Gastric cancer is a global health burden with high incidence and mortality rates with more than 1 million new cases, primarily gastric adenocarcinomas, and 768 000 deaths according to the International Agency for Research on Cancer 2020 data. Helicobacter pylori (H. pylori) infection, a prevalent bacterial infection affecting more than half of the world's population, has been identified as a major risk factor for gastric cancer. Other risk factors are poor diet, smoking, and genetic predispositions. The vast majority of gastric cancer is the consequence of these environmental exposures, and only 1% to 3% of cases are characterized as inherited gastric cancer predisposition syndromes, called hereditary diffuse gastric cancer, with a very poor prognosis. It has been reported that germline alterations in the CDH1 gene (encoding E-cadherin) or the MLH1 gene (encoding a mismatch-repair protein) are responsible for hereditary diffuse gastric cancer. The recent article by Usui et al. offers more information about a hereditary component to gastric carcinogenesis, following their study on 2 Japanese databases of more than 10 000 samples, including 27 cancer-predisposing genes. This study highlights the role of germline pathogenic variants, especially homologous-recombination genes, in the risk of this type of cancer (1).
In recent years, the role of homologous recombination deficiency (HRD), a condition characterized by an impaired DNA repair pathway, has emerged as a critical molecular event in gastric carcinogenesis. This comprehensive perspective aims to provide a detailed analysis of the intricate relationship between H. pylori infection, HRD, and gastric cancer. The following points will be considered in this article: the impact of H. pylori-induced DNA damage and chronic inflammation on homologous recombination, the mechanisms underlying HRD in gastric cancer, the interactions between H. pylori infection and HRD in gastric cancer risk, the clinical implications for diagnosis and therapy, as well as challenges and future directions for research. A thorough understanding of the interplay between H. pylori infection and HRD may pave the way for novel diagnostic markers, targeted therapies, and personalized management strategies for gastric cancer patients.
H. pylori-Induced DNA Damage and Inflammation
H. pylori infection triggers a cascade of events leading to chronic inflammation, DNA damage, and genomic instability in the gastric epithelium. The bacterium's virulence factors, such as the cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A, contribute to cellular disruption and inflammation. CagA is injected into gastric epithelial cells, leading to morphological changes and activation of various pro-oncogenic signaling pathways. Vacuolating cytotoxin A disrupts host cellular functions, inducing inflammatory cytokine expression and playing a role in maintaining colonization. Studies show that H. pylori infection induces double-strand breaks in the host genome, which may elicit genome instability in the infected host cells. There are 2 main pathways through which H. pylori induces double-strand breaks, by both CagA-dependent and CagA-independent mechanisms. These pathways are complex, likely to work together synergistically, and primarily target cells during the S phase of the cell cycle. Even though H. pylori's ability to induce DNA damage was discovered more than 10 years ago, our understanding of how this pathogen’s DNA damage contributes to malignant transformation has only recently emerged, thanks to the work of Usui et al. (1). The authors described that DNA damage caused by H. pylori promotes malignant transformation within a genetic context. These results illustrated that the gene-environment interaction increases disease susceptibility and underlines the critical need for H. pylori eradication, particularly in individuals who are genetically vulnerable.
Homologous Recombination Deficiency in Gastric Cancer
Homologous recombination (HR) is an essential mechanism for repairing DNA double-strand breaks. The HR pathway is susceptible to germline variants in at least 10 genes including BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK2, NBS1(NBN), PALB2, RAD51C, and RAD51D, which can lead to a hereditary predisposition to particular forms of cancer, including breast, ovarian, prostate, pancreatic, and gastric cancer (2). Moreover, Imai et al. showed that CagA/PAR1b interaction inhibits PAR1b-mediated BRCA1 phosphorylation, thereby preventing nuclear translocation of BRCA1 (3). These findings suggest a significant alteration in the choice of DNA repair pathway during H. pylori infection, leading to a diminished reliance on HR. Epigenetic modifications, including DNA methylation or histone modifications, can also silence HR genes, leading to HRD. The impaired HR pathway results in inefficient repair of DNA damage and increased genomic instability, contributing to the development and progression of gastric cancer.
Interactions of HRD and H. pylori Infection in Gastric Cancer
Usui et al. demonstrated that germline pathogenic variants in HR genes and H. pylori infection interacted to markedly increase the risk of gastric cancer in persons with both risk factors (1). Precisely, at 85 years of age, the cumulative risk of malignant transformation is 45.5% for people with both risk factors instead of 14.4% for noncarriers infected with H. pylori (Fig. 1). The occurrence of pathogenic variants in 4 genes—ATM, BRCA1, BRCA2, and PALB2—which play a crucial role in the early stages of HR, is higher than that of the CDH1 or MLH1 genes associated with the hereditary diffuse gastric cancer. If any of these 4 HR factors are missing, cells often turn to alternative methods like nonhomologous end joining, microhomology-mediated end joining, or other mechanisms that are prone to introduce mistakes into the sequence of the repaired DNA. Contrarily to these alternative pathways, the process of HR is often deemed error-free due to its ability to restore damaged DNA to its exact original sequence The authors claimed that the possible mechanism of this high risk of carcinogenesis is the genome instability caused by H. pylori infection. DNA damage caused by H. pylori-induced oxidative stress and inflammation can directly affect the HR pathway and compromise its efficiency. Thus, individuals with pathogenic variants in the HR genes that are associated with less efficacious DNA damage-repair pathways have an increased susceptibility to gastric carcinogenesis-related DNA damage due to H. pylori infection. The mechanisms underlying HRD in H. pylori-associated gastric cancer are complex and multifactorial. Understanding these mechanisms will provide valuable insights into the interplay between H. pylori infection and HRD in gastric carcinogenesis.
Interaction between H. pylori and HRD. Mutations in homologous recombination genes (blue stars) impact the repair of DNA damage induced in response to H. pylori infection and the cumulative lifetime risk (up to 85 years) of gastric cancer.
Clinical Implications of HRD and H. pylori Infection in Gastric Cancer
Understanding the clinical implications of the interaction between HRD and H. pylori infection in gastric cancer can provide valuable insights for diagnosis and therapy.
Diagnosis for hereditary gastric cancer until now has relied on the detection of variants in specific genes such as CDH1, MLH1, MSH2, or MSH6. CDH1 is a well-known gene associated with an increased risk of hereditary gastric cancer, and also breast cancer. DNA mismatch repair deficiency is commonly investigated through immunohistochemical staining, which involves analyzing the expression of MMR proteins (MLH1/PMS2, MSH2/MSH6). These proteins are also linked to Lynch syndrome, microsatellite instability, and various types of cancer including colorectal, gastric, and breast cancer. According to the study conducted by Usui et al., the occurrence of pathogenic variants in these genes is relatively low, with the highest percentage being 0.13% for the MLH1 gene (1). Furthermore, there appears to be no combined effect between these genetic variants and H. pylori infection. That is the reason why HRD can serve as a new prognostic marker for gastric cancer, indicating a higher risk of disease progression and poorer outcomes, especially in the context of H. pylori infection. Various diagnostic approaches, including next-generation sequencing, can identify germline or post-infection HRD signatures in tumors and guide treatment decisions. However, those approaches are still clinically limited. Thus, the main challenge resides in the clinical identification of HRD-positive tumors, which depends on various elements, including mutations, DNA copy scores, RNA-sequencing-based HRD signatures, and functional assays (4). The identification of HRD-positive tumors in H. pylori-positive patients may help in selecting patients who are likely to benefit from specific therapies, such as poly ADP ribose polymerase inhibitors. Poly ADP ribose polymerase inhibitors selectively target cancer cells with HRD by inhibiting the alternative DNA repair pathways, leading to synthetic lethality. Clinical trials evaluating the efficacy of poly ADP ribose polymerase inhibitors in HRD-positive gastric cancer are in progress, and preliminary results are promising (5). Furthermore, novel immunotherapeutic strategies like immune checkpoint inhibitors are being actively investigated for their potential effectiveness in HRD-positive gastric cancer. Additionally, it is essential to study the mechanisms of resistance to therapies targeting HR and explore combinational approaches to increase the efficacy of treatment.
The complex relationship between H. pylori infection, HRD, and gastric cancer warrants further investigation. The findings from Usui et al. may offer new opportunities for early detection, risk stratification, and tailored treatments, ultimately leading to improved outcomes for patients with pathogenic variants in HR genes in the link with H. pylori infection. Further evaluation needs to be investigated especially with the Western type of H. pylori in order to extend this study in a large-scale evaluation and eradication of H. pylori. Efforts to understand the intricate interplay between H. pylori infection, HRD, and gastric carcinogenesis will pave the way for precision medicine approaches in the diagnosis and treatment of gastric cancer. The development of effective therapeutic strategies targeting HRD in gastric cancer, combined with the eradication of H. pylori infection, holds great promise for reducing the burden of this disease worldwide.
Nonstandard Abbreviations
H. pylori, Helicobacter pylori; HRD, homologous recombination deficiency; CagA, cytotoxin-associated gene A; HR, homologous recombination.
Human Genes
ATM, ATM serine/threonine kinase; BARD1, BRCA1 associated RING domain 1; BRCA1, BRCA1 DNA repair associated; BRCA2, BRCA2 DNA repair associated; BRIP1, BRCA1 interacting helicase 1; CDH1, cadherin 1; CHEK2, checkpoint kinase 2; MLH1, mutL homolog 1; MSH2, mutS homolog 2; MSH6, mutS homolog 6; NBN, nibrin; PALB2, partner and localizer of BRCA2; PMS2, PMS1 homolog 2, mismatch repair system component; RAD51C, RAD51 paralog C; RAD51D, RAD51 paralog D.
Author Contributions
The corresponding author takes full responsibility that all authors on this publication have met the following required criteria of eligibility for authorship: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Nobody who qualifies for authorship has been omitted from the list.
Tra Ly Nguyen (Conceptualization-Equal, Data curation-Lead, Formal analysis-Lead, Investigation-Lead, Methodology-Lead, Project administration-Supporting, Resources-Equal, Visualization-Lead, Writing—original draft-Lead, Writing—review & editing-Equal), Francis Mégraud (Formal analysis-Equal, Project administration-Supporting, Validation-Equal, Visualization-Supporting, Writing—original draft-Supporting, Writing—review & editing-Supporting), and Christine Varon (Conceptualization-Equal, Formal analysis-Equal, Project administration-Lead, Resources-Supporting, Supervision-Lead, Validation-Equal, Visualization-Supporting, Writing—original draft-Supporting, Writing—review & editing-Equal).
Authors’ Disclosures or Potential Conflicts of Interest
Upon manuscript submission, all authors completed the author disclosure form.
Research Funding
T.-L. Nguyen is funded by the French Alliance Nationale pour les Sciences de la Vie et de la Santé and Institut National de la Santé et de la Recherche Médicale (call of project ITMO Cancer MCMP grant number ASC22021GSA).
Disclosures
None declared.
