those at high risk of gastric cancer [81]. This guideline recommends a gastroscopy every 3 years if a patient has broad AG or IM. In countries with a high incidence of gastric cancer, such as Korea, China, and Japan, periodic gastroscopy is recommended since it is cost-effective [82-86]. According to a Korean report in 2012, rates of early gastric cancer in subjects who undergo annual and biennial gastroscopies were 98.6% and 80.7%, respectively, and the rates of endoscopically treatable lesions were 56.9% and 33.3%, respectively [87]. In comparison, the rate of early gastric cancer in those who underwent gastroscopies at intervals greater than 2 years was 54.6% [87]. In addition, the 5-year survival rates of the three groups were 98.5%, 92.0%, and 86.1%, respectively [87]. Therefore, annual gastroscopies in those at high risk for gastric cancer enable detection of endoscopically treatable early gastric cancer [88]. Moreover, based on a recent study [89], Korean Americans have a gastric cancer risk more similar to that of Koreans than do Americans of European descent. Therefore, regular endoscopic screening for gastric cancer in Korean Americans should be considered.