Nora Rios-Sarabia

Background: The metabolome of COVID-19 patients has been studied sparsely, with most research focusing on a limited number of plasma metabolites or small cohorts. This is the first study to test saliva metabolites in COVID-19 patients in a comprehensive way, revealing patterns significantly linked to disease and severity, highlighting saliva’s potential as a non-invasive tool for pathogenesis or diagnostic studies. Methods: We included 30 asymptomatic subjects with no prior COVID-19 infection or vaccination, 102 patients with mild SARS-CoV-2 infection, and 61 hospitalized patients with confirmed SARS-CoV-2 status. Saliva samples were analyzed using hydrophilic interaction liquid chromatography–mass spectrometry (HILIC-MS/MS) in positive and negative ionization modes. Results: Significant differences in metabolites were identified in COVID-19 patients, with distinct patterns associated with disease severity. Dipeptides such as Val-Glu and Met-Gln were highly elevated in moderate cases, suggesting specific protease activity related to SARS-CoV-2. Acetylated amino acids like N-acetylserine and N-acetylhistidine increased in severe cases. Bacterial metabolites, including muramic acid and indole-3-carboxaldehyde, were higher in mild–moderate cases, indicating that oral microbiota differs according to disease severity. In severe cases, polyamines and organ-damage-related metabolites, such as N-acetylspermine and 3-methylcytidine, were significantly increased. Interestingly, most metabolites that were reduced in moderate cases were elevated in severe cases. Conclusions: Saliva metabolomics offers insightful information that is potentially useful in studying COVID-19 severity and for diagnosis.

Spreadsheet of sample mean sequencing depths

PDF file of supplementary methods and materials, and supplementary figures and tables

Spreadsheet of counts of patients with SNV/indel mutations in each gene

PDF file of supplementary methods and materials, and supplementary figures and tables

Gastric cancer is a leading cause of cancer mortality and health disparities in Latinos. We evaluated gastric intratumoral heterogeneity using multiregional sequencing of >700 cancer genes in 115 tumor biopsies from 32 patients, 29 who were Latinos. Analyses focused on comparisons with The Cancer Genome Atlas (TCGA) and on mutation clonality, druggability, and signatures. We found that only approximately 30% of all mutations were clonal and that only 61% of the known TCGA gastric cancer drivers harbored clonal mutations. Multiple clonal mutations were found in new candidate gastric cancer 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 nonclonal. In microsatellite-unstable tumors, nonclonal tobacco-associated mutations were common. Our study, therefore, contributed to advancing gastric cancer 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 gastric cancer etiology also advance cancer disparities research.Significance:Our study contributes to advancing our knowledge of gastric carcinogenesis, diagnostics, and cancer health disparities.

Gastric cancer is a leading cause of cancer mortality and health disparities in Latinos. We evaluated gastric intratumoral heterogeneity using multiregional sequencing of >700 cancer genes in 115 tumor biopsies from 32 patients, 29 who were Latinos. Analyses focused on comparisons with The Cancer Genome Atlas (TCGA) and on mutation clonality, druggability, and signatures. We found that only approximately 30% of all mutations were clonal and that only 61% of the known TCGA gastric cancer drivers harbored clonal mutations. Multiple clonal mutations were found in new candidate gastric cancer 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 nonclonal. In microsatellite-unstable tumors, nonclonal tobacco-associated mutations were common. Our study, therefore, contributed to advancing gastric cancer 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 gastric cancer etiology also advance cancer disparities research.Significance:Our study contributes to advancing our knowledge of gastric carcinogenesis, diagnostics, and cancer health disparities.

Spreadsheet of counts of patients with SNV/indel mutations in each gene

Spreadsheet of pan-cancer panel gene composition, with citation codes

Spreadsheet of sample mean sequencing depths