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Mutational landscape of gastric adenocarcinoma in Latin America: A genetic approach for precision medicine.

ABSTRACT: Latin-America (LATAM) is the second region in gastric cancer incidence; gastric adenocarcinoma (GA) represents 95% of all cases. We provide a mutational landscape of GA highlighting a) germline pathogenic variants associated with hereditary GA, b) germline risk variants associated with sporadic GA, and c) somatic variants present in sporadic GA in LATAM, and analyze how this landscape can be applied for precision medicine. We found that Brazil, Chile, Colombia, Mexico, Peru, and Venezuela are the countries with more published studies from LATAM explicitly related to GA. Our analysis displayed that different germline pathogenic variants for the CDH1 gene have been identified for hereditary GA in Brazilian, Chilean, Colombian, and Mexican populations. An increased risk of developing somatic GA is associated with the following germline risk variants: IL-4, IL-8, TNF-α, PTGS2, NFKB1, RAF1, KRAS and MAPK1 in Brazilian; IL-10 in Chilean; IL-10 in Colombian; EGFR and ERRB2 in Mexican, TCF7L2 and Chr8q24 in Venezuelan population. The path from mutational landscape to precision medicine requires four development levels: 1) Data compilation, 2) Data analysis and integration, 3) Development and approval of clinical approaches, and 4) Population benefits. Generating local genomic information is the initial padlock to overcome to generate and apply precision medicine.

SUBMITTER: Cerrato-Izaguirre D

PROVIDER: S-EPMC9170608 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Mutational landscape of gastric adenocarcinoma in Latin America: A genetic approach for precision medicine.

Cerrato-Izaguirre Dennis D Chirino Yolanda I YI García-Cuellar Claudia M CM Santibáñez-Andrade Miguel M Prada Diddier D Hernández-Guerrero Angélica A Larraga Octavio Alonso OA Camacho Javier J Sánchez-Pérez Yesennia Y

Genes & diseases 20210424 4

Latin-America (LATAM) is the second region in gastric cancer incidence; gastric adenocarcinoma (GA) represents 95% of all cases. We provide a mutational landscape of GA highlighting a) germline pathogenic variants associated with hereditary GA, b) germline risk variants associated with sporadic GA, and c) somatic variants present in sporadic GA in LATAM, and analyze how this landscape can be applied for precision medicine. We found that Brazil, Chile, Colombia, Mexico, Peru, and Venezuela are th ...[more]

PMID: 35685475

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Project description:BackgroundCancer is a somatic evolutionary disease and adenocarcinomas of the stomach and gastroesophageal junction (GC) may serve as a two-dimensional model of cancer expansion, in which tumor subclones are not evenly mixed during tumor progression but rather spatially separated and diversified. We hypothesize that precision medicine efforts are compromised when clinical decisions are based on a single-sample analysis, which ignores the mechanisms of cancer evolution and resulting intratumoral heterogeneity. Using multiregional whole-exome sequencing, we investigated the effect of somatic evolution on intratumoral heterogeneity aiming to shed light on the evolutionary biology of GC.MethodsThe study comprised a prospective discovery cohort of 9 and a validation cohort of 463 GCs. Multiregional whole-exome sequencing was performed using samples form 45 primary tumors and 3 lymph node metastases (range 3-10 tumor samples/patient) of the discovery cohort.ResultsIn total, the discovery cohort harbored 16,537 non-synonymous mutations. Intratumoral heterogeneity of somatic mutations and copy number variants were present in all tumors of the discovery cohort. Of the non-synonymous mutations, 53-91% were not present in each patient's sample; 399 genes harbored 2-4 different non-synonymous mutations in the same patient; 175 genes showed copy number variations, the majority being heterogeneous, including CD274 (PD-L1). Multi-sample tree-based analyses provided evidence for branched evolution being most complex in a microsatellite instable GC. The analysis of the mode of evolution showed a high degree of heterogeneity in deviation from neutrality within each tumor. We found evidence of parallel evolution and evolutionary trajectories: different mutations of SMAD4 aligned with different subclones and were found only in TP53 mutant GCs.ConclusionsNeutral and non-neutral somatic evolution shape the mutational landscape in GC along its lateral expansions. It leads to complex spatial intratumoral heterogeneity, where lymph node metastases may stem from different areas of the primary tumor, synchronously. Our findings may have profound effects on future patient management. They illustrate the risk of mis-interpreting tumor genetics based on single-sample analysis and open new avenues for an evolutionary classification of GC, i.e., the discovery of distinct evolutionary trajectories which can be utilized for precision medicine.

Project description:PurposeLatin America is one of the regions with the highest incidence of gastric cancer. Even though, there are not reports about the patterns of pleuro-pulmonary metastases in patients with gastric adenocarcinoma treated with curative intent and the prognosis according to each dissemination pattern.Material and methodsWe conducted a retrospective analysis of patients with gastric adenocarcinoma treated with curative intent at the National Cancer Institute (INC) between 2010 and 2017. Demographic variables, variables associated with the primary disease and variables associated with the presence of pleuro-pulmonary opacities and metastases were collected. A univariate and multivariate logistic regression analysis was performed and survival curves were presented using the Kaplan Meier method and compared using the log-rank test. A Cox regression model was performed for multivariate analysis for overall survival.ResultsThe study included 450 patients, 51.3% were male and the median age was 63 years. Intestinal adenocarcinoma was the most frequent histological subtype, in 261 cases (58.0%). Gastric cancer initial pathological stage was stage I in 23.3% of the patients, stage II in 19.3% and stage III in 53.6%. During a median follow-up of 31.9 months, 37 (8.2%) patients developed pleuro-pulmonary opacities; among those, 14 (3.1%) met the criteria for pleuro-pulmonary metastases: 6 (1.3%) had lymphangitic metastasis, 4 (0.9%) had a mixed pattern of pleural and lung nodules, 3 (0.7%) had pleural metastasis, and only one (0.2%) had hematogenous metastasis. The median OS was 114.5 months for the entire cohort and 38.2 (95%CI, 19.2-57.2) months for patients with pleuro-pulmonary metastases. Patients with pleural metastasis and lymphangitic carcinomatosis had median survival of 24.3 (95%CI, 0.01-51.0) and 26.4 (95%CI, 18.2-34.7) months, respectively.Conclusionsincidence of pleuro-pulmonary metastases in patients with gastric adenocarcinoma treated with curative intention was low. In our series, lymphangitic carcinomatosis was the main pattern of dissemination; meanwhile, hematogenous metastasis was rare and patients with pleural carcinomatosis had the lowest median survival.

Dataset Information

Mutational landscape of gastric adenocarcinoma in Latin America: A genetic approach for precision medicine.

Publications

Mutational landscape of gastric adenocarcinoma in Latin America: A genetic approach for precision medicine.

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