Purpose: To understand the role of nuclear factor erythroid-2–related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) in non–small cell lung cancer (NSCLC), we studied their expression in a large series of tumors with annotated clinicopathologic data, including response to platinum-based adjuvant chemotherapy. Experimental Design: We determined the immunohistochemical expression of nuclear Nrf2 and cytoplasmic Keap1 in 304 NSCLCs and its association with patients' clinicopathologic characteristics, and in 89 tumors from patients who received neoadjuvant (n = 26) or adjuvant platinum-based chemotherapy (n = 63). We evaluated NFE2L2 and KEAP1 mutations in 31 tumor specimens. Results: We detected nuclear Nrf2 expression in 26% of NSCLCs; it was significantly more common in squamous cell carcinomas (38%) than in adenocarcinomas (18%; P < 0.0001). Low or absent Keap1 expression was detected in 56% of NSCLCs; it was significantly more common in adenocarcinomas (62%) than in squamous cell carcinomas (46%; P = 0.0057). In NSCLC, mutations of NFE2L2 and KEAP1 were very uncommon (2 of 29 and 1 of 31 cases, respectively). In multivariate analysis, Nrf2 expression was associated with worse overall survival [P = 0.0139; hazard ratio (HR), 1.75] in NSCLC patients, and low or absent Keap1 expression was associated with worse overall survival (P = 0.0181; HR, 2.09) in squamous cell carcinoma. In univariate analysis, nuclear Nrf2 expression was associated with worse recurrence-free survival in squamous cell carcinoma patients who received adjuvant treatment (P = 0.0410; HR, 3.37). Conclusions: Increased expression of Nrf2 and decreased expression of Keap1 are common abnormalities in NSCLC and are associated with a poor outcome. Nuclear expression of Nrf2 in malignant lung cancer cells may play a role in resistance to platinum-based treatment in squamous cell carcinoma. Clin Cancer Res; 16(14); 3743–53. ©2010 AACR.

Background and objective About 9% of gastric carcinomas have Epstein–Barr virus (EBV) in the tumour cells, but it is unclear whether viral presence influences clinical progression. We therefore examined a large multicentre case series for the association of tumour EBV status with survival after gastric cancer diagnosis, accounting for surgical stage and other prognostic factors. Methods We combined individual-level data on 4599 gastric cancer patients diagnosed between 1976 and 2010 from 13 studies in Asia (n=8), Europe (n=3), and Latin America (n=2). EBV positivity of tumours was assessed by in situ hybridisation. Mortality HRs for EBV positivity were estimated by Cox regression models stratified by study, adjusted for distributions of sex (71% male), age (mean 58 years), stage (52% tumour-node-metastasis stages III or IV), tumour histology (49% poorly differentiated, 57% Lauren intestinal-type), anatomic subsite (70% non-cardia) and year of diagnosis. Variations by study and continent were assessed using study-specific HRs for EBV positivity. Results During median 3.0 years follow-up, 49% of patients died. Stage was strongly predictive of mortality, with unadjusted HRs (vs stage I) of 3.1 for stage II, 8.1 for stage III and 13.2 for stage IV. Tumour EBV positivity was 8.2% overall and inversely associated with stage (adjusted OR: 0.79 per unit change). Adjusted for stage and other confounders, EBV positivity was associated with lower mortality (HR, 0.72; 95% CI 0.61 to 0.86), with low heterogeneity among the study populations (p=0.2). The association did not significantly vary across patient or tumour characteristics. There was no significant variation among the three continent-specific HRs (p=0.4). Conclusions Our findings suggest that tumour EBV positivity is an additional prognostic indicator in gastric cancer. Further studies are warranted to identify the mechanisms underlying this protective association.

Purpose: Prospectively identifying who will benefit from adjuvant chemotherapy (ACT) would improve clinical decisions for non–small cell lung cancer (NSCLC) patients. In this study, we aim to develop and validate a functional gene set that predicts the clinical benefits of ACT in NSCLC. Experimental Design: An 18-hub-gene prognosis signature was developed through a systems biology approach, and its prognostic value was evaluated in six independent cohorts. The 18-hub-gene set was then integrated with genome-wide functional (RNAi) data and genetic aberration data to derive a 12-gene predictive signature for ACT benefits in NSCLC. Results: Using a cohort of 442 stage I to III NSCLC patients who underwent surgical resection, we identified an 18-hub-gene set that robustly predicted the prognosis of patients with adenocarcinoma in all validation datasets across four microarray platforms. The hub genes, identified through a purely data-driven approach, have significant biological implications in tumor pathogenesis, including NKX2-1, Aurora Kinase A, PRC1, CDKN3, MBIP, and RRM2. The 12-gene predictive signature was successfully validated in two independent datasets (n = 90 and 176). The predicted benefit group showed significant improvement in survival after ACT (UT Lung SPORE data: HR = 0.34, P = 0.017; JBR.10 clinical trial data: HR = 0.36, P = 0.038), whereas the predicted nonbenefit group showed no survival benefit for 2 datasets (HR = 0.80, P = 0.70; HR = 0.91, P = 0.82). Conclusions: This is the first study to integrate genetic aberration, genome-wide RNAi data, and mRNA expression data to identify a functional gene set that predicts which resectable patients with non–small cell lung cancer will have a survival benefit with ACT. Clin Cancer Res; 19(6); 1577–86. ©2013 AACR.

Inflammation is an important physiological response of the organism to restore homeostasis upon pathogenic or damaging stimuli. However, the persistence of the harmful trigger or a deficient resolution of the process can evolve into a state of low-grade, chronic inflammation. This condition is strongly associated with the development of several increasingly prevalent and serious chronic conditions, such as obesity, cancer, and cardiovascular diseases, elevating overall morbidity and mortality worldwide. The current pandemic of chronic diseases underscores the need to address chronic inflammation, its pathogenic mechanisms, and potential preventive measures to limit its current widespread impact. The present review discusses the current knowledge and research gaps regarding the association between low-grade chronic inflammation and chronic diseases, focusing on obesity, cardiovascular diseases, digestive diseases, and cancer. We examine the state of the art in selected aspects of the topic and propose future directions and approaches for the field.

Background: Methods: Results: Conclusion:

The sequence of events associated with the development of gastric cancer has been described as “the gastric precancerous cascade”. This cascade is a dynamic process that includes lesions, such as atrophic gastritis, intestinal metaplasia and dysplasia. According to this model, Helicobacter pylori (H. pylori) infection targets the normal gastric mucosa causing non-atrophic gastritis, an initiating lesion that can be cured by clearing H. pylori with antibiotics or that may then linger in the case of chronic infection and progress to atrophic gastritis. The presence of virulence factors in the infecting H. pylori drives the carcinogenesis process. Independent epidemiological and animal studies have confirmed the sequential progression of these precancerous lesions. Particularly long-term follow-up studies estimated a risk of 0.1% for atrophic gastritis/intestinal metaplasia and 6% in case of dysplasia for the long-term development of gastric cancer. With this in mind, a better understanding of the genetic and epigenetic changes associated with progression of the cascade is critical in determining the risk of gastric cancer associated with H. pylori infection. In this review, we will summarize some of the most relevant mechanisms and focus predominantly but not exclusively on the discussion of gene promoter methylation and miRNAs in this context.