ABSTRACT
Gastric cancer (GC) is a heterogeneous disease. This heterogeneity applies not only to morphological and phenotypic features but also to geographical variations in incidence and mortality rates. As Chile has one of the highest mortality rates within South America, we sought to define a molecular profile of Chilean GCs (ClinicalTrials.gov identifier: NCT03158571/(FORCE1)). Solid tumor samples and clinical data were obtained from 224 patients, with subsets analyzed by tissue microarray (TMA; n = 90) and next generation sequencing (NGS; n = 101). Most demographic and clinical data were in line with previous reports. TMA data indicated that 60% of patients displayed potentially actionable alterations. Furthermore, 20.5% were categorized as having a high tumor mutational burden, and 13% possessed micro-satellite instability (MSI). Results also confirmed previous studies reporting high Epstein-Barr virus (EBV) positivity (13%) in Chilean-derived GC samples suggesting a high proportion of patients could benefit from immunotherapy. As expected, TP53 and PIK3CA were the most frequently altered genes. However, NGS demonstrated the presence of TP53, NRAS, and BRAF variants previously unreported in current GC databases. Finally, using the Kendall method, we report a significant correlation between EBV+ status and programmed death ligand-1 (PDL1)+ and an inverse correlation between p53 mutational status and MSI. Our results suggest that in this Chilean cohort, a high proportion of patients are potential candidates for immunotherapy treatment. To the best of our knowledge, this study is the first in South America to assess the prevalence of actionable targets and to examine a molecular profile of GC patients.
ABSTRACT
Gastric cancer (GC) is the world's second-leading cause of neoplastic mortality. Genetic alterations, response to treatments, and mortality rates are highly heterogeneous across different regions. Within Latin America, GC is the leading cause of cancer death in Chile, affecting 17.6 per 100,000 people and causing >3000âdeaths/y. Clinical outcomes and response to "one size fits all" therapies are highly heterogeneous and thus a better stratification of patients may aid cancer treatment and response.The Gastric Cancer Task Force is a Chilean collaborative, noninterventional study that seeks to stratify gastric adenocarcinomas using clinical outcomes and genomic, epigenomic, and protein alterations in a cohort of 200 patients. Tumor samples from the Pathology Department and the Cancer Center at UC-Christus healthcare network, Pontificia Universidad Católica de Chile will be analyzed using a panel of 143 known cancer genes (Oncomine Comprehensive Assay) at the Center of Excellence in Precision Medicine in Santiago, Chile. In addition, promoter methylation for selected genes will be performed along with tissue microarray for clinically relevant proteins (e.g., PD-L1, Erb-2, VEGFR2, among others) and Helicobacter pylori and Epstein-Barr virus status. Obtained data will be correlated to 120 clinical parameters retrieve from medical records, including general patient information, cancer history, laboratory studies, comorbidity index, chemotherapy, targeted therapies, efficacy, and follow-up.The development of a clinically meaningful classification that encompasses comprehensive clinical and molecular parameters may improve patient treatment, predict clinical outcomes, aid patient selection/stratification for clinical trials and may offer insights into future preventive and/or therapeutic strategies in patients from Latin America region. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03158571, Registered on May 18, 2017.
Subject(s)
Adenocarcinoma/classification , Stomach Neoplasms/classification , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Adult , Chile , DNA Methylation , Female , Herpesvirus 4, Human/genetics , Humans , Male , Mutation , Polymorphism, Single Nucleotide , Prognosis , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Tissue Array AnalysisABSTRACT
La participación de mecanismos epigenéticos, junto con infecciones en etapas tempranas de la vida, moldean lesiones premalignas del cáncer, en particular el cáncer gástrico, uno de los tumores más frecuentes en Chile, Latinoamérica y el mundo. El principal objetivo de este artículo, como parte de la serie de revisiones en torno a mecanismos epigenéticos en el desarrollo de enfermedades crónicas, es actualizar el rol de alteraciones epigenéticas (i.e. metilación del ADN) en el contexto de la infección crónica por H. pylori en las etapas precursoras del cáncer gástrico. Las investigaciones desarrolladas en esta área permiten delinear desafíos e interrogantes, en los cuales la pediatría tiene un papel preponderante en el desarrollo de estrategias de prevención y detección temprana de esta enfermedad.
The role of epigenetics and infectious diseases at early stages of life influence pre-malignant lesions of cancer, in particular, gastric cancer, one of the most frequent tumours in Chile, Latin America, and worldwide. This article examines the role of H.pylori and epigenetic alterations (i.e. DNA methylation) at early stages of gastric cancer and proposes, from the paediatric point of view, strategies for prevention and early detection.
Subject(s)
Humans , Child , Stomach Neoplasms/prevention & control , Helicobacter Infections/complications , Epigenesis, Genetic , Stomach Neoplasms/genetics , Stomach Neoplasms/microbiology , Chile , Helicobacter pylori/isolation & purification , Helicobacter Infections/microbiology , Helicobacter Infections/epidemiology , DNA Methylation , Early Detection of Cancer/methodsABSTRACT
The role of epigenetics and infectious diseases at early stages of life influence pre-malignant lesions of cancer, in particular, gastric cancer, one of the most frequent tumours in Chile, Latin America, and worldwide. This article examines the role of H.pylori and epigenetic alterations (i.e. DNA methylation) at early stages of gastric cancer and proposes, from the paediatric point of view, strategies for prevention and early detection.
