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

Autor:	Toal TW; Genome Center, University of California, Davis, California., Estrada-Florez AP; Genome Center, University of California, Davis, California.; Grupo de Citogenética, Filogenia y Evolución de las Poblaciones, Universidad del Tolima, Ibagué, Colombia., Polanco-Echeverry GM; Genome Center, University of California, Davis, California., Sahasrabudhe RM; Genome Center, University of California, Davis, California., Lott PC; Genome Center, University of California, Davis, California., Suarez-Olaya JJ; Grupo de Citogenética, Filogenia y Evolución de las Poblaciones, Universidad del Tolima, Ibagué, Colombia., Guevara-Tique AA; Grupo de Citogenética, Filogenia y Evolución de las Poblaciones, Universidad del Tolima, Ibagué, Colombia., Rocha S; Genome Center, University of California, Davis, California., Morales-Arana A; Genome Center, University of California, Davis, California., Castro-Valencia F; Grupo de Citogenética, Filogenia y Evolución de las Poblaciones, Universidad del Tolima, Ibagué, Colombia., Urayama S; UC Davis Comprehensive Cancer Center, Sacramento, California.; Division of Gastroenterology & Hepatology, University of California, Davis, California., Kirane A; UC Davis Comprehensive Cancer Center, Sacramento, California., Wei D; Department of Pathology and Laboratory Medicine, University of California, Davis, California., Rios-Sarabia N; Unidad de Investigación en Enfermedades Infecciosas y Parasitarias, Unidad Médica de Alta Especialidad en Pediatría, Instituto Mexicano del Seguro Social, México City, México., Medrano R; Departamento de Sarcomas y Tubo Digestivo Alto, Unidad Medica de Alta Especialidad en Oncología Instituto Mexicano del Seguro Social (IMSS), México City, México., Mantilla A; Departamento de Patología, Unidad Medica de Alta Especialidad en Oncología, Instituto Mexicano del Seguro Social (IMSS), México City, México., Echeverry de Polanco M; Grupo de Citogenética, Filogenia y Evolución de las Poblaciones, Universidad del Tolima, Ibagué, Colombia., Torres J; Unidad de Investigación en Enfermedades Infecciosas y Parasitarias, Unidad Médica de Alta Especialidad en Pediatría, Instituto Mexicano del Seguro Social, México City, México., Bohorquez-Lozano ME; Grupo de Citogenética, Filogenia y Evolución de las Poblaciones, Universidad del Tolima, Ibagué, Colombia., Carvajal-Carmona LG; Genome Center, University of California, Davis, California.; UC Davis Comprehensive Cancer Center, Sacramento, California.; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, California.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2022 Nov 28; Vol. 2 (11), pp. 1487-1496. Date of Electronic Publication: 2022 Nov 28 (Print Publication: 2022).
DOI:	10.1158/2767-9764.CRC-22-0149
Abstrakt:	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. Competing Interests: S. Urayama reports other from CellMax, Noah Medical, and Olympus America outside the submitted work. No disclosures were reported by the other authors. (© 2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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