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To explore the association of β-defensin gene copy number variations (CNVs) with ankylosing spondylitis (AS).In this study, 405 unrelated Chinese Han patients with AS and 401 unrelated healthy controls were enrolled. The copy numbers of DEFB4 gene (2 fragments) were measured by AccuCopy™ methods. The association of DEFB4 gene CNVs with AS susceptibility was analyzed by chi-square and logistic regression models. Besides, P values, odds ratio, and 95% confidence intervals (CIs) were used to estimate the effects of risk.The range of DEFB4_1 CN was 0-7 and the range of DEFB4_2 CN was 1-8 both in patients and controls. P values of χ(2) trend test for the association of DEFB4_1 and DEFB4_2 with AS were 0.607 and 0.005, respectively. The results of DEFB4_2, compared with the individual having median 3 copies, those carrying ≤ 2-copies [OR = 0.68, 95%CI: (0.46, 0.99), P = 0.049; adjusted OR = 0.69, 95%CI(0.47, 1.03), P = 0.067.]; and those carrying ≥ 4-copies [OR = 0.62, 95%CI: (0.45, 0.86), P = 0.004; adjusted OR = 0.64, 95%CI: (0.46, 0.88), P = 0.006], were significantly associated with decreasing risk of AS. Univariate analysis showed that both DEFB4_1 and DEFB4_2 were associated with Bath AS Disease Activity Index or BASDAI. After adjusted by age, sex, and disease duration, the results changed little, which demonstrated that high copies may be linked with decrease in the risk of disease severity [OR = 0.71, 95%CI: (0.56, 0.90), P = 0.005; OR = 0.75, 95%CI: (0.60, 0.94), P = 0.013, respectively].The CNs of DEFB4 gene may be associated with AS and involved in disease progression.

Recent findings implicate the complement C4 gene in gray matter loss in schizophrenia. In a large cohort of patients with first-episode psychosis (FEP), we aimed to (1) characterize the frequency of C4 gene copy number variations (CNVs) and HERV-K Ins/Del events as compared to that in healthy controls (HCs) and (2) evaluate whether C4 gene structural variants influence baseline clinical symptoms and treatment response to amisulpride. A total of 271 FEP subjects and 221 HCs were genotyped for C4 CNV and HERV-Ins/Del (C4A and C4B isoforms; C4-HERV structural forms [C4AL, C4AS, C4BL, C4BS] variations using droplet digital PCR. Overall, the gene frequencies of both C4 isoforms and C4-HERV structural forms did not significantly differ between groups. At the genotype level, we found that the C4 AL-AL-BL-BL genotype (AL-BL haplotype) was significantly more frequent in FEP as compared to HC. Apart from a marginal observation concerning the C4 AL-AL-BL-BL genotype (AL-BL haplotype), possibly reflecting a relationship with schizophrenia, we did not find any correlation between C4 genetic and clinical characteristics or treatment response in FEP.

There is a critical need for better methodologies to diagnose and monitor patients with central nervous system (CNS) tumors. Recent advancements in the use of circulating tumor DNA (ctDNA) show that it is a promising tool for the evaluation of patients with primary or metastatic CNS tumors. Cerebrospinal fluid (CSF) is a more suitable sample type to evaluate metastatic CNS cancers than plasma. The current techniques for diagnosing metastatic CNS tumors include imaging (e.g., MRI), examination of tumor cells in CSF (CSF-cytology) and biopsies. However, MRI and CSF-cytology have poor specificity and sensitivity, respectively, and brain biopsies are invasive. The objective of this study is to optimize and validate a next generation sequencing (NGS) assay to detect ctDNA in the CSF of patients with metastatic CNS tumors. We have compared several methods to isolate ctDNA from CSF and identified the optimal method based on the quantity and quality of ctDNA obtained. CSF-ctDNA was extracted using QIAamp Circulating Nucleic Acid kit from CSF patient samples (CNS tumor= 10, Breast cancer=17, Lung cancer=8, Ovarian cancer=1, Melanoma=1, B-cell lymphoma=2, and Uterine cancer=1). We analyzed CSF-ctDNA mutations with the OncomineTM Pan-Cancer cell-free assay and found mutations in 19/40 (47.5%) CSF samples. The targeted panel detected 22 single nucleotide variations involving 11 genes and TP53 was the most commonly mutated gene. Copy number variations were detected in FGFR3, MYC, CCND1, CCND3, FGFR1, and CDK4 genes. We compared the sensitivity of the NGS assay to detect ctDNA with CSF-cytology and found that 7/22 (31.8%) CSF-cytology negative patients were positive for CSF-ctDNA. In conclusion, CSF-ctDNA targeted sequencing is more sensitive than CSF-cytology in the evaluation of patients with CNS metastasis. This approach will improve the diagnosis and management of primary and metastatic CNS tumors.

Background IDH-mutant glioblastoma is classified by the 2016 CNS WHO as a group with good prognosis. However, the actual number of cases examined in the literature is relatively small. We hypothesize that IDH-mutant glioblastoma is not a uniform group and should be further stratified. Methods We conducted methylation profiles and estimated copy number variations of 57 IDH-mutant glioblastomas. Results Our results showed that 59.6% and 40.4% of tumors belonged to glioma-CpG island methylator phenotype (G-CIMP)-high and G-CIMP-low methylation subgroups, respectively. G-CIMP-low subgroup was associated with significantly worse overall survival (OS) as compared to G-CIMP-high (P = .005). CDKN2A deletion (42.1%) was the most common gene copy number variation, and was significantly associated with G-CIMP-low subgroup (P = .004). Other frequent copy number changes included mesenchymal–epithelial transition (MET) (5.3%), CCND2 (19.3%), PDGFRA (14.0%), CDK4 (12.3%), and EGFR (12.3%) amplification. Both CDKN2A deletion (P = .036) and MET amplification (P < .001) were associated with poor OS in IDH-mutant glioblastomas. Combined epigenetic signature and gene copy number variations separated IDH-mutant glioblastomas into Group 1 (G-CIMP-high), Group 2 (G-CIMP-low without CDKN2A nor MET alteration), and Group 3 (G-CIMP-low with CDKN2A and/or MET alteration). Survival analysis revealed Groups 1 and 2 exhibited a favorable OS (median survival: 619 d [20.6 mo] and 655 d [21.8 mo], respectively). Group 3 exhibited a significant shorter OS (median survival: 252 d [8.4 mo]). Multivariable analysis confirmed the independent prognostic significance of our Groups. Conclusions IDH-mutant glioblastomas should be stratified for risk with combined epigenetic signature and CDKN2A/MET status and some cases have poor outcome.

IDH-mutant glioblastoma is classified by the 2016 CNS WHO as a group with good prognosis. However, the actual number of cases examined in the literature is relatively small. We hypothesize that IDH-mutant glioblastoma is not a uniform group and should be further stratified. We conducted methylation profiles and estimated copy number variations of 57 IDH-mutant glioblastomas. Our results showed that 59.6%, and 40.4% of tumors belonged to G-CIMP-high and G-CIMP-low methylation subgroups, respectively. G-CIMP-low subgroup was associated with significantly worse OS as compared to G-CIMP-high (P=0.005). CDKN2A deletion (42.1%) was the most common gene copy number variation, and was significantly associated with G-CIMP-low subgroup (P=0.004). Other frequent copy number changes included MET (5.3%), CCND2 (19.3%), PDGFRA (14.0%), CDK4 (12.3%), and EGFR (12.3%) amplification. Both CDKN2A deletion (P=0.036) and MET amplification (P< 0.001) were associated with poor OS in IDH-mutant glioblastomas. Combined epigenetic signatures and gene copy number variations separated IDH-mutant glioblastomas into Group 1 (G-CIMP-high), Group 2 (G-CIMP-low without CDKN2A nor MET alterations), and Group 3 (G-CIMP-low with CDKN2A and/or MET alterations). Survival analysis revealed Groups 1 and 2 exhibited a favorable OS (median survival: 619 days (20.6 months), and 655 days (21.8 months), respectively). Group 3 exhibited a significant shorter OS (median survival: 252 days (8.4 months)). Multivariable analysis confirmed the independent prognostic significance of our Groups. IDH-mutant glioblastomas should be stratified for risk with combined epigenetic signature and CDKN2A/MET status and some cases have poor outcome.