Interplay of homologous-recombination genes and Helicobacter pylori in gastric cancer susceptibility

Gastric cancer (GC) ranks as the 5^th most prevalent neoplasm and the 4^th primary contributor to cancer-related fatalities worldwide (1). Despite a global reduction in GC incidence, the year 2020 marked the diagnosis of 1.1 million individuals and the unfortunate occurrence of 770,000 subsequent fatalities due to this disease. Furthermore, the overall 5-year relative survival rate for individuals with GC remains diminished (2). Looking ahead to 2040, recent projections indicate a significant surge of 62% in case numbers, reaching a staggering 1.77 million, should the current rates persist (3).

In light of the well-documented correlation between Helicobacter pylori (H. pylori) infection and GC development, the International Agency for Research on Cancer (IARC) Working Group, a subsidiary of the World Health Organization (WHO), has categorized H. pylori as a Group 1 carcinogen (4). This decision was grounded in both compelling epidemiological data and solid biological plausibility (5). Despite advancing insight into the virulence factors of this bacterium, the specific causes behind differing individual susceptibilities to GC remain elusive. Among these mechanisms, cagA, a prominent gene encoding an oncogenic protein, emerges as a key factor in the context of H. pylori-related gastric carcinogenesis (6). Biological differences between the Eastern Asian and Western variants of cagA have been suggested as potential factors explaining the highest age-standardized global incidence rate of cancer attributed to H. pylori infection, particularly prevalent in East Asia (7,8). However, uncertainty remains concerning whether the factors contributing to this variation in GC incidence are solely confined to microbial biology.

Certainly, over the past few years, a growing body of evidence has emphasized the significant contribution of genetic predisposition when combined with H. pylori infection, towards influencing the risk of GC (9). In their groundbreaking publication in The New England Journal of Medicine, Usui et al. [2023] ratificate that the presence of pathogenic variants in homologous-recombination (HR) genes, combined with H. pylori infection, significantly amplifies the risk of GC in individuals with both risk factors (10). This research not only deepens our understanding of the intricate interaction but also provides valuable insights into the multifaceted etiology of GC.

Germline pathogenic variants in cancer-predisposing genes play a significant role in familial cancer risk syndromes (11). For instance, the inclination towards diffuse gastric cancer (DGC) is currently attributed to the presence of pathogenic and likely pathogenic variants (P/LP) in genes such as CDH1 and CTNNA1, resulting in the development of hereditary diffuse gastric cancer (HDGC) (12,13). Families meeting specific criteria for HDGC are recommended to undergo genetic testing. Subsequently, individuals carrying deleterious alterations in the CDH1 gene are considered potential candidates for preventive gastrectomy (14). This example illustrates how targeted screening for germline pathogenic variants in cancer-predisposing genes can identify high-risk individuals, facilitating early intervention and surveillance.

Additionally, apart from CDH1, Usui et al. identified eight genes—BRCA1, BRCA2, APC, ATM, MLH1, MSH2, MSH3, and PALB2—each harboring distinct pathogenic variants intricately linked to GC predisposition (10). These findings hold considerable significance, as targeted screening for germline pathogenic variants in cancer-predisposing genes could aid in identifying high-risk individuals who might benefit from early intervention and surveillance (15). Nevertheless, the realization of this hypothesis remains uncertain, prompting the need for subsequent clinical investigations and comprehensive cost-effectiveness analyses of these strategies.

Thereafter, the authors intriguingly demonstrated an association between H. pylori infection and pathogenic variants in HR genes regarding the susceptibility to GC [relative excess risk attributed to this interaction: 16.01; 95% confidence interval (CI): 2.22 to 29.81; P=0.02] (10). Notably, pathogenic variants within HR genes can impede DNA repair efficacy, predisposing to pro-oncogenic genetic modifications (16). In this context, the authors propose that the underlying mechanism driving this elevated risk entails genome instability induced by H. pylori infection, thereby contributing substantively to the progression of gastric carcinogenesis (10).

Indeed, upon translocation and subsequent tyrosine phosphorylation at EPIYA (Glu-Pro-Ile-Tyr-Ala) motifs, the oncogenic protein CagA relocates to the cell membrane, serving as a pathological scaffold. It disrupts various intracellular signaling pathways, leading to disturbances in cell proliferation, differentiation, and apoptosis (17). In turn, these alterations elevate the likelihood of cells acquiring pro-oncogenic genetic mutations. For instance, CagA inhibits PAR1b kinase activity, impacting the phosphorylation status of the BRCA1 gene (18,19). Consequently, this alteration contributes to an increased frequency of DNA double-strand breaks (DSBs). The observed phenotype thus underscores the potential linkage between CagA-mediated signaling disturbances and heightened genetic instability (Figure 1).

Figure 1 Basic illustration: how homologous recombination genes and H. pylori interact in gastric cancer susceptibility. Phosphorylation-triggered translocation of CagA to the inner lipid layer of the plasma membrane is depicted. Functioning as a versatile scaffold or hub protein, CagA simultaneously disrupts multiple host signaling pathways. These pathways play a pivotal role in regulating various cellular processes including proliferation, differentiation, and apoptosis. The resultant incongruent interaction between CagA and host proteins leads to oncogenic alterations in cells. The potential link between the alignment of pro-oncogenic insults and variations in cancer-predisposing host genes is proposed to be connected with the progression to gastric cancer. H. pylori, Helicobacter pylori.

Based on these findings, the authors propose that addressing the susceptibility to GC in individuals with germline pathogenic variants in cancer-related genes could be effectively achieved through the eradication of H. pylori (10). As a result, this approach holds the potential for tailored interventions encompassing prophylactic antibiotic regimens, adjustments in lifestyle factors, and vigilant surveillance. Furthermore, these potential benefits may extend to immediate family members of individuals carrying HR gene variants or those affected by GC. This cohort could benefit from proactive screening for H. pylori infection, especially considering that relatives of GC patients are commonly colonized by the most virulent H. pylori cagA genotypes, potentially elevating the risk of gastric carcinogenesis (20,21).

However, as underscored by the authors, although randomized controlled trials represent the ultimate approach for addressing these inquiries, the ethical complexities associated with the implementation of such trials within the context of H. pylori eradication and its potential impact on GC prevention warrant significant attention (10). Considering the potential contributions of the study, integrating its outcomes into clinical practice guidelines demands a rigorous assessment by experts, who must scrupulously evaluate the strengths, limitations, and applicability of the findings.

In line with any pioneering study, novel inquiries inevitably arise, prompting the need for subsequent investigations to directly address these emerging questions. Future research should delve into the precise molecular pathways and interactions that underlie the synergy between germline pathogenic variants and H. pylori infection in influencing susceptibility to GC. Additionally, exploring the role of other genetic factors and their interactions with H. pylori could provide a more comprehensive understanding of the disease’s complexity.

It is noteworthy that Usui et al. highlighted they could not accurately detect copy-number variants (CNVs) using amplicon-target sequencing and available single-nucleotide polymorphism (SNP) array data. This limitation is particularly significant due to the pivotal role CNVs can play in cancer development and predisposition (22,23). Such structural variations can cause changes in the copy count of specific genes, potentially altering gene dosage and expression levels, which in turn contribute to GC risk (24). Therefore, this aspect should be addressed in future studies.

Given the distinct variations between Western and Eastern H. pylori strains, it is crucial to initiate similar research efforts specifically focused on Western populations. In a recent genotype-driven study by Garcia-Pelaez et al., the links between CDH1 germline variations and GC were explored, revealing significant associations (25). However, there remain unexplored aspects concerning how pathogenic gene variants interact with H. pylori infection to influence cancer susceptibility. Furthermore, a noticeable gap exists in assessments in regions with lower GC rates, such as African nations, and a lack of comparative studies among East Asian countries. Conducting cross-population comparisons can significantly enhance our understanding of the interplay between HR genes and H. pylori in the context of GC development.

In conclusion, the paper “Helicobacter pylori, Homologous Recombination Genes, and Gastric Cancer” ratificate a compelling interplay between germline pathogenic variants in cancer-predisposing genes and the presence of H. pylori infection. This association significantly heightens the susceptibility to GC, indicating a prospective era wherein tailored preventive and therapeutic approaches could transform the approach to addressing this lethal ailment. The findings emphasize the vital role of interdisciplinary investigation, amalgamating genetics, microbiology, and gastrointestinal oncology, to lay the groundwork for enhanced patient outcomes. However, given the limitations of the study, the need for subsequent clinical investigations and comprehensive cost-effectiveness assessments of these approaches is underscored.

Acknowledgments

Funding: This work was supported by the Scientific Initiation Scholarship Programme (PIBIC) of Bahia State Research Support Foundation, FAPESB, Brazil (N°BOL1825/2022); and the National Council for Scientific and Technological Development, CNPq, Brazil (No. 317005/2021-9).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1570/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1570/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
2. Li Y, Feng A, Zheng S, et al. Recent Estimates and Predictions of 5-Year Survival in Patients with Gastric Cancer: A Model-Based Period Analysis. Cancer Control 2022;29:10732748221099227. [Crossref] [PubMed]
3. Morgan E, Arnold M, Camargo MC, et al. The current and future incidence and mortality of gastric cancer in 185 countries, 2020-40: A population-based modelling study. EClinicalMedicine 2022;47:101404. [Crossref] [PubMed]
4. Schistosomes, liver flukes and Helicobacter pylori. IARC Monogr Eval Carcinog Risks Hum 1994;61:1-241. [PubMed]
5. Malfertheiner P, Camargo MC, El-Omar E, et al. Helicobacter pylori infection. Nat Rev Dis Primers 2023;9:19. [Crossref] [PubMed]
6. Takahashi-Kanemitsu A, Knight CT, Hatakeyama M. Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis. Cell Mol Immunol 2020;17:50-63. [Crossref] [PubMed]
7. Freire de Melo F, Marques HS, Rocha Pinheiro SL, et al. Influence of Helicobacter pylori oncoprotein CagA in gastric cancer: A critical-reflective analysis. World J Clin Oncol 2022;13:866-79. [Crossref] [PubMed]
8. Hayashi T, Senda M, Suzuki N, et al. Differential Mechanisms for SHP2 Binding and Activation Are Exploited by Geographically Distinct Helicobacter pylori CagA Oncoproteins. Cell Rep 2017;20:2876-90. [Crossref] [PubMed]
9. Mommersteeg MC, Yu J, Peppelenbosch MP, et al. Genetic host factors in Helicobacter pylori-induced carcinogenesis: Emerging new paradigms. Biochim Biophys Acta Rev Cancer 2018;1869:42-52. [Crossref] [PubMed]
10. Usui Y, Taniyama Y, Endo M, et al. Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. N Engl J Med 2023;388:1181-90. [Crossref] [PubMed]
11. Garcia-Pelaez J, Barbosa-Matos R, São José C, et al. Gastric cancer genetic predisposition and clinical presentations: Established heritable causes and potential candidate genes. Eur J Med Genet 2022;65:104401. [Crossref] [PubMed]
12. Luo W, Fedda F, Lynch P, et al. CDH1 Gene and Hereditary Diffuse Gastric Cancer Syndrome: Molecular and Histological Alterations and Implications for Diagnosis And Treatment. Front Pharmacol 2018;9:1421. [Crossref] [PubMed]
13. Lobo S, Benusiglio PR, Coulet F, et al. Cancer predisposition and germline CTNNA1 variants. Eur J Med Genet 2021;64:104316. [Crossref] [PubMed]
14. Blair VR, McLeod M, Carneiro F, et al. Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncol 2020;21:e386-97. [Crossref] [PubMed]
15. Adib E, El Zarif T, Nassar AH, et al. CDH1 germline variants are enriched in patients with colorectal cancer, gastric cancer, and breast cancer. Br J Cancer 2022;126:797-803. [Crossref] [PubMed]
16. Stewart MD, Merino Vega D, Arend RC, et al. Homologous Recombination Deficiency: Concepts, Definitions, and Assays. Oncologist 2022;27:167-74. [Crossref] [PubMed]
17. Hatakeyama M. Structure and function of Helicobacter pylori CagA, the first-identified bacterial protein involved in human cancer. Proc Jpn Acad Ser B Phys Biol Sci 2017;93:196-219. [Crossref] [PubMed]
18. Imai S, Ooki T, Murata-Kamiya N, et al. Helicobacter pylori CagA elicits BRCAness to induce genome instability that may underlie bacterial gastric carcinogenesis. Cell Host Microbe 2021;29:941-958.e10. [Crossref] [PubMed]
19. Murata-Kamiya N, Hatakeyama M. Helicobacter pylori-induced DNA double-stranded break in the development of gastric cancer. Cancer Sci 2022;113:1909-18. [Crossref] [PubMed]
20. Queiroz DM, Silva CI, Goncalves MH, et al. Higher frequency of cagA EPIYA-C phosphorylation sites in H. pylori strains from first-degree relatives of gastric cancer patients. BMC Gastroenterol 2012;12:107. [Crossref] [PubMed]
21. Batista SA, Rocha GA, Rocha AM, et al. Higher number of Helicobacter pylori CagA EPIYA C phosphorylation sites increases the risk of gastric cancer, but not duodenal ulcer. BMC Microbiol 2011;11:61. [Crossref] [PubMed]
22. Liang L, Fang JY, Xu J. Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy. Oncogene 2016;35:1475-82. [Crossref] [PubMed]
23. Li M, Kim Y, Kim TS, et al. Assessment of copy number in protooncogenes are predictive of poor survival in advanced gastric cancer. Sci Rep 2021;11:12117. [Crossref] [PubMed]
24. Shao X, Lv N, Liao J, et al. Copy number variation is highly correlated with differential gene expression: a pan-cancer study. BMC Med Genet 2019;20:175. [Crossref] [PubMed]
25. Garcia-Pelaez J, Barbosa-Matos R, Lobo S, et al. Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes. Lancet Oncol 2023;24:91-106. [Crossref] [PubMed]