Functional interpretation of noncoding genetic variants associated with complex human diseases and traits remains a challenge. In an effort to enhance our understanding of common germline variants associated with lung cancer, we categorize regulatory elements based on eight major cell types of human lung tissue. Our results show that 21.68% of lung cancer‒associated risk variants are linked to noncoding regulatory elements, nearly half of which are cell type‒specific. Integrative analysis of high-resolution long-range chromatin interactome maps and single-cell RNA-sequencing data of lung tumors uncovers number of putative target genes of these variants and functionally relevant cell types, which display a potential biological link to cancer susceptibility. The present study greatly expands the scope of functional annotation of lung cancer‒associated genetic risk factors and dictates probable cell types involved in lung carcinogenesis.

Functional interpretation of noncoding genetic variants associated with complex human diseases and traits remains a challenge. In an effort to enhance our understanding of common germline variants associated with lung cancer, we categorize regulatory elements based on eight major cell types of human lung tissue. Our results show that 21.68% of lung cancer‒associated risk variants are linked to noncoding regulatory elements, nearly half of which are cell type‒specific. Integrative analysis of high-resolution long-range chromatin interactome maps and single-cell RNA-sequencing data of lung tumors uncovers number of putative target genes of these variants and functionally relevant cell types, which display a potential biological link to cancer susceptibility. The present study greatly expands the scope of functional annotation of lung cancer‒associated genetic risk factors and dictates probable cell types involved in lung carcinogenesis.

Aged ; Diagnosis, Differential ; Fluorodeoxyglucose F18 ; Gout ; diagnostic imaging ; Humans ; Joints ; diagnostic imaging ; Male ; Melanoma ; diagnostic imaging ; secondary ; Multimodal Imaging ; Positron-Emission Tomography ; Radiopharmaceuticals ; Skin Neoplasms ; diagnostic imaging ; secondary ; Tomography, X-Ray Computed

BACKGROUND/AIMS: Endoscopic resection is a standard treatment for stage T1a esophageal cancer, with esophagectomy or radical radiation therapy (RT) performed for stage T1b lesions. This study aimed to compare treatment outcomes of each modality for clinical stage T1 esophageal cancer. METHODS: In total, 179 patients with clinical T1N0M0-stage esophageal cancer treated from 2006 to 2016 were retrospectively evaluated. Sixty-two patients with clinical T1a-stage cancer underwent endoscopic resection. Among 117 patients with clinical T1b-stage cancer, 82 underwent esophagectomy, and 35 received chemoradiotherapy or RT. We compared overall survival (OS) and recurrence-free survival (RFS) rates for each treatment modality. RESULTS: The median follow-up time was 32 months (range, 1 to 120 months). The 5-year OS and RFS rates for patients with stage T1a cancer receiving endoscopic resection were 100% and 85%, respectively. For patients with stage T1b, the 5-year OS and RFS rates were 78% and 77%, respectively, for the esophagectomy group; 80% and 44%, respectively, for the RT alone group; and 96% and 80%, respectively, for the chemoradiation group. The esophagectomy group showed significantly higher RFS than the RT alone group (p=0.04). There was no significant difference in RFS between the esophagectomy and chemoradiation groups (p=0.922). Grade 4 or higher treatment-related complications occurred in four patients who underwent esophagectomy. CONCLUSIONS: Endoscopic resection appeared to be an adequate treatment for patients with T1a-stage esophageal cancer. The multidisciplinary approach involving chemoradiation was comparable to esophagectomy in terms of survival outcome without serious complications for T1b-stage esophageal cancer.
Chemoradiotherapy ; Esophageal Neoplasms ; Esophagectomy ; Follow-Up Studies ; Humans ; Radiotherapy ; Retrospective Studies

Tumor necrosis factor-α (TNF) is well known to be involved in the immune system and ovarian inflammation. Ovarian cancer is an inflammation-related malignancy that lacks early screening strategies, resulting in late diagnosis followed by high mortality. Based on our previous data, TNF induced abundant serum amyloid A (SAA), an acute phase protein linked to inflammation, in ovarian granulosal cells. To date, the regulation and expression of SAA in ovarian cancer is not fully elucidated. Here, we investigated the relationship between TNF and SAA by comparing human normal ovarian tissues and serous ovarian tumors. We found that SAA1/2 was significantly expressed in tumor tissues, but no or trace expression levels in normal tissues. TNF was also significantly upregulated in ovarian tumor tissues compared to normal tissues. Moreover, TNF significantly increased SAA1/2 levels in human ovarian cancer cell lines, OVCAR-3 and SKOV-3, in a time-dependent manner. Since the SAA1 promoter contains two nuclear factor (NF)-κB sites, we examined whether TNF regulates SAA1 promoter activity. Deletion analysis revealed that the proximal NF-κB site (−95/−85) played a critical role in regulating TNF-induced SAA1 promoter activity. Within 2 h after intraperitoneal injection of lipopolysaccharide, a product known to stimulate release of TNF, SAA preferably localized to ovarian epithelial cells and the thecal-interstitial layers compared to granulosal cell layers. Based on Gene Expression Omnibus (GEO) database, SAA1/2 and TNF were dominantly expressed in advanced grade ovarian cancer. Taken together, the accumulation of SAA1/2 in ovarian cancer could be mediated by TNF-induced NF-κB activation.
Acute-Phase Proteins ; Amyloid* ; Cell Line ; Delayed Diagnosis ; Epithelial Cells ; Gene Expression ; Humans* ; Immune System ; Inflammation ; Injections, Intraperitoneal ; Mass Screening ; Mortality ; Necrosis ; Ovarian Neoplasms ; Serum Amyloid A Protein ; Tumor Necrosis Factor-alpha

Ovarian cancer (OC) has the highest mortality rate among gynecological malignancies. Because chemokine network is involved in OC progression, we evaluated associations between chemokine expression and survival in tumor suppressor protein p53 (TP53) wild-type (TP53WT) and mutant (TP53m) OC datasets. TP53 was highly mutated in OC compared to other cancer types. Among OC subtypes, CXCL14 was predominantly expressed in clear cell OC, and CCL15 and CCL20 in mucinous OC. TP53WT endometrioid OC highly expressed CXCL14 compared to TP53m, showing better progression-free survival but no difference in overall survival (OS). TP53m serous OC highly expressed CCL8, CCL20, CXCL10 and CXCL11 compared to TP53WT. CXCL12 and CCL21 were associated with poor OS in TP53WT serous OC. CXCR2 was associated with poor OS in TP53m serous OC, while CXCL9, CCL5, CXCR4, CXCL11, and CXCL13 were associated with better OS. Taken together, specific chemokine signatures may differentially influence OS in TP53WT and TP53m OC.
Chemokines ; Dataset ; Disease-Free Survival ; Mortality ; Mucins ; Ovarian Neoplasms* ; Tumor Suppressor Protein p53

One-fifth of cancer deaths are associated with obesity. Because the molecular mechanisms by which obesity affects the progression of ovarian cancer (OC) are poorly understood, we investigated if obesity could promote the progression of OC cells using the postmenopausal ob/ob mouse model and peritoneal dissemination of mouse ID8 OC cells. Compared to lean mice, obese mice had earlier OC occurrence, greater metastasis throughout the peritoneal cavity, a trend toward shorter survival, and higher circulating glucose and proinflammatory chemokine CXCL1 levels. Ascites in obese mice had higher levels of macrophages (Mφ) and chemokines including CCL2, CXCL12, CXCL13, G-CSF and M-CSF. Omental tumor tissues in obese mice had more adipocytes than lean mice. Our data suggest that obesity may accelerate the peritoneal dissemination of OC through higher production of pro-inflammatory chemokines and Mφ recruitment.
Adipocytes ; Animals ; Ascites* ; Chemokine CXCL1 ; Chemokines ; Glucose ; Granulocyte Colony-Stimulating Factor ; Macrophage Colony-Stimulating Factor ; Macrophages* ; Mice ; Mice, Obese ; Neoplasm Metastasis ; Obesity ; Ovarian Neoplasms* ; Peritoneal Cavity

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.
Adenocarcinoma of Lung/genetics* ; Carcinoma, Non-Small-Cell Lung/genetics* ; Carcinoma, Squamous Cell/genetics* ; Genetic Heterogeneity ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Lung Neoplasms/genetics* ; Polymorphism, Single Nucleotide