We performed a genome-wide association study of esophageal squamous cell carcinoma (ESCC) by genotyping 1,077 individuals with ESCC and 1,733 control subjects of Chinese Han descent. We selected 18 promising SNPs for replication in an additional 7,673 cases of ESCC and 11,013 control subjects of Chinese Han descent and 303 cases of ESCC and 537 control subjects of Chinese Uygur-Kazakh descent. We identified two previously unknown susceptibility loci for ESCC: PLCE1 at 10q23 (P(Han combined for ESCC) = 7.46 x 10(-56), odds ratio (OR) = 1.43; P(Uygur-Kazakh for ESCC) = 5.70 x 10(-4), OR = 1.53) and C20orf54 at 20p13 (P(Han combined for ESCC) = 1.21 x 10(-11), OR = 0.86; P(Uygur-Kazakh for ESCC) = 7.88 x 10(-3), OR = 0.66). We also confirmed association in 2,766 cases of gastric cardia adenocarcinoma cases and the same 11,013 control subjects (PLCE1, P(Han for GCA) = 1.74 x 10(-39), OR = 1.55 and C20orf54, P(Han for GCA) = 3.02 x 10(-3), OR = 0.91). PLCE1 and C20orf54 have important biological implications for both ESCC and GCA. PLCE1 might regulate cell growth, differentiation, apoptosis and angiogenesis. C20orf54 is responsible for transporting riboflavin, and deficiency of riboflavin has been documented as a risk factor for ESCC and GCA.

Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10(-8), and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19-1.40) and P= 7.63 × 10(-10). An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.

Regulation of ubiquitination is involved in various processes in cancer occurrence and development, including cell cycle arrest, cell proliferation, apoptosis, invasion, metastasis, and immunity. Ubiquitination plays an important role not only at the transcriptional and post-translational levels but also at the protein level. When ubiquitination is in a pathological state, abnormally activated biological processes will not only induce cancer progression but also induce immune evasion. The main function of deubiquitinases (DUBs) is to remove ubiquitin chains from substrates, changing the biological activity of the substrates. It has great potential to improve the prognosis of cancer by targeting DUB to regulate proteome. Ubiquitin-specific peptidase 22 (USP22) belongs to the ubiquitin-specific protease (USP) family of DUBs and has been reported to be related to various physiological and pathological processes. USP22 is abnormally expressed in various malignant tumors such as prostate cancer, lung cancer, liver cancer, and colorectal cancer, which suggests that USP22 may play an important role in tumors. USP22 may stabilize programmed death ligand 1 (PD-L1) by deubiquitination while also regulating T-cell infiltration into tumors. Regulatory T cells (Tregs) are a unique class of immunosuppressive CD4+ T cells that primarily suppress the immune system by expressing the master transcription factor forkhead box protein 3 (FOXP3). USP22 was found to be a positive regulator of stable FOXP3 expression. Treg-specific ablation of USP22 leads to reduced tumor volume in multiple cancer models. This suggests that USP22 may regulate tumor resistance to immunotherapy. In this article, we review and summarize the biological functions of USP22 in multiple signal transduction pathways during tumorigenesis, immune evasion, and drug resistance. Furthermore, we propose a new possibility of combining USP22 with chemotherapeutic, targeted, and immunosuppressive drugs in the treatment of cancer.

AimsConsidering morphological heterogeneity of lung adenocarcinoma (LUAD) and no objective prognostic grading system existing currently, we aim to establish an ‘optimised architecture-based grading system’ (OAGS) to predict prognosis for resected LUAD.MethodsA multicentral study involving three independent cohorts of LUAD was conducted. Predictive ability of the OAGS for recurrence-free probability (RFP) and overall survival (OS) was assessed in training cohort (n=228) by the area under the receiver operating characteristic curve (AUC), Harrell’s concordance index (C-index) and Kaplan-Meier survival analyses, which was validated in testing (n=135) and validation (n=226) cohorts.ResultsThe OAGS consists of: grade 1 for lepidic, papillary or acinar predominant tumour with no or less than 5% of high-grade patterns (cribriform, solid and or micropapillary), grade 2 for lepidic, papillary or acinar predominant tumour with 5% or more of high-grade patterns, and grade 3 for cribriform, solid or micropapillary predominant tumour. In all stages, the OAGS outperformed the pattern-dominant grading system and IASLC grading system for predicting RFP (C-index, 0.649; AUC, 0.742) and OS (C-index, 0.685; AUC, 0.754). Multivariate analysis identified it as an independent predictor of both (RFP, p<0.001; OS, p<0.001). Furthermore, in pT1-2aN0M0 subgroup, the OAGS maintained its ability to predict recurrence (C-index, 0.699; AUC, 0.769) and stratified patients into different risk groups of RFP (p<0.001). These results were confirmed in testing and validation cohorts.ConclusionsThe OAGS is an independent prognostic factor and shows a robust ability to predict prognosis for resected LUAD.

Hypospadias is a common congenital genitourinary malformation characterized by ventral opening of the urethral meatus. As a member of the bone morphogenic protein antagonist family, GREM1 has been identified as associated with susceptibility to hypospadias in the European population. The present study was designed to elaborate on the mutual relationship between replicated single-nucleotide polymorphisms (SNPs) and hypospadias in Asia's largest case-control study in the Southern Han Chinese population involving 577 patients and 654 controls. Our results demonstrate that the GREM1 risk allele rs3743104[G] markedly increases the risk of mild/moderate and severe hypospadias ( P<0.01 , 0.28 ≤OR≤ 0.66). GTEx expression quantitative trait locus data revealed that the eQTL SNP rs3743104 has more associations of eQTL SNP rs3743104 and GREM1 targets in pituitary tissues. Additionally, Bioinformatics and Luciferase Assays show that miR-182 is identified as a suppressor for GREM1 expression, likely through regulation of its binding affinity to rs3743104 locus. In conclusion, the GREM1 risk allele rs3743104[G] increases hypospadias susceptibility in mild/moderate and severe cases among the southern Han population. rs3743104 regulates GREM1 expression by altering the binding affinity of miR-182 to their locus. Collectively, this study provides new evidence that GREM1 rs3743104 is associated with an increased risk of hypospadias. These findings provide a promising biomarker and merit further exploration.