Multiregional Sequencing Analysis Reveals Extensive Genetic Heterogeneity in Gastric Tumors from Latinos

Abstract

Gastric cancer (GC) is a leading cause of cancer mortality and health disparities in Latinos. We evaluated gastric intratumoral heterogeneity using multi-regional sequencing of >700 cancer genes in 115 tumor biopsies from 32 patients, 29 who were Latinos. Analyses focused on comparisons with TCGA and on mutation clonality, druggability and signatures. We found that only ~30% of all mutations were clonal and that only 61% of the known TCGA GC drivers harbored clonal mutations. Multiple clonal mutations were found in new candidate GC drivers such as EYS, FAT4, PCDHA1, RAD50, EXO1, RECQL4, and FSIP2. The genomically stable (GS) molecular subtype, which has the worse prognosis, was identified in 48% of our Latino patients, a fraction that was >2.3-fold higher than in TCGA Asian and White patients. Only a third of all tumors harbored clonal pathogenic mutations in druggable genes, with most (93%) GS tumors lacking actionable clonal mutations. Mutation signature analyses revealed that, in microsatellite-stable (MSS) tumors, DNA repair mutations were common for both tumor initiation and progression, while tobacco, POLE, and inflammation signatures likely initiate carcinogenesis. MSS tumor progression was likely driven by aging- and aflatoxin-associated mutations, as these latter changes were usually non-clonal. In microsatellite-unstable tumors (MSI), non-clonal tobacco-associated mutations were common. Our study, therefore, contributed to advancing GC molecular diagnostics and suggests clonal status is important to understanding gastric tumorigenesis. Our findings of a higher frequency of a poor prognosis associated molecular subtype in Latinos and a possible new aflatoxin GC etiology also advance cancer disparities research.

Modifiable Risk Factors in Hispanic Adults With Gastric Cancer in the United States

“…Narasimman et al demonstrated that Hispanic patients had a higher incidence of early-onset gastric cancer compared to non-Hispanic individuals in both rural and urban areas [ 14 ]. A study by Toal et al showed that Hispanic patients with gastric cancer have a higher prevalence of molecular subtypes associated with poorer prognosis compared to Asian and White patients [ 15 ]. Additionally, studies have demonstrated that outcomes also differ between Hispanic and non-Hispanic individuals.…”

Genomic ancestry and cancer among Latin Americans

“…Additionally, new potential gastric cancer drivers, namely EYS, FAT4, PCDHA1, RAD50, EXO1, RECQL4, and FSIP2, demonstrated multiple clonal mutations. Furthermore, the GST molecular subtype, linked to a worse prognosis, was identified in 48% of Latin American patients, surpassing that of TCGA Asian and White patients by more than 2.3-fold [ 104 ]. In microsatellite-stable tumors, mutation signature analyses revealed common DNA repair mutations during both tumor initiation and progression.…”

Advancing gastric cancer precision medicine with novel genomic screens†

“…Together, these therapeutics target a relatively small subset of GCs, leaving many patients without molecularly guided therapy as an option. Moreover, high levels of GC intratumoral heterogeneity (ITH), both within the primary tumor and between primary and metastatic sites, have limited biomarker-driven clinical trial success with variable biomarker expression and an increased likelihood of genomic alterations that confer therapeutic resistance [5]. Thus, the discovery of new GC drug targets, especially those with a broad molecular subtype application, is a critical and immediate goal for cancer precision medicine.…”

“…This study provided a critical discovery for novel molecular targets for GC therapeutic development. These results highlighted druggable pathways applicable for the diffuse histological GC subtype, which is associated with a poorer prognosis, a lack of molecular targets, and worse survival than intestinal‐type tumors [5]. While long defining distinct GC clinical presentations, the Laurén histological classification of intestinal and diffuse subtypes has previously failed to demonstrate therapeutically relevant stratification [7].…”

“…Despite these advances, more work is still required to translate these discoveries into clinical usenamely, greater use of more translational preclinical cancer models and candidate drug target refinement for toxicity considerations. As previously mentioned, a major obstacle in targeted therapy clinical trial success is high ITH among GC tumors [5,7]. As the authors pointed out, the use of established GC cell lines, which are monoclonal in nature, precludes the ability to investigate the effect of ITH on therapeutic response.…”