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PubMed2026

Insights into the regulatory roles of LIKE-HETEROCHROMATIN PROTEIN 1 and its targeting to different nuclear compartments modulated by NLS and the conserved domains in the moss Physcomitrium patens.

LIKE-HETEROCHROMATIN PROTEIN 1 (LHP1) is a polycomb group protein that exists in shared multiprotein complexes that harbor core PRC1 and PRC2 proteins. We previously characterized LHP1 in the moss Physcomitrium patens and showed that its function is closely linked with regulation of RNA metabolic processes and the protein is distributed in the nucleoplasm, subnuclear foci, and the nucleolus. To gain mechanistic insight into PpLHP1-mediated gene regulation, in the present study genome-wide changes in transcript profiles of genes affected by loss-of-PpLHP1 function were studied using pplhp1 mutants. RNA-seq analysis reveals a key role for PpLHP1 in regulating energy metabolic processes, ribosome-related pathways, stress signaling/responsive pathways, DNA transcription, etc. ChIP using H3K27me3 coupled with qRT-PCR shows that PpLHP1 suppresses transcription at 5S rRNA promoters and the untimely activation of genes regulating developmental transition by PRC2-dependent and independent mechanisms. To study how PpLHP1 finds its targets in different nuclear compartments and the roles of the multiple NLSs and the conserved domains in guiding the protein, FRAP and deletion studies were performed. These show that PpLHP1 is a mobile protein that diffuses freely in the nucleoplasmic space showing different retention times in the nucleolus, nucleoplasm, and the subnuclear foci indicating its differential affinity for targets at these sites. Expression of PpLHP1 fragments in protonema cells and its subsequent visualization under confocal microscope shows that localization of PpLHP1 to different subnuclear compartments is guided by the monopartite NLS2, CD, and CSD that also play a key role in promoting subnuclear foci formation in the nucleoplasm.

Bryopsida↗
PubMed2000

Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas.

Angiogenesis is essential to the growth and metastasis of solid tumours. Vascular endothelial growth factor (VEGF) is a potent pro-angiogenic cytokine that is overexpressed in malignant tumours such as invasive carcinoma of the breast. The low oxygen tensions (hypoxia) present in these tumours are known to up-regulate the expression of VEGF by tumour cells. Human macrophages also respond to hypoxia by increasing their release of VEGF in vitro, although the effect of hypoxia on VEGF expression by macrophages in vivo has yet to be demonstrated. The present study compared the expression of VEGF by macrophages in areas of low and high vascularity in 24 invasive breast carcinomas (12 lobular, 12 ductal). The cellular distributions of VEGF protein, CD31 (vessels), and CD68 (macrophages) were compared in sequential sections for each tumour. In ten tumours, both tumour cells and macrophages were immunoreactive for VEGF protein. Use of non-isotopic in situ hybridization to localize VEGF mRNA showed that these cell types also expressed VEGF mRNA. No significant differences in the cellular distribution of VEGF protein were found between lobular and ductal carcinomas. In all tumours, macrophages accumulated in higher numbers in poorly vascularized than in highly vascularized areas. In VEGF-positive tumours, macrophages were immunoreactive for VEGF only in avascular areas where tumour cells also expressed VEGF. This suggests that VEGF expression by these two cell types may be regulated by the same microenvironmental stimuli in breast carcinomas. In addition, significantly more macrophages were present in poorly vascularized areas of VEGF-positive than VEGF-negative tumours. This suggests that VEGF may exert a chemotactic action on macrophages in vivo and guide their migration into avascular tumour sites.

Adult↗
PubMed1998

Different modes of cell death induced by 5-fluoro-2'-deoxyuridine in two clones of the mouse mammary tumor FM3A cell line.

The mode of cell death induced by 1 microM 5-fluoro-2'-deoxyuridine (FdUrd) changed in a wild-type F28-7 clone of mouse mammary tumor FM3A cells after a six-month culture. In the original stocked F28-7 clone, FdUrd-induced cell death was accompanied by necrosis-like cell swelling and DNA fragmentation to 100-200 kbp. In subclone F28-7-A isolated from F28-7 cells, which had been cultured for six months, apoptotic bodies and nucleosomal DNA-ladder fragments were observed with the treatment. Furthermore, we investigated the differences in FdUrd-induced intracellular signals between these clones. In F28-7 cells, FdUrd induced increases in caspase-3-like activity, and the mRNA levels of the c-jun, c-fos and c-myc genes, which were greater and earlier than those in F28-7-A cells. Moreover, intracellular acidification occurred in F28-7-A cells treated with FdUrd, though it was not observed in F28-7 cells. These findings suggest that FdUrd-induced cell death occurred through the death program to cell lysis (necrosis) without apoptosis when the induction of these intracellular signals was very high and when intracellular acidification was deficient. Investigation of the differences in the mode of FdUrd-induced cell death between these clones would be important for elucidating the molecular mechanism of pivotal events guiding cells toward either apoptosis or necrosis.

Animals↗
PubMed1997

Vessel patterning in the embryo of the zebrafish: guidance by notochord.

We have cloned the zebrafish homolog of the receptor tyrosine kinase flk-1 to provide us with a tool to study normal vascular pattern formation in the developing zebrafish embryo and to compare it to mutants in which vascular pattern is perturbed. We find that during normal development the first angioblasts arise laterally in the mesoderm and then migrate medially to form the primordia of the large axial vessels, the dorsal aorta (axial artery) and the axial vein. Lumen formation occurs shortly before onset of circulation at 24 hr postfertilization. We examined the specification of vascular progenitors in the mutant cloche, which fails to form both vessels and blood. cloche lacks all flk-expressing cells and therefore appears to lack angioblasts. The axial vessels of the trunk form in close proximity to notochord and endoderm, which may provide cues for their formation. The dorsal aorta is normally just ventral to the notochord; the axial vein is just below the dorsal aorta and above the endoderm. floating head (flh) and no tail (ntl) mutants both have defects in the formation of notochord. Both are cell-autonomous lesions, flh abolishing notochord and ntl preventing its differentiation. In both mutants the dorsal aorta fails to form, while formation of the axial vein is less affected. Mosaic analysis of mutant embryos shows that transplanted wild-type cells can become notochord in mutant flh embryos. In these mosaic embryos flh cells expressing flk assemble at the midline, beneath the wild-type notochord, and form an aortic primordium. This suggests that signals from the notochord may guide angioblasts in the fashioning of the dorsal aorta. The notochord seems to be less important for the formation of the vein.

Amino Acid Sequence↗
PubMed1992

UNC-6, a laminin-related protein, guides cell and pioneer axon migrations in C. elegans.

The unc-6 gene is required for the guidance of pioneer axons and migrating cells along the body wall in C. elegans. In mutants, dorsal and ventral migrations are disrupted, but longitudinal movements are largely unaffected. The gene was tagged for molecular cloning by two independent transposon insertions. Based on genomic and cDNA sequencing, the gene encodes a novel laminin-related protein, UNC-6 (591 amino acids). The N-terminus is homologous to the N-termini (i.e., domains V1, V-1, V-2, and V-3) of laminin subunits, while the C-terminus is a unique domain. We propose that UNC-6 is a component of an extracellular matrix cue that guides dorsoventral migrations on the epidermis.

Amino Acid Sequence↗
PubMed2000

Sequence bias in edited kinetoplastid RNAs.

Uridylate residues (Us) are inserted and deleted at precise positions in mitochondrial transcripts of Trypanosoma brucei. These sequence changes are determined by interactions with small guide RNAs (gRNAs) that are complementary to edited sequence. Adenylate (A) and guanylate (G) residues in gRNAs across from editing sites pair with inserted Us. We evaluate whether sequence bias exists in the bases surrounding insertion sites. Upon analyzing all reported insertion sites in T. brucei, we find that the predicted base pairs flanking insertion sites show a strong bias. Specifically, guiding As and Gs tend to be flanked by cytosine residues and Us. This bias is expected if precise base-pair interactions at the editing site determine the number of inserted Us.

Adenine↗
PubMed2002

Molecular diagnosis of viral hepatitis.

Molecular biology-based assays are invaluable tools for the management of chronic viral hepatitis. They can be used to test blood donations, diagnose active infection, help to establish the prognosis, guide treatment decisions, and assess the virological response to therapy. This article reviews current molecular biology-based techniques and assays, and their practical use in the management of hepatitis B and C virus infection.

DNA, Viral↗
PubMed1999

Proteins connecting the nuclear pore complex with the nuclear interior.

While much has been learned in recent years about the movement of soluble transport factors across the nuclear pore complex (NPC), comparatively little is known about intranuclear trafficking. We isolated the previously identified Saccharomyces protein Mlp1p (myosin-like protein) by an assay designed to find nuclear envelope (NE) associated proteins that are not nucleoporins. We localized both Mlp1p and a closely related protein that we termed Mlp2p to filamentous structures stretching from the nucleoplasmic face of the NE into the nucleoplasm, similar to the homologous vertebrate and Drosophila Tpr proteins. Mlp1p can be imported into the nucleus by virtue of a nuclear localization sequence (NLS) within its COOH-terminal domain. Overexpression experiments indicate that Mlp1p can form large structures within the nucleus which exclude chromatin but appear highly permeable to proteins. Remarkably, cells harboring a double deletion of MLP1 and MLP2 were viable, although they showed a slower net rate of active nuclear import and faster passive efflux of a reporter protein. Our data indicate that the Tpr homologues are not merely NPC-associated proteins but that they can be part of NPC-independent, peripheral intranuclear structures. In addition, we suggest that the Tpr filaments could provide chromatin-free conduits or tracks to guide the efficient translocation of macromolecules between the nucleoplasm and the NPC.

Amino Acid Sequence↗
PubMed2002

Guide oligonucleotide-dependent DNA linkage that facilitates controllable polymerization of microgene blocks.

Faster and more efficient searches of a huge protein sequence space for the purpose of conducting experiments in protein evolution can be achieved through the development of a block shuffling-based evolution system. One of the key components of such a system is the accurate and efficient linkage of gene units. Here we introduce a new method that allows accurate and controllable linkage of microgene blocks. This method employs a thermostable DNA ligase that links two single-stranded microgene blocks when they hybridize a complementary guide oligonucleotide. At high temperature, the ligation of the microgene units is fully dependent on the guide oligonucleotide, which can exclude undesired polymer formation, including the incorporation of microgenes having illegitimate sizes and "head-to-head" and "tail-to-tail" ligation of blocks. We were also able to assemble three microgene units using two guide oligonucleotides. Using this method of controllable linkage should facilitate further development of a step-by-step system for the polymerization of gene blocks, leading to a versatile block shuffling-based protein evolution system.

DNA↗
PubMed2004

Transcriptional down-regulation of the platelet ADP receptor P2Y(12) and clusterin in patients with systemic lupus erythematosus.

Cardiovascular complications are common in systemic lupus erythematosus (SLE) and myocardial infarctions are the leading cause of increased mortality. The ADP receptor P2Y(12) plays a central role in platelet activation and the P2Y(12) blocker clopidogrel reduces the incidence of cardiovascular events. Clusterin, a complement inhibitory protein suggested to be involved in the pathogenesis of SLE, has been found recently in a microarray study to be expressed at very high levels in platelets. Using a new protocol for mRNA quantification in platelets we set out to study if gene expression is altered in SLE patients compared with a healthy control group. Quantitative assay based on real-time PCR was used to measure mRNA expression, Western blot for P2 receptor protein expression and PFA-100 for platelet aggregation. The P2Y(12) receptor expression was decreased in SLE compared to the controls (P < 0.05), while expression of P2Y(1) and P2X(1) were unaltered. These findings were consistent at the protein level. The clusterin mRNA expression was very high. However, SLE patients had significantly lower levels than controls (P < 0.05). Platelet aggregation was similar in both groups. It may be suggested that a decreased level of P2Y(12) receptors could represent a protective response in SLE against thrombotic complications. Lowered clusterin levels could be involved in the pathogenesis of SLE due to decreased protective effects. These findings could help to achieve a better understanding of the platelet function in SLE and serve as a guide for further research and drug use.

Adolescent↗
PubMed2005

A genome-wide analysis of C/D and H/ACA-like small nucleolar RNAs in Trypanosoma brucei reveals a trypanosome-specific pattern of rRNA modification.

Small nucleolar RNAs (snoRNAs) constitute newly discovered noncoding small RNAs, most of which function in guiding modifications such as 2'-O-ribose methylation and pseudouridylation on rRNAs and snRNAs. To investigate the genome organization of Trypanosoma brucei snoRNAs and the pattern of rRNA modifications, we used a whole-genome approach to identify the repertoire of these guide RNAs. Twenty-one clusters encoding for 57 C/D snoRNAs and 34 H/ACA-like RNAs, which have the potential to direct 84 methylations and 32 pseudouridines, respectively, were identified. The number of 2'-O-methyls (Nms) identified on rRNA represent 80% of the expected modifications. The modifications guided by these RNAs suggest that trypanosomes contain many modifications and guide RNAs relative to their genome size. Interestingly, approximately 40% of the Nms are species-specific modifications that do not exist in yeast, humans, or plants, and 40% of the species-specific predicted modifications are located in unique positions outside the highly conserved domains. Although most of the guide RNAs were found in reiterated clusters, a few single-copy genes were identified. The large repertoire of modifications and guide RNAs in trypanosomes suggests that these modifications possibly play a central role in these parasites.

Animals↗
PubMed1997

Transrectal ultrasound-guided biopsy causes hematogenous dissemination of prostate cells as determined by RT-PCR.

OBJECTIVES: To determine if transrectal ultrasound-guided (TRUS) prostate biopsy causes dissemination of prostate cells into the circulation as assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) targeted against prostate-specific antigen (PSA) mRNA. METHODS: RT-PCR PSA analysis was performed before and after prostatic invasive manipulations in 50 men. The cases consisted of 47 patients with TRUS and 3 with transurethral resection of the prostate (TURP). Peripheral venous blood (8 mL) was drawn before and within 60 minutes after the procedure. Total RNA was extracted from fractionated blood, and RNA/cDNA quality was assured and normalized with beta-actin RT-PCR analysis. The PSA primers hybridize exons 3 and 5, yielding a 254-basepair PCR product. The assay detects one LNCaP cell in a background of 100 million lymphoid cells and a single copy of PSA cDNA on an ethidium bromide gel. RESULTS: Among the 47 TRUS cases, 43 specimens were evaluable. Forty-two cases were negative before biopsy; among these patients, 4 cases (9.5%) converted to a positive RT-PCR PSA result. Both benign and malignant TRUS biopsies were capable of producing a positive RT-PCR PSA signal implicating iatrogenic dissemination of cells. All three TURP cases converted from a negative to a highly intense positive signal. CONCLUSIONS: We conclude that a positive RT-PCR PSA signal may result from release of prostate cells into the peripheral circulation after a TRUS biopsy and TURP. TURP causes greater dissemination than TRUS. Based on these preliminary data, we recommend that future molecular staging studies should be based on blood specimens drawn before performance of TRUS biopsy. This may be an important mechanism of prostate cancer dissemination meriting further investigations.

Aged↗
PubMed1997

Human gene therapy for melanoma: CT-guided interstitial injection.

OBJECTIVE: Our intent is to describe the role of CT in the intratumoral injection of Allovectin-7 (Vical, San Diego, CA), an allogeneic class I major histocompatibility complex antigen, HLA-B7, formulated with cationic lipid, in the treatment of metastatic malignant melanoma. MATERIALS AND METHODS: Ten patients with metastatic malignant melanoma were treated with gene therapy in which we used CT-guided intratumoral injection of plasmid DNA containing the HLA-B7 gene. This therapy was part of a phase I gene therapy trial in patients with metastatic melanoma. CT guidance was chosen as an accurate way to direct gene delivery in patients with deep, impalpable lesions. Tumor locations included pulmonary, mediastinal, hepatic, adrenal, and paracaval sites. Patients in the CT protocol underwent baseline CT studies. Examinations were repeated 2, 4, and 8 weeks after gene therapy and thereafter at 3-month intervals. Both injected and noninjected tumors were measured. CT-guided injections of 10, 50, or 250 micrograms of plasmid DNA were performed with 22-gauge spinal needles. Injection volumes were between 1.0 and 4.0 ml, depending on tumor size. CT-guided core biopsy specimens were obtained (with 18- or 20-gauge needles) from the selected tumor before therapy and 2, 4, and 8 weeks after therapy to assess HLA-B7 plasmid DNA and gene expression. Peripheral blood was analyzed for cytotoxic T lymphocytes directed against HLA-B7. RESULTS: CT-guided intratumoral injections were successful in delivering genetic material to all patients with impalpable tumors. Significant responses (as defined by a decrease of 25% or more in the product of the length and width of the injected tumor) were observed in six of the 10 patients. One of these six patients who had a solitary lesion remains free of disease 19 months after gene therapy. HLA-B7 protein expression was detected in 89% of biopsy specimens, and plasmid DNA and messenger RNA were detected in 56% and 22% of biopsy specimens, respectively. CONCLUSION: CT provides a safe, accurate, and efficacious way to monitor and assess tumor progression and response, and it provides guidance for biopsies and intratumoral injections during gene therapy. Significant responses in injected tumors of six of the 10 patients in our study suggest that further clinical trials of this gene therapy are warranted.

Adult↗
PubMed2025

Whole-Genome Conservation Analysis for the Specific and Accurate Detection of Influenza A and B Viruses and Respiratory Syncytial Virus by Quadruplex RT-qPCR.

Influenza virus (Flu) and respiratory syncytial virus (RSV) are the primary pathogens responsible for acute respiratory infections. Both viruses are prone to mutations due to the seasonal epidemic, leading to an increasing rate of false-negative results. In this study, comprehensive meta-analyses of the genomes focusing on most conserved fragments have been performed for the four seasonal influenza viruses (two subtypes of Flu A: H1N1 and H3N2; two subtypes of Flu B: Yamagata and Victoria) and the two types of RSV: RSVA and RSVB), respectively. The most conserved sequences of 200&#x2009;bp were identified as targets of the designed primer/probe sets for RT-qPCR were screened and optimized. Good sensitivities of the optimized primer/probe sets were obtained with the limits of detections of 2.95, 2.82, 1.57, 2.8, 1.19, and 2.12 copies/reaction for H1N1, H3N2, Yamagata, Victoria, RSVA and RSVB, respectively. Eventually, quadruplex qPCR using the four designed primer/probe sets can achieve simultaneous screening of the four viruses at a single tube. Furthermore, the assay's good performance in detecting target viruses from clinical throat swab samples demonstrated its potential for diagnosis of these viruses. The method, based on the identified conserved sequences and primer/probe sets, can effectively reduce false-negative results and rapidly respond to these viruses during respiratory disease outbreaks, or even before their widespread emergence, which aid in preventing outbreaks and guiding clinical treatment.

Humans↗
PubMedDate not supplied

Subcellular localization of specific mRNAs and their protein products in Purkinje cells by combined fluorescence in situ hybridization and immunocytochemistry.

In this study we have investigated the subcellular distribution of two mRNAs coding for the Purkinje cell-specific proteins, calbindin D28K and L7 (L7/pcp-2). Whereas calbindin mRNA was found to be in the cell body only, L7 transcripts could be detected within the molecular layer, corresponding to Purkinje cell dendrites. We have now combined a highly sensitive fluorescence-based in situ hybridization protocol with immunofluorescence in conjunction with confocal optical sectioning to analyze the precise localization of these mRNAs in individual Purkinje neurons. We show that L7 mRNA is localized in clusters within the proximal and distal branches of dendrites, but also in the proximal part of Purkinje cell axons. In contrast, calbindin transcripts are restricted to the axonal pole of the perikaryon. Purkinje cells grown in primary cultures reveal similar mRNA distribution patterns for the two transcripts. Thus, the mechanism underlying localization of mRNA within Purkinje cells seems to function in a cell-intrinsic manner, guiding specific transcripts, such as L7 mRNA, to neuronal processes while restricting others, such as calbindin mRNA, to the perikaryon.

Alkaline Phosphatase↗
PubMed1990

DNA replication in Escherichia coli is initiated by membrane detachment of oriC. A model.

An adequate model for the initiation of chromosome replication in Escherichia coli should explain why the introduction of multiple copies of the chromosomal origin of replication, oriC, does not perturb cells seriously and why such multiple origins are replicated synchronously; it should explain why the key initiator protein, DnaA, is activated in vitro by binding specifically to acidic phospholipids and why the Dam methyltransferase is essential for the correct timing of initiation; it should explain why phospholipid synthesis and fluidity are necessary for initiation. In the detachment model, presented here, cyclical changes in the phospholipid composition of the cytoplasmic membrane activate initiator proteins such as DnaA protein and cause origins to detach; this detachment allows torsional stresses to open 13mer sequences in oriC; DnaA assists in the serial opening of these sequences and guides the entry of the helicase to form a pre-priming complex and trigger initiation; the greater affinity of hemi-methylated origin for membrane is re-interpreted as a mechanism for preventing re-initiation.

Cell Cycle↗
PubMed2001

The survivin:fas ratio in pediatric renal tumors.

BACKGROUND/PURPOSE: Apoptosis factors inducing or preventing cell death may govern the behavior of certain tumors. Fas is a pro-apoptotic receptor that induces cell death when bound by its ligand and is expressed at greater levels in pediatric renal tumors of good prognosis. Survivin is a novel inhibitor of apoptosis that is expressed in a cell cycle-dependent manner and is abundantly expressed in several tumors of unfavorable histology. This study evaluates the expression of survivin, as well as the prognostic value of the survivin:fas ratio in various types and stages of pediatric renal tumors. METHODS: Multiple apoptosis mRNA species were quantified by Rnase protection assay (RPA) in 32 pediatric renal tumors and adjacent normal kidney specimens before chemotherapy: Wilms' tumor (WT), n = 9; clear cell sarcoma (CCS), n = 4; rhabdoid tumor of the kidney (RTK), n = 5; mesoblastic nephroma (MN), n = 3 and normal kidney, n = 11. Western Blot and immunocytochemistry were used to confirm survivin protein expression in a selective specimen survey. Follow-up data were obtained on patient outcomes, and antiapoptotic to proapoptotic ratios were calculated and correlated with clinical recurrence of disease. RESULTS: Pediatric renal tumors express greater levels of both pro- and antiapoptotic factors than normal kidney. Survivin and fas appeared to be expressed differentially in the tumor specimens sampled. Five of 10 (50%) tumors that went on to recur expressed survivin, whereas survivin was present in only 2 of 11 (18%) nonrecurrent tumors. Conversely, only 2 of 10 (20%) tumors that recurred were fas positive, whereas 5 of 11 (45%) tumors that did not recur expressed fas. The mean survivin:fas ratio was significantly greater in the 10 tumors that went on to recur after treatment (4 RTK, 3 CCS, 3 WT), than in tumors not recurring (2.16+/-1.4 v 1.0+/-1.07; P =.01, Kruskal-Wallis test). The positive predictive value of tumor recurrence was 85.7% (CI: 42.1%, 99.6%) and the negative predictive value was 71.4% (CI: 41.9%, 91.6%) when a cutoff ratio of 1.6 was considered. CONCLUSIONS: The survivin:fas mRNA ratio is of prognostic value in its ability to predict recurrent disease in children undergoing treatment for pediatric renal tumors. In this series, a ratio of greater than 1.6 predicted recurrent disease with a high probability irrespective of clinical stage or pathologic type. Determining the survivin:fas ratio may guide treatment, follow-up and counseling of patients with pediatric renal tumors.

Apoptosis↗
PubMed2025

Genomic subtypes of non-muscle-invasive bladder cancer: guiding immunotherapy decision-making for patients exposed to aristolochic acid.

BACKGROUND: The limited genomic data on non-muscle-invasive bladder cancer (NMIBC) hampers our understanding of its carcinogenesis and development. Specifically, Aristolochic acid (AA), a potent human carcinogenic compound from aristolochia plants and commonly found in Chinese herbal medicine, has been extensively documented as being closely associated with the onset and progression of bladder cancer. However, the field of AA-induced NMIBC remains largely unexplored in terms of its genomic and molecular characteristics, as well as clinical therapeutic strategies. METHODS: To bridge this knowledge gap, we conducted a comprehensive study using a cohort of 81 NMIBC samples. We performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) to obtain detailed genomic and transcriptomic data. We subjected these datasets to genomic analysis and subtype analysis to gain valuable insights into NMIBC. RESULTS: By temporally dissecting mutations in NMIBC specimens, we identified a comprehensive mutational landscape of NMIBC and the associations of these mutations with recurrence-free survival. Additionally, we discerned four genomic subtypes of NMIBC: AA-like, FGFR3/HRAS, FGFR3 & chr9Del, and genome instability (GI). The AA-like subtype presented a high frequency of gene mutations along with a pronounced AA mutagenesis signature of SBS22 (Fisher test: P-value 3.5e-4, OR 25.25) even after temporal dissection. The FGFR3/HRAS subtype exhibited FGFR3 or HRAS mutations with few copy number alterations (CNAs). The FGFR3 & chr9Del subtype was characterized by the co-occurrence of chr9p and chr9q deletions as well as FGFR3 mutations, while the GI subtype showed a high frequency of CNAs. Notably, the AA-like and GI subtypes demonstrated better outcomes after immunotherapy, whereas the FGFR3/HRAS subtype showed poorer outcomes. CONCLUSIONS: Our findings provide novel perspectives on the genomics of NMIBC, unveiling four prominent genomic subtypes, each showing different outcomes following immunotherapy. TRIAL REGISTRATION: No. 2019PHB268-01 (retrospectively registered on February 14, 2020).

Humans↗