Research due to be presented at Digestive Disease Week 2025 shows that mutations in four genes—BRCA2, CDH1, RhoA, and TP53—are associated with an increased risk for relapse and death in people with gastric cancer.
The findings will allow clinicians to identify “high-risk patients based on their individual genetic profile, and may help guide more personalized treatment decisions in the future, in addition to adding new data that may contribute to the development of more targeted therapeutic strategies,” said Ulysses Ribeiro, MD, PhD, the study’s lead author and a professor at the Instituto do Câncer do Estado de São Paulo in Brazil.
He explained that “gastric cancer is a complex and heterogeneous disease that involves a series of genetic, epigenetic, and phenotypic changes.” Patients who have tumors with the same histologic type and stage may have different prognoses and responses to chemotherapy due to various genetic mutations and abnormal signaling pathways underlying disease progression.
Although the treatment strategies for gastric cancer have improved in recent years, the mortality rate is still high. It is therefore important to understand the genetic mutations driving this aggressive disease.
Using the Illumina MiSeq sequencing platform, Ribiero and team sequenced 21 genes from DNA extracted from 87 patients with gastric cancer who underwent curative gastrectomy. The genes selected were known to have relevant alterations associated with gastric cancer.
Analyses showed that one-third of the patients evaluated carried pathogenic variants or variants of unknown significance (VUS) in BRCA2, CDH1, RhoA, and TP53 and that these variants were associated with significantly worse outcomes.
The median overall survival (OS) of the patients has not yet been reached, but Ribeiro reported that the estimated five-year OS rate was 58.6% among patients carrying a variant in at least one of BRCA2, CDH1, RhoA, or TP53 compared with 84.7% among those with wild-type copies of the four genes. The corresponding estimated five-year disease-free survival (DFS) rates were 52.6% and 84.3%.
In multivariate analysis, the presence of a pathogenic variant and/or VUS in at least one of the four genes was associated with an independent 3.25-fold increased risk for disease recurrence or death.
Ribeiro commented that the findings add to what is already known about genes associated with breast cancer. “Although TP53 and CDH1 are already widely recognized for their involvement in gastric cancer, RhoA and BRCA are less well addressed but have been highlighted in data from the Cancer Genome Atlas,” he said.
“RhoA, for example, has been described in diffuse-type gastric cancer, which reinforces that its prognostic role should be better described. BRCA, on the other hand, is better known in the context of breast and ovarian cancer, and may need to be better understood in gastric cancer.”
Of note, the study focused on patients from a Western population—a group that has been underrepresented in gastric cancer research. Most past studies have been conducted in East Asia, where the disease is more common.
While more research is needed before these findings change medical practice, they offer a promising path forward, said Ribeiro. “We believe that these findings move us closer to more personalized treatment based on each tumor’s biology.”
