RESUMO
BACKGROUND AND AIMS: Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here, we investigate the causal effects of risk factors considered in current GBC prevention programs as well as C-reactive protein (CRP) level as a marker of chronic inflammation. APPROACH AND RESULTS: We applied two-sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR-Egger regression, and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two-step MR, and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (P = 9 × 10-5 ) and Europeans (P = 9 × 10-5 ). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (P = 0.03), while higher CRP concentrations increased GBC risk in Europeans (P = 4.1 × 10-6 ). European results suggest causal effects of BMI on gallstone disease (P = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors. CONCLUSIONS: Two risk factors considered in the current Chilean program for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk.
Assuntos
Índice de Massa Corporal , Proteína C-Reativa/análise , Neoplasias da Vesícula Biliar/etiologia , Cálculos Biliares/complicações , Adulto , Fatores Etários , Chile/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Neoplasias da Vesícula Biliar/epidemiologia , Neoplasias da Vesícula Biliar/genética , Cálculos Biliares/epidemiologia , Predisposição Genética para Doença/genética , Variação Genética , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Fatores de RiscoRESUMO
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.
RESUMO
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.