Study reveals genetic risk factors for gastric cancer and their interaction with H. pylori infection

A groundbreaking case-control study conducted by international researchers at Japan’s RIKEN Center for Integrative Medical Sciences (IMS) has discovered a significant correlation between certain genetic risk factors for gastric (stomach) cancer and the presence of Helicobacter pylori infection. The study, recently published in The New England Journal of Medicine, has the potential to shape personalized genomic medicine approaches for the treatment of stomach cancer.

Stomach cancer stands as the fourth leading cause of cancer-related deaths worldwide and arises from a combination of environmental and genetic factors. In terms of environmental factors, infection by H. pylori significantly heightens the risk of developing stomach cancer. Due to the elevated virulence of H. pylori in East Asia, countries like Japan experience higher incidences of stomach cancer. On the genetic front, while hereditary gene variation contributes to our unique traits such as eye color, certain gene variants can also increase the susceptibility to diseases. For instance, individuals carrying a specific hereditary pathogenic variant of the CDH1 gene face an augmented risk of gastric cancer.

Currently, testing for the presence of pathogenic variants represents one of the strategies employed for cancer prevention, surveillance, and treatment selection. However, the absence of large-scale case-control studies, particularly ones assessing how the risk of stomach cancer varies when pathogenic variants interact with environmental factors like H. pylori, has left clinical measures uncertain. To address this crucial knowledge gap, researchers conducted a comprehensive evaluation of gastric cancer risk in a sizeable case-control study involving Japanese individuals. The study considered both pathogenic variant carriers and H. pylori infection status to shed light on effective clinical interventions.

Utilizing a genomic analysis technique initially developed at RIKEN, a collaborative team led by Yukihide Momozawa at RIKEN IMS and Keitaro Matsuo at Aichi Cancer Center conducted a comprehensive examination of DNA samples from over 11,000 stomach cancer patients and 44,000 cancer-free individuals. The focus was on studying 27 genes linked to hereditary tumors, aiming to identify genetic markers associated with an increased risk of stomach cancer.

Through their analysis, the researchers pinpointed nine genes that exhibited a strong correlation with the risk of developing stomach cancer. Subsequently, they delved into the interaction between pathogenic variants within these nine genes and the patients’ history of H. pylori infection. The findings revealed a remarkable escalation in gastric cancer risk when a pathogenic variant coincided with H. pylori infection, surpassing the risks associated with either factor individually. Notably, among the nine genes, four stood out as they encode proteins responsible for DNA repair. Lead author Yoshiaki Usui proposes that these specific pathogenic variants exacerbate the damage caused by H. pylori infection. According to Usui, H. pylori infection contributes to cancer development by fostering DNA double-strand breaks and destabilizing stomach cell DNA. When combined with genetic variants impeding proper damage repair, the risk of gastric cancer appears to be substantially heightened.

Considering the high prevalence of H. pylori infection and the challenges associated with its eradication, screening for pathogenic variants could aid in determining priority individuals for interventions. Regardless of whether individuals carry these pathogenic variants, reducing the risk of stomach cancer remains a top priority for everyone by testing for H. pylori infection and eradicating it. Matsuo emphasizes the need to ascertain the extent to which H. pylori eradication genuinely prevents cancer and determine the appropriate circumstances for its consideration.

This study forms part of a broader initiative to enhance cancer prevention and treatment through a comprehensive understanding of the interplay between environmental and genetic factors. The insights gained from this research are expected to contribute to the development of medical practice guidelines concerning gastric cancer and pathogenic variants. Moreover, they hold the potential to advance the establishment of a personalized genomic medicine framework, encompassing enhanced diagnostic accuracy, targeted therapies addressing causative genes, and more effective preventive measures for gastric cancer, as emphasized by Momozawa.

Source: RIKEN

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