Merging Helicobacter pylori eradication and family history-based genetic counseling in patients with gastric cancer: towards an overarching approach in clinical practice

Helicobacter pylori (H. pylori) represents the prototype chronic infection of the gastric and potentially the gastrointestinal system, and it is a key model for studying microbially-induced oncogenesis in humans [1,2]. H. pylori is now a well-established risk factor for gastric cancer [3], especially through the action of certain microbial genes, such as CagA [4], whereas its eradication has been robustly linked to gastric cancer reduction, especially for those harboring non-atrophic or atrophic gastritis as precancerous lesions [5]. Although perhaps not oft-discussed in daily practice, a family history of gastric cancer is also a major contributing factor [6].

A recent study by Choi et al assessed whether H. pylori eradication can reduce the risk for gastric cancer in individuals with a family history of this cancer type in first-degree relatives [7]. The study built upon previous systematic findings that first-degree relatives of patients with gastric cancer present with a higher risk of developing gastric cancer themselves, as evidenced both by H. pylori prevalence rates per se and by markers of gastric atrophy and intestinal metaplasia [8]. In that novel study, the authors showed a statistically significant difference in the proportion of patients developing gastric cancer between those treated for H. pylori and those who did not receive any treatment (1.2% vs. 2.7%, hazard ratio 0.45, 95% confidence interval 0.21-0.94; P=0.03) [7]. These results imply that the risk posed by having a family history of gastric cancer can be mitigated by addressing an environmental (in this case, microbial) factor [7]. Nonetheless, they should be interpreted with caution, especially upon considering some methodological caveats in this study, which diminish their broader clinical usefulness (as observed in other H. pylori-related studies [9]). Specifically, the family history of gastric cancer was defined as having at least one first-degree relative with gastric cancer whose diagnosis had been histologically confirmed [7]. However, no search for variants in well-established oncogenes and tumor suppressor genes and, in turn, no stratification based on such genetic biomarkers (e.g., E-cadherin or ARID1A) were performed in that study. Doing so would have allowed a more robust genetic confirmation of gastric cancer predisposition [10-12].

Moving forward, a broader question arises, important for clinical practice and clinical cancer genetics counseling: is having a first-degree relative with gastric cancer a sufficient criterion for family history? This question is crucial, not only from a clinical, cancer genetics viewpoint, but also when viewed in the context of H. pylori. In many family settings, previous studies have observed the intrafamilial presence of phylogenetically identical H. pylori strains (as assessed by rRNA gene patterns, called ribopatterns) [13]. Regardless of whether these findings are explained by person-to-person transmission or, alternatively, by the presence of a common source of infection, they collectively highlight the potential for intrafamilial transmission of H. pylori [13]. Mother-to-child and sibling-to-sibling transmission have also been reported [14]. Therefore, could this intrafamilial transmission of H. pylori strains contribute to the family history of gastric cancer?

On this basis, future studies considering the ties between a family history of gastric cancer and H. pylori eradication should also assess the molecular subtypes (e.g., analysis of CagA and the CagA-associated EPIYA polymorphisms [15]) and potential clonality of H. pylori strains, both in the examined individuals and in their first-degree affected relatives. Such study designs could ultimately contribute to a precision oncomicrobiology approach (for further description, see [1]) and could have far-reaching implications.

H. pylori infection is a communicable disorder (i.e., an infectious disease), whereas gastric cancer is considered a chronic, non-communicable disease. Thus, the suggestion that intrafamilial transmission of H. pylori contributes to shared strain-induced common gastric cancer needs to be validated in independent settings before concrete clinical guidelines are formulated; nevertheless, the margins between the notion of communicable and non-communicable diseases would become looser if that scenario is validated. Besides, the idea that non-communicable diseases may in fact be communicable is not novel; this notion has been previously suggested in different contexts and settings [16,17].

In conclusion, the study by Choi et al highlights that H. pylori eradication is of merit even in the presence of a family history of cancer; however, the methodological criteria implemented in this study should be viewed with caution before conclusive clinical guidelines are established. More importantly, clinical gastroenterologists should work closely with both clinical molecular geneticists and clinical molecular microbiologists to offer an overarching approach in clinical practice, by concurrently considering: (a) the family’s genetic predisposition to gastric cancer; and (b) oncogenesis-related microbial genetic features of H. pylori strains isolated from these patients.