Abstract
BRCA1 and BRCA2 carriers may be at increased risk for gastric cancer; however, the mechanisms of gastric carcinogenesis remain poorly understood. We sought to determine the prevalence of gastric cancer risk factors Helicobacter pylori (H. pylori) infection and gastric intestinal metaplasia (GIM) among BRCA1/2 carriers to gain insight into the pathogenesis of gastric cancer in this population. A total of 100 unselected BRCA1/2 carriers who underwent endoscopic ultrasound from March 2022 to March 2023 underwent concomitant upper endoscopy with nontargeted gastric antrum and body biopsies. The study population (70% women; mean age 60.1 years) included 66% BRCA2 carriers. H. pylori was detected in one (1%) individual, 7 (7%) had GIM, 2 (2%) had autoimmune atrophic gastritis, and no gastric cancers were diagnosed. Among BRCA1/2 carriers, H. pylori prevalence was low and GIM prevalence was similar to that in the general population; however, identification of H. pylori or GIM may help inform future gastric cancer risk management strategies in BRCA1/2 carriers.
Introduction
Mounting evidence over the last two decades suggests that carriers of pathogenic germline variants (PGVs) in BRCA1 or BRCA2 (BRCA1/2 carriers) are at increased risk for gastric cancer (refs. 1–5). BRCA2 carriers appear to be at higher risk for gastric cancer than BRCA1 carriers, with a 2022 multinational study reporting relative risks of gastric cancer of 2.17 (95% confidence interval, 1.25–3.77) and 3.69 (95% confidence interval, 2.40–5.67) among BRCA1 and BRCA2 carriers, respectively, compared with the general population (5). However, the mechanisms of gastric carcinogenesis among BRCA1/2 carriers remain poorly understood (3). A recent study demonstrated an additive interaction of Helicobacter pylori (H. pylori) infection and PGVs in homologous recombination genes (BRCA1/2, ATM, and PALB2) with respect to gastric cancer risk, with carriers of PGVs in homologous recombination genes that were infected with H. pylori having a nine-fold higher cumulative risk of gastric cancer at age 85 compared to non-infected PGV carriers (6). This suggests that H. pylori drives the development of at least a subset of gastric cancers in BRCA1/2 carriers (6). However, fundamental questions persist about gastric cancer pathogenesis in this population, including whether BRCA1/2-associated gastric cancer develops through the progression of gastric intestinal metaplasia (GIM) to invasive carcinoma (i.e., the Correa cascade; ref. 7) or via an alternative route.
Furthermore, the prevalence of H. pylori and the rate of other gastric cancer risk factors, such as GIM, among BRCA1/2 carriers have not been established. Additionally, recent studies reporting gastric cancer risk in BRCA1/2 carriers have had limitations, including that some of the studies were conducted in Eastern populations (4, 6), in which H. pylori and gastric cancer are more prevalent than in Western populations (8, 9), and reliance on self-reporting of familial gastric cancers (5), which in the presence of a BRCA1/2 PGV may be confounded by ovarian cancer mimicking primary gastric cancer. Given these uncertainties, gastric cancer screening is currently not part of BRCA1/2 management guidelines (10). In this prospective study, we aimed to determine the prevalence of H. pylori infection and GIM in consecutive BRCA1/2 carriers undergoing endoscopic ultrasound (EUS) for pancreatic cancer surveillance to better understand the contributors to gastric cancer pathogenesis in these high-risk individuals.
Methods
One hundred consecutive BRCA1/2 carriers who underwent EUS for pancreatic cancer surveillance at the University of Pennsylvania from March 2, 2022, to March 22, 2023, underwent concomitant upper endoscopy with four non-targeted gastric antrum and body biopsies. All individuals provided written informed consent for one or more pancreatic cancer surveillance protocols (NCT02478892, NCT02000089, and NCT04970056) approved by the University of Pennsylvania Institutional Review Board, and the study was conducted in accordance with the US Common Rule. Biopsies were performed with jumbo forceps regardless of the appearance of the gastric mucosa and were analyzed as routine clinical samples by expert gastrointestinal pathologists. Medical records of BRCA1/2 carriers were reviewed to collect demographic information, alcohol use history, smoking history, personal history of cancer, and family history of gastric cancer as reported by the carrier and not confirmed by medical records. The primary outcomes were prevalence of H. pylori and/or GIM. The secondary outcomes included rates of other pathologic findings in gastric biopsy specimens, personal history of cancer, and family history of gastric cancer.
Primary and secondary outcomes were calculated for the combined population and stratified by BRCA1/2 gene. Rates of GIM were additionally stratified by anatomic location. Given similar clinical significance, gastritis, chronic inflammation, and reactive changes were analyzed as a combined variable. Outcomes were compared between BRCA1 and BRCA2 carriers, and baseline characteristics were compared between those who tested positive for H. pylori and/or GIM and those who tested negative for both. Continuous variables were confirmed to be normally distributed and reported as mean and SD. Standard t tests were used to compare the means of continuous variables. All binary and categorical variables of interest were reported as proportions and counts. Pearson χ2 tests were used to estimate P-values comparing binary and categorical variables. All analyses were performed using Stata/IC 15.0 or RStudio statistical programs.
Data availability
The data generated in this study are available upon request from the corresponding author.
Results
Of the 100 consecutive BRCA1/2 carriers undergoing EUS, the majority (66%) were BRCA2 carriers (Table 1). The mean age was 60.1 years (SD 9.0 years), 70% were female, and 96% were White; 75% reported active alcohol use, and 35% reported active or former smoking. None had a history of gastric cancer, but 47% had a history of non-gastric cancer, with breast cancer being most common (36%). Fourteen (14%) carriers reported a family history of gastric cancer.
Table 1.
Baseline characteristics of the BRCA1/2 study cohort.
| Characteristic | BRCA1/2 carriers (n = 100) |
|---|---|
|
| |
| BRCA1/2 PGVs | |
| BRCA1, n (%) | 34 (34%) |
| BRCA2, n (%) | 66 (66%) |
| Age (years), mean (SD) | 60.1 (9.0) |
| Female, n (%) | 70 (70%) |
| White, n (%) | 96 (96%) |
| Any active alcohol consumption, n (%) | 75 (75%) |
| Active or former smoking, n (%) | 35 (35%) |
| Personal history of gastric cancer, n (%) | 0 (0%) |
| Personal history of non-gastric cancer, n (%) | 47 (47%) |
| Anal cancer, n (MAD) | 2 (60) |
| Bladder cancer, n (MAD) | 1 (61) |
| Breast cancer, n (MAD) | 36 (48) |
| Colorectal cancer, n (MAD) | 1 (47) |
| Melanoma, n (MAD) | 2 (62) |
| Ovarian cancer, n (MAD) | 3 (56) |
| Prostate cancer, n (MAD) | 2 (52) |
| Thyroid cancer, n (MAD) | 5 (42) |
| Uterine cancer, n (MAD) | 1 (52) |
| Family history of gastric cancer, n (%) | 14 (14%) |
Abbreviation: MAD, mean age at diagnosis (years).
Only one individual (1%) was H. pylori positive (Table 2), with H. pylori detected in both the antrum and the body, whereas seven (7%) individuals had GIM, including four (12%) BRCA1 carriers and three (5%) BRCA2 carriers (P = 0.180). Of the four BRCA1 carriers with GIM, two had GIM detected only in the antrum and two had GIM detected only in the body. Likewise, of the three BRCA2 carriers with GIM, two had GIM detected only in the antrum and one had GIM detected only in the body. GIM was not detected in both the antrum and the body in any BRCA1/2 carrier or in the individual who tested positive for H. pylori.
Table 2.
Prevalence of H. pylori and GIM among BRCA1/2 carriers.
| Gastric biopsy pathology findings | BRCA1/2 carriers (n = 100) | BRCA1 carriers (n = 34) | BRCA2 carriers (n = 66) | P-value |
|---|---|---|---|---|
|
| ||||
| Gastritis, chronic inflammation, and/or reactive changes, n (%) | 79 (79.0%) | 27 (79.4%) | 52 (78.8%) | 0.940 |
| H. pylori, n (%) | 1 (1.0%) | 1 (2.9%) | 0 (0%) | 0.160 |
| GIM, n (%) | 7 (7.0%) | 4 (11.7%) | 3 (4.5%) | 0.180 |
| Detected in gastric antrum, n (%) | 4 (4.0%) | 2 (5.9%) | 2 (3.0%) | 0.490 |
| Detected in gastric body, n (%) | 3 (3.0%) | 2 (5.9%) | 1 (1.5%) | 0.230 |
| Detected in gastric antrum and gastric body, n (%) | 0 (0%) | 0 (0%) | 0 (0%) | – |
| AAG,a n (%) | 2 (2.0%) | 2 (5.9%) | 0 (0%) | 0.047 |
| Dysplasia, n (%) | 0 (0%) | 0 (0%) | 0 (0%) | – |
| Adenocarcinoma, n (%) | 0 (0%) | 0 (0%) | 0 (0%) | – |
Both cases of AAG coincided with GIM.
Additionally, 79 (79%) BRCA1/2 carriers were found to have gastritis, chronic inflammation, and/or reactive changes on nontargeted gastric biopsies. Two individuals, both BRCA1 carriers, had autoimmune atrophic gastritis (AAG; 5.9% of BRCA1 carriers vs. 0.0% of BRCA2 carriers; P = 0.047). In both cases, AAG was detected only in the gastric body along with GIM, but without active H. pylori infection. There were no individuals with gastric dysplasia or gastric cancer identified.
In the composite analysis accounting for both H. pylori and GIM status, individuals who tested positive for H. pylori and/or GIM were less likely to be White than those who tested negative for both (75% vs. 98%; P = 0.002; Table 3). However, given the small number of non-White individuals in the cohort, this result should be interpreted with caution. Age, sex, alcohol use, smoking, personal history of non-gastric cancer, and family history of gastric cancer were not associated with the detection of H. pylori and/or GIM.
Table 3.
Stratification of baseline characteristics by H. pylori and GIM status.
| Characteristic | Positive for H. pylori and/or GIM (n = 8) | Negative for H. pylori and GIM (n = 92) | P-value |
|---|---|---|---|
|
| |||
| Age (years), mean (SD) | 61.3 (11.8) | 60.0 (8.8) | 0.700 |
| Female, n (%) | 5 (62.5%) | 65 (70.7%) | 0.630 |
| White, n (%) | 6 (75.0%) | 90 (97.8%) | 0.002 |
| Any active alcohol consumption, n (%) | 6 (75.0%) | 69 (75.0%) | 1.000 |
| Active or former smoking, n (%) | 1 (12.5%) | 34 (37.0%) | 0.164 |
| Personal history of non-gastric cancer, n (%) | 5 (62.5%) | 42 (45.7%) | 0.390 |
| Family history of gastric cancer, n (%) | 0 (0%) | 14 (15.2%) | 0.230 |
Discussion
In this prospective study among consecutive unselected BRCA1/2 carriers undergoing pancreatic cancer surveillance, the prevalence of H. pylori infection and GIM was 1% and 7%, respectively. To our knowledge, this is the first study to report the rates of H. pylori and GIM among BRCA1/2 carriers.
As the prevalence of H. pylori in the US population is estimated at 35.6% overall and 18.4% to 26.2% among nonHispanic Whites (8), the low rate of H. pylori detected in our study cohort is striking and suggests that the overall prevalence of H. pylori and the risk of H. pylori acquisition are unlikely to be elevated among BRCA1/2 carriers compared with the general population in the United States. Despite rates of H. pylori being low, identification of H. pylori–positive BRCA1/2 carriers may have clinical relevance. Given the recent report of an additive interaction between PGVs in BRCA1/2 and H. pylori leading to increased gastric cancer risk (6), BRCA1/2 carriers may have heightened sensitivity to the cancer-causing mechanisms of H. pylori. H. pylori strains positive for CagA, a prevalent virulence factor associated with gastric cancer development, induce changes similar to those found in BRCA1/2-mutated cells, including double-strand DNA breaks and impairment of HR as a means of error-free DNA repair (11). Therefore, it seems plausible that BRCA1/2 carriers infected with CagA-positive strains of H. pylori may accumulate more DNA damage than infected noncarriers, potentially contributing to the increased gastric cancer risk observed in this population (12).
At this time, H. pylori testing is not currently recommended in BRCA1/2 management guidelines (10). However, given the recent evidence demonstrating that H. pylori infections and PGVs in BRCA1/2 increase the risk of gastric cancer through an additive interaction (6), and as performing noninvasive H. pylori testing (i.e., stool antigen or breath test) is easy and low-risk, we believe that one-time H. pylori testing should be considered in all BRCA1/2 carriers at the time these individuals are diagnosed as a BRCA1/2 PGV carrier. Infection with H. pylori typically occurs during childhood (13); therefore, H. pylori testing at the time of BRCA1/2 PGV diagnosis would be optimal, as there would not be added value to delaying H. pylori testing after BRCA1/2 PGV diagnosis. Additionally, we believe that H. pylori testing should be performed independent of whether there is a family history of gastric cancer. Alternatively, gastric biopsies can be performed to assess for H. pylori during any upper endoscopic procedure that is being performed on a BRCA1/2 carrier for other indications such as pancreatic cancer surveillance or evaluation of upper gastrointestinal symptoms. Although our findings suggest that the prevalence of H. pylori may be low in certain BRCA1/2 carrier cohorts, identification of any affected individuals, even if a small number, may have clinical relevance. Although current guidelines do not recommend H. pylori testing among BRCA1/2 carriers, we anticipate that future guidelines will need to address this topic as further data accumulate demonstrating an increased risk of gastric cancer among BRCA1/2 carriers, perhaps modeled similarly to the current guidelines for Lynch syndrome. Lynch syndrome is a hereditary cancer risk syndrome associated with increased gastric cancer risk, and the current guidelines recommend assessment of H. pylori via gastric biopsies on initial surveillance upper endoscopy or one-time noninvasive testing at the time of Lynch syndrome diagnosis (14).
Detection of GIM in 7% of our study cohort is similar to the prevalence of GIM in the general population (4.8%; ref. 15), which suggests that BRCA1/2 carriers may not have a substantially higher rate of GIM. However, it remains unclear at this time whether BRCA1/2 carriers with GIM are at higher risk for neoplastic progression of their GIM, which warrants further study. Likewise, although the difference in the rates of GIM among BRCA1 (12%) and BRCA2 (5%) PGV carriers was not statistically significant in our cohort, further study is needed to determine if this discrepancy reflects a true underlying difference.
Notably, nearly 80% of BRCA1/2 carriers had gastritis, chronic inflammation, and/or reactive changes noted on gastric biopsies. Although the prevalence of similar findings in the general population is not precisely known, limited data suggest that the rate of these changes in our study population may be elevated compared with that in the general population (16, 17). Although it is also plausible that chronic gastric inflammation may increase gastric cancer risk in BRCA1/2 carriers, further study is needed to confirm causation. Moreover, the rate of AAG in the study population (2%) matches the estimated prevalence of AAG in the general population of 2% (18). Although the contribution of AAG to gastric cancer risk in BRCA1/2 carriers remains uncertain, we chose to track AAG as a secondary endpoint as AAG is associated with increased risk of gastric cancer in the general population and given a small 2018 study of a cohort of individuals with Lynch syndrome in which chronic immune gastritis was detected in 71% of those with gastric cancer (18, 19).
Limitations of our study include the limited racial and ethnic diversity, which is particularly important given variations in H. pylori prevalence (20), and restriction of our study population to BRCA1/2 carriers undergoing pancreatic cancer surveillance via EUS, which may have led to an underestimation of H. pylori prevalence among BRCA1/2 carriers. Additionally, our sample size is limited and does not include any BRCA1/2 carriers with gastric cancer. Studies with larger and more diverse populations are warranted to further explore the role that H. pylori and GIM may play in gastric cancer development among BRCA1/2 carriers. Furthermore, although to our knowledge no individuals in our cohort had a known H. pylori infection preceding the study, it is conceivable that a subset of BRCA1/2 carriers could have previously had an H. pylori infection but tested negative on gastric biopsies if they underwent H. pylori treatment before the study or had prior spontaneous clearance of H. pylori (21). Future studies aimed at evaluating the prevalence of positive H. pylori serologies among BRCA1/2 carriers are warranted to better capture the burden of prior and active H. pylori infections in this population.
Conclusions
In this prospective study among unselected BRCA1/2 carriers undergoing EUS for pancreatic cancer surveillance, the prevalence of H. pylori was low and the prevalence of GIM was similar to that in the general population, suggesting that BRCA1/2 carriers may not have increased susceptibility to H. pylori or GIM. However, as H. pylori infection or GIM may confer increased gastric cancer risk, identification of this subgroup of BRCA1/2 carriers may have clinical relevance to inform gastric cancer risk management strategies. Furthermore, given recent evidence that H. pylori infections and PGVs in BRCA1/2 increase gastric cancer risk through an additive interaction (6), performing baseline H. pylori testing in BRCA1/2 carriers should be considered.
Prevention Relevance:
Evaluating the burden of H. pylori infection and GIM among BRCA1/2 carriers is warranted to better understand the mechanisms of gastric carcinogenesis and to help inform risk management strategies for gastric cancer among this at-risk population.
Acknowledgments
This study was supported by funding received by B.W. Katona from the Smith Family Research Fund and the Basser Center’s Men & BRCA Program.
Authors’ Disclosures
S. Coughlin reports other support from Invitae outside the submitted work. S.M. Domchek reports personal fees from Intellia, AstraZeneca, and GSK outside the submitted work. M.L. Kochman reports personal fees from ACI, BSC, Castle Pharmaceuticals, Medtronic, and Olympus; personal fees and other support from Endiatx, Virgo, and DCL; and other support from EndoSound, AGA Varia, and Varia outside the submitted work. B.W. Katona reports other support from Janssen, Immunovia, Epigenomics, Guardant, Freenome, Universal Diagnostics, Recursion, and Immunovia outside the submitted work. No disclosures were reported by the other authors.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data generated in this study are available upon request from the corresponding author.