Background: Defects in replication repair-associated DNA polymerases often manifest an ultra-high tumor mutational burden (TMB), which is associated with higher probabilities of response to immunotherapies. The functional and clinical implications of different polymerase variants remain unclear. Methods: Targeted next-generation sequencing using a 425-cancer gene panel, which covers all exonic regions of three polymerase genes (POLE, POLD1, and POLH), was conducted in a cohort of 12,266 patients across 16 different tumor types from January 2017 to January 2019. Prognostication of POL variant-positive patients was performed using a cohort of 4679 patients from the The Cancer Genome Atlas (TCGA) datasets. Results: The overall prevalence of somatic and germline polymerase variants was 4.2% (95% CI 3.8% to 4.5%) and 0.7% (95% CI 0.5% to 0.8%), respectively, with highest frequencies in endometrial, urinary, prostate, and colorectal cancers (CRCs). While most germline polymerase variants showed no clear functional consequences, we identified a candidate p.T466A affecting the exonuclease domain of POLE, which might be underlying the early onset in a case with childhood CRC. Low frequencies of known hot-spot somatic mutations in POLE were detected and were associated with younger age, the male sex, and microsatellite stability. In both the panel and TCGA cohorts, POLE drivers exhibited high frequencies of alterations in genes in the DNA damage and repair (DDR) pathways, including BRCA2, ATM, MSH6, and ATR. Variants of unknown significance (VUS) of different polymerase domains showed variable penetrance with those in the exonuclease domain of POLE and POLD1 displaying high TMB. VUS in POL genes exhibited an additive effect as carriers of multiple VUS had exponentially increased TMB and prolonged overall survival. Similar to cases with driver mutations, the TMB-high POL VUS samples showed DDR pathway involvement and polymerase hypermutation signatures. Combinatorial analysis of POL and DDR pathway status further supported the potential additive effects of POL VUS and DDR pathway genes and revealed distinct prognostic subclasses that were independent of cancer type and TMB. Conclusions: Our results demonstrate the pathogenicity and additive prognostic value of POL VUS and DDR pathway gene alterations and suggest that genetic testing may be warranted in patients with diverse solid tumors.

Background: Non-suicidal self-injury (NSSI) is a significant predictor of completed suicide and is increasingly recognized as a serious public health concern. Multiple factors, including social, familial, mental, and genetic factors could influence the occurrence of this behavior. Identifying the early risk factors is important for screening and preventing this behavior.Methods: Here, we recruited a total of 742 adolescent inpatient participants from a mental health center and conducted a series of diagnostic interviews and questionnaires to assess NSSI behavior and other events. Bivariate analysis was used to detect differences between groups in NSSI and non-NSSI. Then, binary logistic regression was fitted to identify predictors of NSSI as a function of these questionnaire scores.Results: Of the 742 adolescents examined, a total of 382 (51.5%) participants engaged in NSSI. Bivariate analysis showed that age, gender, depression, anxiety, insomnia, and childhood trauma was significantly associated with NSSI. Logistic regression results suggested that females had 2.43 higher odds of engaging in NSSI when compared to their male counterparts (OR = 3.43, 95%CI = 2.09–5.74, p = 1.70 × 10⁻⁶). Depression was a primary risk predictor for NSSI with each additional increase in symptoms of depression increasing the odds of engaging in NSSI by 18% (OR = 1.18, 95%CI = 1.12–1.25, p = 2.25 × 10⁻⁸).Conclusion: More than half of the adolescent inpatients with psychiatric disorders have NSSI experience. Depression and gender were the risk factors for NSSI. Age at a specific range had a high prevalence of NSSI.

Genome-wide association studies (GWASs) have reported multiple single nucleotide polymorphisms (SNPs) associated with schizophrenia, yet the underlying molecular mechanisms are largely unknown. In this study, we aimed to identify schizophrenia relevant genes showing alterations in mRNA and protein expression associated with risk SNPs at the 10q24.32-33 GWAS locus. We carried out the quantitative trait loci (QTL) and summary data-based Mendelian randomization (SMR) analyses, using the PsychENCODE dorsolateral prefrontal cortex (DLPFC) expression QTL (eQTL) database, as well as the ROSMAP and Banner DLPFC protein QTL (pQTL) datasets. The gene CNNM2 (encoding a magnesium transporter) at 10q24.32-33 was identified to be a robust schizophrenia risk gene, and was highly expressed in human neurons according to single cell RNA-seq (scRNA-seq) data. We further revealed that reduced Cnnm2 in the mPFC of mice led to impaired cognition and compromised sensorimotor gating function, and decreased Cnnm2 in primary cortical neurons altered dendritic spine morphogenesis, confirming the link between CNNM2 and endophenotypes of schizophrenia. Proteomics analyses showed that reduced Cnnm2 level changed expression of proteins associated with neuronal structure and function. Together, these results identify a robust gene in the pathogenesis of schizophrenia.

The stimulator of IFN genes (STING; also known as MITA, TMEM173, MPYS, or ERIS) is generally regarded as a key adaptor protein for sensing pathogenic DNA genomes. However, its role in RNA viral signaling as part of the innate immunity system remains controversial. In this study, we identified two isoforms of STING (a full-length Tupaia STING [tSTING-FL] and a Tupaia STING short isoform [tSTING-mini]) in the Chinese tree shrew (Tupaia belangeri chinensis), a close relative of primates. tSTING-FL played a key role in the HSV-1–triggered type I IFN signaling pathway, whereas tSTING-mini was critical for RNA virus-induced antiviral signaling transduction. tSTING-mini, but not tSTING-FL, interacted with tMDA5–tLGP2 and tIRF3 in resting cells. Upon RNA virus infection, tSTING-mini caused a rapid enhancement of the tMDA5–tLGP2-mediated antiviral response and acted earlier than tSTING-FL. Furthermore, tSTING-mini was translocated from the cytoplasm to the nucleus during RNA virus infection and promoted tIRF3 phosphorylation through tSTING-mini–tIRF3 interaction, leading to a restriction of viral replication. After the initiation of antiviral effect, tSTING-mini underwent rapid degradation by tDTX3L–tPAPR9 via k48-linked ubiquitination through a proteasome-dependent pathway. Our results have shown alternative isoforms of STING counteract RNA virus infection in different ways. Key Points Tupaia STING has two alternative splicing isoforms, tSTING-FL and tSTING-mini. tSTING-mini is critical for RNA virus-induced antiviral signaling transduction. tSTING-mini enhances MDA5–LGP2-mediated antiviral response and IRF3 phosphorylation.

Hepatitis C virus (HCV) infection is the cause of severe liver disease in many people. The restricted species tropism of HCV hinders the research and development of drugs and vaccines. The Chinese tree shrew (Tupaia belangeri chinensis) is a close relative of primates and can be infected by HCV, but the underlying mechanisms are unknown. In this study, we have characterized the functions of tree shrew MAVS (tMAVS) in response to HCV infection and defined the capacity of HCV replication. HCV was shown to be colocalized with tMAVS in primary tree shrew hepatocytes and cleaved tMAVS at site Cys508 via its NS3/4A protease, with a modulating effect by site Glu⁵⁰⁶ of tMAVS. The tMAVS cleavage by HCV NS3/4A impaired the IRF3-mediated induction of IFN-β but maintained the activated NF-κB signaling in the tree shrew primary cells. Activation of the tMAVS-dependent NF-κB signaling inversely inhibited HCV replication and might limit the establishment of persistent infection. Overall, our study has revealed an elegant example of the balance between the host defenses and HCV infection via the MAVS-mediated antiviral signaling and has provided an insight into the mechanisms underpinning HCV infection in the Chinese tree shrew. Key Points Tupaia MAVS can be cleaved by HCV NS3/4A. tMAVS impaired the IRF3-mediated, but not NF-κB–mediated, antiviral signaling. The activation of NF-κB inhibited HCV replication and persistent infection.