Gastric cancer risk and BRCA1/2 mutations: a systematic review and meta-analysis

Gastric cancer is an aggressive and heterogeneous disease, primarily sporadic, with only 1–3% of cases being hereditary. However, gastric cancer is a component of several hereditary cancer syndromes. The BRCA1 and BRCA2 genes encode key DNA repair proteins involved in homologous recombination. Studies suggest a significantly increased risk of gastric cancer in first-degree relatives of BRCA1/2 mutation carriers. We systematically searched PubMed, Scopus, and Web of Science for relevant studies. Risk ratios (RRs) with 95% confidence intervals (CIs) were computed using DerSimonian and Laird random-effect models. Heterogeneity was assessed via I² statistics. Statistical analyses were performed using R (version 4.2.3). Fourteen studies with 160,551 patients were included, of whom 25,934 had BRCA1/2 mutations (BRCA1: 14322; BRCA2: 11612). BRCA1 and BRCA2 mutations were significantly associated with increased gastric cancer risk (RR 2.30; 95% CI: 1.33–3.97; <i>p</i> = 0.003; I² = 82% and RR 2.45; 95% CI: 1.82–3.28; <i>p</i> &lt; 0.001; I² = 25%). Among the gastric cancer patients, BRCA1 and BRCA2 mutations were associated with RRs of 3.02 (<i>p</i> = 0.101; I² = 65%) and 4.86 (<i>p</i> &lt; 0.001; I² = 0%), respectively. This meta-analysis suggests that BRCA1/2 mutation carriers have a higher risk of developing gastric cancer. Stomach cancer is one of the most common and deadly cancers worldwide. While most cases happen by chance, a small number are linked to inherited genetic changes. Two important genes, BRCA1 and BRCA2, are known for increasing the risk of breast and ovarian cancer, especially in women. However, recent studies suggest that changes in these genes might also raise the risk of stomach cancer. In this study, we reviewed and combined data from multiple previous studies to better understand the link between BRCA1/2 mutations and stomach cancer. We found that people with these mutations are more likely to develop the disease. This risk was especially clear in those with BRCA2 mutations. We also found that stomach cancer patients who carry these mutations may be more common than expected. Our findings highlight the importance of genetic testing in people with a family history of stomach cancer, even if they have not had breast or ovarian cancer. Men, who are often less likely to be tested for BRCA mutations, may also benefit from earlier screening. This research may help doctors identify high-risk individuals and offer personalized strategies for prevention, early detection, and treatment.

胃癌是一类侵袭性强、异质性显著的疾病，绝大多数为散发性病例，仅1%~3%的病例属于遗传性范畴。不过，胃癌亦是多种遗传性癌症综合征的组成部分。BRCA1与BRCA2基因编码参与同源重组（homologous recombination）的关键DNA修复蛋白。研究表明，BRCA1/2突变携带者的一级亲属罹患胃癌的风险显著升高。
本研究系统性检索了PubMed、Scopus及Web of Science数据库中的相关研究。采用德西蒙尼安-莱尔德随机效应模型（DerSimonian and Laird random-effect models）计算风险比（risk ratio, RR）及其95%置信区间（confidence interval, CI）。通过I²统计量评估研究间异质性。统计分析使用R软件（版本4.2.3）完成。
最终纳入14项相关研究，共计160551名受试者，其中25934名携带BRCA1/2突变（BRCA1突变者14322名，BRCA2突变者11612名）。BRCA1及BRCA2突变均与胃癌风险升高显著相关（BRCA1：RR=2.30，95%CI=1.33~3.97，p=0.003，I²=82%；BRCA2：RR=2.45，95%CI=1.82~3.28，p<0.001，I²=25%）。在胃癌患者亚组中，BRCA1突变与BRCA2突变对应的风险比分别为3.02（p=0.101，I²=65%）与4.86（p<0.001，I²=0%）。
本荟萃分析结果表明，BRCA1/2突变携带者罹患胃癌的风险更高。胃癌是全球范围内最常见且致死率最高的癌症之一。尽管大多数病例为偶发，但少数病例与遗传性基因改变相关。BRCA1与BRCA2这两个重要基因，因可增加乳腺癌与卵巢癌（尤其女性）的发病风险而为人熟知。然而，近期研究提示，这两个基因的突变或许也会升高胃癌的发病风险。
本研究通过汇总并整合多项既往研究的数据，以更深入地阐明BRCA1/2突变与胃癌之间的关联。研究发现，携带此类突变的人群更易罹患胃癌，其中BRCA2突变携带者的风险尤为显著。此外，我们还观察到，胃癌患者中携带BRCA1/2突变的比例或高于预期。本研究结果凸显了对有胃癌家族史的人群进行基因检测的重要性，即便这类人群并无乳腺癌或卵巢癌病史亦然。通常较少接受BRCA突变检测的男性群体，也可从早期筛查中获益。本研究可为临床医生识别高危人群、制定个体化的预防、早期筛查及治疗策略提供参考依据。