WW domain-containing oxidoreductase (WWOX) is a tumor suppressor that has been reported to lose function due to genetic alterations in several cancers. WWOX maps to the common chromosomal fragile site FRA16D and several copy number variations (CNVs) were found within this gene. In this study, we investigated the association between the CNVs of WWOX and lung cancer risk in four independent case-control studies, which are on 2942 lung cancer cases and 3074 cancer-free controls of southern, eastern and northern Chinese. A common CNV-67048 was genotyped by the Taqman real-time PCR, and its biological effect was accessed with protein expression and sequencing assays. We found that in comparison with the common 2-copy genotype, the carriers of loss variant genotypes (1-copy or 0-copy) had a significantly increased risk of lung cancer (adjusted OR = 1.39, 95% CI = 1.24-1.55, P = 9.01×10(-9)) in a dose-response manner (Ptrend = 1.12 × 10(-10)), and the WWOX protein expressions in lung cancer tissues were significantly lower (P = 0.036), accompanying a higher rate of exons absence (P = 0.021) in subjects with loss genotypes of CNV-67048. Our data suggest that the loss genotypes of CNV-67048 in WWOX predispose their carriers to lung cancer; this might be related with altered WWOX gene expression and exons absence in them.

BackgroundsImmunotherapy is less effective in patients with epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC). Lower programmed cell death-ligand 1 (PD-L1) expression and tumor mutation burden (TMB) are reported to be the underlying mechanism. Being another important factor to affect the efficacy of immunotherapy, tumor microenvironment (TME) characteristics of this subgroup of NSCLC are not comprehensively understood up to date. Hence, we initiated this study to describe the specific TME of EGFR-mutant lung adenocarcinoma (LUAD) from cellular compositional and functional perspectives to better understand the immune landscape of this most common subtype of NSCLC.MethodsWe used single-cell transcriptome sequencing and multiplex immunohistochemistry to investigate the immune microenvironment of EGFR-mutant and EGFR wild-type LUADs and determined the efficacy of immunotherapy. We analyzed single cells from nine treatment-naïve samples and compared them to three post-immunotherapy samples previously reported from single cell perspective using bioinformatics methods.ResultsWe found that EGFR-mutant malignant epithelial cells had similar characteristics to the epithelial cells in non-responders. EGFR-mutant LUAD lacked CD8+ tissue-resident memory (TRM) cells, which could promote tertiary lymphoid structure generation by secreting CXCL13. In addition, other cell types, including tumor-associated macrophages and cancer-associated fibroblasts, which are capable of recruiting, retaining, and expanding CD8+ TRM cells in the TME, were also deficient in EGFR-mutant LUAD. Furthermore, EGFR-mutant LUAD had significantly less crosstalk between T cells and other cell types via programmed cell death-1 (PD-1) and PD-L1 or other immune checkpoints compared with EGFR wild-type LUAD.ConclusionsOur findings provide a comprehensive understanding of the immune landscape of EGFR-mutant LUAD at the single-cell level. Based on the results, many cellular components might have negative impact on the specific TME of EGFR-mutant LUAD through influencing CD8+ TRM. Lack of CD8+ TRM might be a key factor responsible for the suppressive TME of EGFR-mutant LUAD.

Serum microRNA-21 (miR-21) expression has been shown to be significantly up-regulated in breast cancer, which implies that it could be a biomarker to discriminate breast cancer patients from healthy controls. We therefore performed this meta-analysis to assess the diagnostic value of miR-21 for breast cancer. Relevant articles were collected from PubMed, Scopus, Embase, the Cochrane Library, BioMed Central, ISI Web of Knowledge, China National Knowledge Infrastructure, Wan Fang Data and Technology of Chongqing databases, from inception to June 10, 2014 by two independent researchers. Diagnostic capacity of miR-21 for breast cancer was assessed using pooled sensitivity and specificity, diagnostic odds ratio (DOR), area under the summary receiver operating characteristic (AUC) and Fagan's nomogram. Meta-Disc software and Stata SE 12.0 were used to investigate the source of heterogeneity and to perform the meta-analysis. We used six studies with a total of 438 patients and 228 healthy controls in this meta-analysis. The pooled sensitivity, specificity and DOR were 0.79 [95 % confidence interval (CI) 0.66-0.87], 0.85 (95 % CI 0.75-0.91) and 19.46 (95 % CI 8.74-43.30), respectively; positive and negative likelihood ratios were 5 and 0.25, and AUC was 0.89 (95 % CI 0.86-0.91). In addition, heterogeneity was clearly apparent but was not caused by the threshold effect. This meta-analysis suggests that miR-21 is a potential biomarker for early diagnosis of breast cancer with high sensitivity and specificity, and its clinical application warrants further investigation.

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