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.

Helicobacter pylori have coevolved with mankind since its origins, adapting to different human groups. In America H. pylori has evolved in several subpopulations specific for regions or even countries. In this study we analyzed the genome of 163 Colombian strains along with 1,113 strains that represent worldwide H. pylori populations to better discern the ancestry and adaption to Colombian people. Population structure was inferred with FineStructure and chromosome painting identifying the proportion of ancestries in Colombian isolates. Phylogenetic relationship was analyzed using the SNPs present in the core genome. Also, a Fst analysis was done to identify the gene variants with the strongest fixation in the identified Colombian subpopulations in relation to their parent population hspSWEurope. Worldwide, population structure analysis allowed the identification of two Colombian subpopulations, the previously described hspSWEuropeColombia and a novel subpopulation named hspColombia. In addition, three subgroups of H. pylori were identified within hspColombia that follow their geographic origin. The Colombian H. pylori subpopulations represent an admixture of European, African and Native indigenous ancestry; although some genomes showed a high proportion of self-identity, suggesting a strong adaption to these mestizo Colombian groups. The Fst analysis identified 82 SNPs significantly fixed in 26 genes of the hspColombia subpopulation that encode mainly for outer membrane proteins and proteins involved in central metabolism. The strongest fixation indices were identified in genes encoding the membrane proteins HofC, HopE, FrpB-4 and Sialidase A. These findings demonstrate that H. pylori has evolved in Colombia to give rise to subpopulations following a geographical structure, evolving to an autochthonous genetic pool, drive by a positive selective pressure especially on genes encoding for outer membrane proteins.

Background: Infection with Helicobacter pylori is recognized as the main risk factor for gastric cancer (GC); the clinical outcome of this infection is variable and partially depends on the virulence of the infective strain. This study characterizes H. pylori virulence genes in patients with diverse gastric lesions, from preneoplasia to GC, from a South American region with high GC mortality rates.Methods: We studied the virulence profiles of H. pylori strains to colonize the antrum of 318 patients with non-atrophic gastritis (NAG), 58 patients with preneoplastic lesions (PN), and 90 with GC from Ibagué, Colombia. The presence of 16S rDNA, the cagA and cagE genes, and the vacA s1, s2, m1, and m2 alleles were determined by PCR.Results: H. pylori infection was detected in 44% of all patients, 41.2% in NAG, 43.1% in PN and 54.4% of GC patients (p= 0.0813). cagA and cagE genes were significantly more frequent in and GC than in NAG (p= <.0001). The vacA s1m1 haplotype was significantly more frequent in PN (68%) and GC (65.3%) than in NAG (37.4%). The frequency of vacA s2m2 haplotype decreased significantly from NAG (42.7%) to PN (12%) and this to GC (4.1%). A total of 23 different genotypes were identified, with cagA+/cagE+/vacA s1m1 (84/205) as the more frequent in PN and GC and cagA-/cagE-/vacA s2m2 in NAG (49/205).Conclusions: In the population studied, vacA s2m2 was identified as a significant marker for protection against PN and GC, and genotype cagA+/cagE+/vacA s1m1 as a marker for increased GC risk. We also found that patients with PN and GC had a higher frequency of cagA+/cagE+/vacA s1m1 H. pylori strains known to be aggressive.

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

<p>Spreadsheet of pan-cancer panel gene composition, with citation codes</p>