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

Author:

Toal Ted W.1ORCID,Estrada-Florez Ana P.12ORCID,Polanco-Echeverry Guadalupe M.1,Sahasrabudhe Ruta M.1,Lott Paul C.1ORCID,Suarez-Olaya John J.2,Guevara-Tique Alix A.2ORCID,Rocha Sienna1,Morales-Arana Alexa1ORCID,Castro-Valencia Fabian2,Urayama Shiro34ORCID,Kirane Amanda3,Wei Dongguang5ORCID,Rios-Sarabia Nora6ORCID,Medrano Rafael7ORCID,Mantilla Alejandra8ORCID,Echeverry de Polanco Magdalena2,Torres Javier6ORCID,Bohorquez-Lozano Mabel E.2,Carvajal-Carmona Luis G.139ORCID

Affiliation:

1. 1Genome Center, University of California, Davis, California.

2. 2Grupo de Citogenética, Filogenia y Evolución de las Poblaciones, Universidad del Tolima, Ibagué, Colombia.

3. 3UC Davis Comprehensive Cancer Center, Sacramento, California.

4. 4Division of Gastroenterology & Hepatology, University of California, Davis, California.

5. 5Department of Pathology and Laboratory Medicine, University of California, Davis, California.

6. 6Unidad de Investigación en Enfermedades Infecciosas y Parasitarias, Unidad Médica de Alta Especialidad en Pediatría, Instituto Mexicano del Seguro Social, México City, México.

7. 7Departamento de Sarcomas y Tubo Digestivo Alto, Unidad Medica de Alta Especialidad en Oncología Instituto Mexicano del Seguro Social (IMSS), México City, México.

8. 8Departamento de Patología, Unidad Medica de Alta Especialidad en Oncología, Instituto Mexicano del Seguro Social (IMSS), México City, México.

9. 9Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, California.

Abstract

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.

Funder

Universidad del Tolima

MINCIENCIAS, Colombia

Departamento Administrativo de Ciencia, Tecnología e Innovación

LOREAL-UNESCO-ICETEX-COLCIENCIAS, Colombia

Instituto Mexicano del Seguro Social and Consejo Nacional de Ciencia y Tecnología, México

American Association for Cancer Research

The Auburn Community Endowed Chair in Basic Cancer Research, U.S

HHS | NIH | National Cancer Institute

Publisher

American Association for Cancer Research (AACR)

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