Recent breakthroughs in next-generation DNA sequencing have revealed four key genetic mutations—BRCA2, CDH1, RHOA, and TP53—that significantly influence the prognosis and treatment of stomach cancer. This discovery, presented at Digestive Disease Week® (DDW) 2025, marks a pivotal advancement in the shift toward personalized, molecularly informed cancer care.
Defining the Genetic Landscape of Gastric Cancer
In a study conducted by researchers at the University of São Paulo, tumor samples from 87 gastric cancer patients were analyzed using a 21-gene sequencing panel. The results demonstrated that nearly one-third of patients carried somatic mutations or variants of uncertain significance in at least one of the four identified genes. Notably, alterations in these genes were strongly correlated with disease recurrence and poor survival outcomes. For example, mutations in RHOA, a GTPase involved in cytoskeletal dynamics, were associated with a hazard ratio of 29.24 for disease recurrence, while CDH1 mutations, linked to cell adhesion dysfunction, carried a hazard ratio of 7.54.
Each gene plays a distinct role in tumor biology. BRCA2, best known for its function in DNA repair, is typically associated with hereditary breast and ovarian cancers but now appears significant in gastric cancer as well. TP53, often called the "guardian of the genome," is a tumor suppressor gene that regulates cell cycle arrest and apoptosis, and is frequently mutated across many cancer types. CDH1 encodes E-cadherin, crucial for epithelial integrity, and its loss is a hallmark of hereditary diffuse gastric cancer. Meanwhile, RHOA mutations have emerged as especially prevalent in diffuse-type gastric cancers, where they disrupt cell movement and tissue architecture.
From Molecular Insight to Precision Oncology
These genetic insights are more than academic; they represent a practical opportunity to refine how gastric cancer is diagnosed, risk-stratified, and treated. By identifying somatic mutations that drive disease progression, oncologists can more accurately tailor therapeutic strategies. This marks a departure from conventional, one-size-fits-all treatment plans toward a more individualized, mutation-informed approach.
The integration of tumor genomic profiling into standard clinical workflows offers twofold benefits: improving patient outcomes and reducing exposure to overtreatment. For instance, patients harboring BRCA2 mutations might benefit from DNA repair-targeted therapies, while those with CDH1 alterations could be candidates for intensified surveillance or prophylactic interventions.
Importantly, this study reinforces the clinical value of molecular subtyping. As highlighted in DDW’s 2025 presentation, implementing genomic data into real-time care enables a level of therapeutic precision previously unattainable with histological analysis alone.
A New Era for Gastric Cancer Care
While further validation in larger cohorts is warranted, the evidence thus far suggests that profiling tumors for mutations in BRCA2, CDH1, RHOA, and TP53 could soon become standard in gastric cancer management. Doing so allows clinicians to predict disease behavior more accurately and apply therapies that directly address the molecular drivers of malignancy.
As our understanding of cancer genomics continues to evolve, this study stands as a compelling example of how translational research can reshape clinical practice. By embracing the principles of precision medicine, the field of gastro-oncology moves closer to its ultimate goal: improving survival while preserving quality of life for patients battling one of the world’s most challenging cancers.