Adenoid cystic carcinoma (ACC) is a malignant tumor that originates from exocrine gland epithelial cells. We profiled the transcriptomes of 49,948 cells from paracarcinoma and carcinoma tissues of three patients using single-cell RNA sequencing. Three main types of the epithelial cells were identified into myoepithelial-like cells, intercalated duct-like cells, and duct-like cells by marker genes. And part of intercalated duct-like cells with special copy number variations which altered with MYB family gene and EN1 transcriptomes were identified as premalignant cells. Developmental pseudo-time analysis showed that the premalignant cells eventually transformed into malignant cells. Furthermore, MYB and MYBL1 were found to belong to two different gene modules and were expressed in a mutually exclusive manner. The two gene modules drove ACC progression into different directions. Our findings provide novel evidence to explain the high recurrence rate of ACC and its characteristic biological behavior.
BackgroundGout is a polygenetic inflammatory disease. Although hundreds of genetic variants associated with gout and serum urate levels have been identified in studies of adults, the pathogenesis of adolescent–onset gout remains unclear. To better characterize the genetic landscape of adolescent–onset gout, a whole genome sequencing study was done in a large Chinese adolescent–onset gout cohort.MethodsWe conducted whole genome sequencing in a discovery adolescent–onset gout cohort of 905 individuals (gout onset 12–19 years) to discover common SNVs, uncommon SNVs, and indels associated with gout. Candidate common SNVs were replicated in an early–onset gout cohort of 2834 individuals (gout onset ≤ 30 years old). Loci associated with early–onset gout (P < 5.0 × 10-8) were identified after meta–analysis with the discovery and replication cohorts. Transcriptome and epigenomic analyses, RT–qPCR and RNA–seq in human peripheral blood leukocytes, and knock–down experiments in human THP–1 macrophage cells investigated regulation and functions of candidate gene RCOR1.FindingsIn addition to ABCG2, a urate transporter previously linked to pediatric–onset and early–onset gout, we identified four novel loci:VPRBP(rs868933181, Pmeta= 6.27 × 10-9; ORmeta= 1.66),NKILA–MIR4532(rs72626599, Pmeta= 6.48 × 10-9; ORmeta= 1.58),RCOR1(rs12887440, Pmeta= 3.37 × 10-8; ORmeta= 1.48), andFSTL5–MIR4454(rs35213808, Pmeta= 4.02 × 10-8; ORmeta= 1.49). Additionally, we found association atABCG2andSLC22A12that was driven by low frequency SNVs. Furthermore, eight uncommon SNVs and three indels in the exome were predicted to be harmful. SNVs inRCOR1were linked to heightened blood leukocyte mRNA levels. THP–1 macrophage culture studies revealed the potential of decreased RCOR1 to suppress gouty inflammation.InterpretationPerforming the first comprehensive characterization of adolescent–onset gout genomes identified risk loci of early–onset gout. Loci mediate inflammatory responsiveness to crystals that could mediate gouty arthritis. This study will contribute to risk prediction and therapeutic interventions to prevent adolescent–onset gout.
Pure ground glass nodules (GGNs) and solid nodules (SNs) represent early and relatively late stages of lung adenocarcinoma (LUAD) in radiology, respectively. The cellular and molecular characteristics of pure GGNs and SNs have not been comprehensively elucidated. Additionally, the mechanism driving the progression of lung adenocarcinoma from pure GGN to SN in radiology is also elusive. In this study, by analyzing the single-cell transcriptomic profiles of 76,762 cells from four pure GGNs, four SNs, and four normal tissues, we found that anti-tumor immunity mediated by NK and CD8+T cells gradually weakened with the progression of LUAD and humoral immunity mediated by plasma B cells was more active in SNs. Additionally, the proliferation ability of some special epithelial cell increased during the progression process from pure GGN to SN. Furthermore, stromal cells and M2 macrophages could assist the progression of LUAD. Through comprehensive analyses, we revealed dynamic changes in cellular components and intercellular interactions during the progression of LUAD. These findings could facilitate our understanding of LUAD and discovery of novel therapeutic targets.
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