ABSTRACT
Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.
Subject(s)
Humans , Adenocarcinoma of Lung/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Squamous Cell/genetics , Genetic Heterogeneity , Genetic Predisposition to Disease , Genome-Wide Association Study , Lung Neoplasms/genetics , Polymorphism, Single NucleotideABSTRACT
BACKGROUND Only a few studies in Western countries have investigated the association between gastroesophageal reflux disease [GERD] and mortality at the general population level and they have shown mixed results
This study investigated the association between GERD symptoms and overall and cause-specific mortality in a large prospective population-based study in Golestan Province, Iran
METHODS: Baseline data on frequency, onset time, and patient-perceived severity of GERD symptoms were available for 50001 participants in the Golestan Cohort Study [GCS]
We identified 3107 deaths [including 1146 circulatory and 470 cancer-related] with an average follow-up of 6.4 years and calculated hazard ratios [HR] and 95% confidence intervals [CI] adjusted for multiple potential confounders
RESULTS: Severe daily symptoms [defined as symptoms interfering with daily work or causing nighttime awakenings on a daily bases, reported by 4.3% of participants] were associated with cancer mortality [HR 1.48, 95% CI: 1.04-2.05]
This increase was too small to noticeably affect overall mortality
Mortality was not associated with onset time or frequency of GERD and was not increased with mild to moderate symptoms
CONCLUSION: We have observed an association with GERD and increased cancer mortality in a small group of individuals that had severe symptoms. Most patients with mild to moderate GERD can be re-assured that their symptoms are not associated with increased mortality
ABSTRACT
The Gastro-Esophageal Malignancies in Northern Iran [GEMINI] research project is an example of recent progress in health research in Iran. The original aim of this project was to identify etiologic factors and prevention measures for upper gastrointestinal cancers in Northern provinces of Iran, but its achievements have gone much beyond this initial goal. GEMINI consists of several projects including cancer registries, pilot studies, case-control studies, and the Golestan Cohort Study. GEMINI has been conducted through extensive collaborations between the Digestive Disease Research Center of Tehran University of Medical Sciences with other domestic and international health organizations. The achievements of GEMINI include producing new knowledge, introducing new research methods, developing and expanding health research and health care infrastructures, investing in human resources, and increasing the awareness and knowledge of policy makers and officials at all levels about the importance of chronic diseases in Iran's health priorities. The success of GEMINI reveals the feasibility of large-scale health research studies in developing countries and serves as a successful model not only for health research in Iran, but also for similar research studies in other developing nations