Actionable Genes and Carcinogenic Pathways for Gastric Cancer in Latinos

Gastric cancer (GC) is the fourth leading cause of cancer-related death globally. Tumor profiling has revealed actionable gene alterations that guide treatment strategies and enhance survival. Among Hispanics living in Puerto Rico (PRH), GC ranks among the top 10 causes of cancer-related death. However, the genetic mutational landscape of GC tumors from PRH remains unexplored. This study aimed to identify the most prevalent genetic alterations in GC tumors among PRH.

We examined tumor mutational profiles of GC from 106 PRH between 2015 and 2022 (provided by CARIS Life Sciences and the Precision Oncology Alliance). Next-generation sequencing data were available for 85 cases, which were categorized as hypermutated (≥ 10 mutations/megabase) or non-hypermutated (< 10 mutations/megabase).

Among the non-hypermutated cases, the most frequently mutated genes were TP53 (56.9%), CDH1 (29.2%), ARID1A (27.4%), and KMT2D (25.7%). Compared to TCGA, a majority non-Hispanic cohort, PRH had significantly higher mutational frequencies in driver genes in both intestinal type (TP53, CBLB, and MYH11) and diffuse type (CDH1, ARID1A, and KMT2D) GC.

Intestinal-type GC in PR aligns with the chromosomal instability (CIN) molecular classification, showing a higher frequency of TP53 mutations than TCGA, potentially indicating more aggressive tumor biology and poorer prognosis. Diffuse-type GC showed higher CDH1 mutations, correlating with the genomically stable (GS) classification, characterized by fewer chromosomal changes but significant genetic alterations, including those in ARID1A and KMT2D.

This study shows that the unique genetic landscape of GC tumors in this group may lead to more aggressive cases and affect treatment responses, contributing to higher mortality rates. The higher mutation rates in biomarkers related to prognosis and therapy suggest that further research might uncover additional susceptibility variants. This underscores the importance of including Hispanics in genomic studies to better understand the genetic pathways associated with the risk and progression of GC.