Esophageal cancer and gastric cancer are two major malignancies of the digestive tract, which pose a significant threat to human health and are ranked among the leading causes of cancer incidence and mortality worldwide (1, 2). According to literature reports, the probability of esophageal cancer patients developing other malignant tumors ranges from 8.3% to 12.6%, with the occurrence of gastric cancer being relatively rare, at only 0.8% to 1.5% (3, 4). The occurrence of dual primary cancers involving esophageal squamous cell carcinoma (ESCC) and gastric antrum adenocarcinoma is extremely rare. Moreover, these two cancers exhibit significant differences in their pathological types, pathogenesis, and treatment strategies, making it clinically challenging to distinguish them from metastatic cancers (5). In recent years, with the continuous advancement of genetic testing technologies, the molecular biological research on dual primary malignancies has gradually deepened. Previous studies have shown that specific chromosomal and genetic mutations may play an important role in the development of dual primary cancers (6). Furthermore, there are notable differences in the pathogenesis of esophageal squamous cell carcinoma and gastric antrum adenocarcinoma (7). For example, the amplification of chromosome 19p in ESCC may promote tumor invasiveness through the RAS signaling pathway (8), while in gastric antrum adenocarcinoma, the amplification of 19p is closely related to the regulation of the cell cycle (9). At present, research on esophagus-gastric dual primary cancers mainly focuses on diagnosis and treatment (10, 11), while studies on the molecular mechanisms of their development remain limited. In addition, due to the complexity of upper gastrointestinal reconstruction, surgical treatment for patients with dual primary cancers is less feasible (12). Furthermore, there are no specific treatment guidelines for these patients. Currently, a combination of radiotherapy, chemotherapy, and immunotherapy is considered the mainstream treatment strategy. However, whether common chromosomal or gene mutations found in genetic testing serve as shared driving factors requires further case studies and molecular mechanism research to provide additional evidence. This case report details a 78-year-old female patient with esophageal-gastric dual primary cancers who received sequential radiotherapy combined with immunotherapy, exploring the relationship between chromosomal variations and the pathogenesis of dual primary cancers, as well as personalized treatment plans, offering new insights for the diagnosis and treatment of such cases.

Initially, for the purpose of elucidating the pathogenesis of the patient’s esophageal squamous cell carcinoma (ESCC) and gastric antrum adenocarcinoma, tumor tissue samples were collected before treatment and underwent genetic testing. After quality control and cleaning procedures to remove low-quality reads and bases, the reliability of the data was ensured ( Supplementary Table 1 in Supplementary Material ).

Subsequently, the patient’s tumor tissue samples were thoroughly analyzed for chromosomal and genetic variations, with a focus on detecting mutations associated with cancer, including single nucleotide variants (SNVs) and copy number variations (CNVs). To ensure the reliability and clinical relevance of the data, a strict quality control standard was applied during the selection process. Specific selection criteria are shown in Supplementary Tables 2 in Supplementary Material .

The sequencing results showed that after quality control screening, key chromosomal and genetic variations were successfully identified in both esophageal squamous cell carcinoma (ESCC) and gastric antrum adenocarcinoma (GAC) tissues. Common amplifications were observed on chromosomes 19p and 21q in both cancer tissues, while differential amplifications and deletions were noted on other chromosomes (Shown in Supplementary Tables 3, 4 in the Supplementary Material ). The specific gene mutations in the two tumor tissues are shown in Supplementary Tables S9 , S10 in Supplementary Material . But no significant common gene mutations were found between the two cancers.

Although no common pathogenic gene mutations were found in the esophageal and gastric cancer tissues at the genetic level.

In this case, genetic testing revealed common chromosomal amplifications on 19p and 21q in both ESCC and GAC tissues (shown in Figure 4a ). Chromosome 19p amplification has previously been associated with increased tumor invasiveness through activation of the RAS signaling pathway in esophageal cancer and with regulation of cell cycle progression in gastric cancer. Although amplification on chromosome 21q is less frequently reported, it may significantly enhance tumor aggressiveness. Notably, RUNX1 (21q22.12) amplification is linked with increased invasiveness and metastatic potential in esophageal cancer, consistent with patterns of chromosomal instability (CIN). In gastric cancer, amplification of ETS2 (21q22.3) promotes tumor proliferation by activating the RAS/MAPK pathway, and it has also been associated with chemotherapy resistance. However, the predominant type of chromosomal alteration on 21q reported in literature remains deletion, with amplification primarily observed in advanced or aggressive cases.

Gene alterations were identified in each tumor, which are of significant clinical and research importance (Show in Figure 4b ). In ESCC tissue, amplification of genes such as WTIP and MCL1 (chromosome 19) may enhance tumor invasiveness and anti-apoptotic capacities, potentially influencing tumor progression and therapeutic response (13, 14). In GAC tissue, the deletion of APC likely activates the Wnt signaling pathway, contributing to poor prognosis, while amplification of ARRDC1 may increase invasiveness through autophagy-related mechanisms (15, 16).

Due to tumor complexity and advanced age, surgery was unsuitable. Instead, synchronous chemoradiotherapy and immunotherapy reduced tumor burden and facilitated immune clearance of residual disease.

Concurrent chemoradiotherapy is an effective treatment for esophageal cancer, showing significant efficacy and survival benefits, particularly in locally advanced patients (17, 18). It also demonstrates some efficacy in patients with synchronous esophagus-gastric dual primary cancers (19). The weekly regimen of cisplatin and albumin-bound paclitaxel combined with radiotherapy has been shown to be safe with manageable toxicity and good antitumor activity in patients with locally advanced esophageal squamous cell carcinoma (20). However, this regimen is rarely used in early-stage patients, and therefore, prognostic information is lacking. In this case, the regimen was successfully applied, significantly reducing the tumor burden and creating optimal conditions for subsequent immunotherapy to enhance immune system activation and tumor clearance.

In elderly patients, the tolerability and safety of immunotherapy are critical. In this case, immunotherapy with Sintilimab significantly improved the patient’s condition while avoiding severe treatment-related toxicities, which aligns with the results of the ORIENT-15 study (21, 22). Furthermore, Sintilimab has also demonstrated promising efficacy in perioperative treatment for locally advanced gastric antrum adenocarcinoma (23). The favorable clinical outcome highlights the efficacy of chemoradiotherapy combined with immunotherapy as a personalized approach for elderly patients with dual primary cancers lacking clear genetic targets.

This case reveals shared chromosomal mutations (19p/21q) in esophageal squamous cell carcinoma and gastric adenocarcinoma, offering initial insights into dual primary cancer pathogenesis. While no common driver genes were identified, tumor-specific mutations may inform future targeted therapies. For non-metastatic dual cancers, functionally-guided radical chemoradiotherapy was successfully implemented, using metabolic activity-based radiation tailored to tumor heterogeneity and tolerability. This precision approach achieved partial response and stable disease (RECIST 1.1), providing critical clinical evidence for optimizing dual cancer management. The findings underscore the importance of genomic profiling and adaptive radiotherapy in advancing pathogenesis research and therapeutic strategies for esophagus-gastric dual malignancies.