Stomach Cancer Risk Lingers for Generations in Japanese American Families

Gastric cancer has long been known as a disease of geography. It is the fifth most commonly diagnosed cancer in the world and the fourth leading cause of cancer death, yet its burden is distributed strikingly unevenly across the globe, with incidence rates in Asia far exceeding those in Western countries. Within the United States, the same pattern repeats itself along racial and ethnic lines: people of Asian, Black, and Hispanic background experience roughly double the incidence seen among non-Hispanic White individuals. A new analysis of one of the largest and longest-running multiethnic health studies in America now adds a crucial layer of nuance to that picture, showing that the elevated risk carried by people of Japanese ancestry does not simply vanish when families leave Japan. Instead, it fades slowly, generation by generation, but never quite disappears.

The study, published in the journal Cancer Causes & Control, drew on the Multiethnic Cohort Study, a prospective population-based investigation that enrolled more than 215,000 residents of Hawaii and California between 1993 and 1996. Participants aged 45 to 75 completed detailed baseline questionnaires covering diet, medications, occupation, physical activity, family history of cancer, and immigration history. The research team, led by Haejin In of the Rutgers Cancer Institute together with Meira Epplein of Duke University, restricted their analysis to individuals who identified as Japanese or non-Hispanic White, ultimately following 94,232 participants for a median of just over 20 years. During that time, 716 primary gastric cancer cases were identified through statewide SEER cancer registries in Hawaii and California.

The central innovation of the study was its use of generational immigration status, a classification built from the birthplaces of the participants and their parents. Japanese descendants were divided into four groups: those born in Japan themselves, US-born individuals with both parents born in Japan, US-born individuals with one parent born in Japan, and US-born individuals whose parents were both born in the United States. Non-Hispanic White participants served as the reference group. The researchers then used Cox proportional hazards models, with age as the time scale, to estimate how gastric cancer risk varied across these groups while adjusting for a wide range of demographic, dietary, and lifestyle variables, including education, body mass index, smoking, alcohol consumption, fruit and sodium intake, diabetes history, and family history of the disease.

The results were unambiguous. Japan-born participants had a 4.62-fold higher hazard of developing gastric cancer compared with non-Hispanic Whites. Among US-born participants, the risk declined in a clear gradient: those with both parents born in Japan had a 3.66-fold higher hazard, those with one Japan-born parent had a 3.39-fold higher hazard, and those whose parents were both born in the United States had a 2.57-fold higher hazard. The trend across generations was highly statistically significant, with a p-value for trend below 0.0001. When the two second-generation groups were combined, their pooled risk was 3.59 times that of non-Hispanic Whites, confirming a progressive attenuation of risk across generations rather than a sharp drop confined to the transition from the first to the second generation.

Perhaps the most striking finding emerged when the researchers broke the results down by anatomical subsite. The generational association was driven almost entirely by non-cardia gastric cancer, the type that arises in the lower portions of the stomach and is most strongly linked to chronic infection with the bacterium Helicobacter pylori. First-generation Japanese descendants had a nearly six-fold increased risk of non-cardia cancer compared with non-Hispanic Whites, second-generation descendants a 4.5-fold increased risk, and third-generation descendants roughly a three-fold increased risk. When the analysis was restricted to precisely defined non-cardia subsites, the associations grew even stronger, with the first-generation hazard ratio reaching 7.13. In contrast, the associations for cardia cancer, the type arising near the junction with the esophagus, were weaker and showed no statistically significant linear trend across generations.

What could explain such a persistent, generational gradient? The leading hypothesis centers on Helicobacter pylori, the bacterium considered one of the major drivers of gastric cancer development. People who migrate from countries where H. pylori is highly prevalent are more likely to have acquired the infection during childhood, a critical window when chronic gastric inflammation can become established and shape long-term susceptibility to carcinogenesis. Persistent childhood infection is also associated with more virulent bacterial strains, such as those carrying the cagA and vacAs1m1 genes, which may disrupt early-life microbiota and immune regulation. Although H. pylori prevalence is known to decline across generations within immigrant families, the fact that third-generation Japanese descendants still face nearly triple the risk of non-Hispanic Whites suggests the bacterium alone cannot account for the full picture.

The authors point to a constellation of additional mechanisms that may be transmitted across generations or interact with the post-migration environment. Dietary acculturation is one candidate: first-generation immigrants in the cohort consumed the most sodium, a known risk factor for non-cardia gastric cancer, with intake declining in each subsequent generation, while body mass index rose across generations. Prior research has shown that a Westernized diet and lifestyle alter the gut microbiome, causing US-associated microbial communities to replace native Asian ones, with effects that intensify the longer a person lives in the United States. Studies of Japanese descendants have also documented a preference for Japanese food in the second generation giving way to Western foods in the third, alongside microbiome alterations linked to insulin resistance. Epigenetic programming may play a role as well; a cross-sectional study of Italian migrants found differences in DNA methylation compared with non-migrants even after adjusting for diet and lifestyle. Genetic variation adds yet another layer, with certain polymorphisms in inflammatory pathway genes, such as interleukin-1, reported among Japanese individuals to modify gastric cancer risk independently of H. pylori infection or smoking.

Notably, the researchers found no evidence that established risk factors, including family history of gastric cancer, education, body mass index, smoking status, and sodium intake, modified the association between generational status and cancer risk. This suggests that the generational gradient reflects distinct environmental, biological, or early-life influences rather than simple differences in these conventional exposures. The findings echo earlier work, including a landmark study by Kamineni and colleagues showing that first-generation Japanese immigrants to the United States had higher gastric cancer incidence than US Whites but lower rates than people in Japan, and a Hawaiian study by Kolonel and colleagues finding higher incidence among Japan-born than US-born Japanese residents. The new study extends this evidence with individual-level exposure data and more than two decades of prospective follow-up, advantages that registry-based studies could not provide.

The clinical implications are significant. Because the United States does not operate population-wide gastric cancer screening programs, unlike Japan and South Korea, identifying which groups stand to benefit most is essential. The marked differences in risk across immigrant generations, even within a single self-identified ethnic group, suggest that generational status could serve as a practical marker for risk-stratified screening. Prior studies have demonstrated the cost-effectiveness of gastric cancer screening among high-risk US groups, including Asian Americans undergoing upper endoscopy, opportunistic endoscopic examination during routine colonoscopy, and non-invasive biomarker approaches such as serum pepsinogen testing. Concentrating surveillance resources on the most at-risk generations could improve both the effectiveness and the accessibility of gastric cancer prevention for minority populations.

The study has limitations worth noting. Self-reported race and ethnicity may not perfectly reflect genetic ancestry, information on H. pylori infection itself was not available, and the cohort was drawn from Hawaii and California, regions with long-established Japanese American communities whose migration and acculturation patterns may differ from those of Japanese descendants elsewhere in the country. The authors call for replication in geographically diverse cohorts with detailed data on age at migration and duration of US residence. Still, the core message stands: the legacy of where a family came from, and when, is written into cancer risk for at least three generations. Understanding these transgenerational determinants, the authors argue, could reshape how the United States screens, detects, and prevents one of the world’s deadliest cancers.

Subject of Research: Generational immigration status and gastric cancer incidence among Japanese descendants in the Multiethnic Cohort Study

Article Title: Generational immigration status and gastric cancer incidence among Japanese descendants: an analysis of the Multiethnic Cohort (MEC) Study

Article References: In, H., De la Torre-Cisneros, K., Adams, A., Chen, C., Rana, B., Wilkens, L., & Epplein, M. (2026). Generational immigration status and gastric cancer incidence among Japanese descendants: an analysis of the Multiethnic Cohort (MEC) Study. Cancer Causes & Control, 37(10), Article 168. https://doi.org/10.1007/s10552-026-02250-0

Image Credits: AI Generated

DOI: 10.1007/s10552-026-02250-0

Keywords: gastric cancer, Japanese descendants, immigration generation, Multiethnic Cohort Study, Helicobacter pylori, non-cardia gastric cancer, health disparities, cancer screening, epidemiology, dietary acculturation, Cox proportional hazards, cancer risk