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Information resources for the bioinformatician.

The collaborative computing project in biosequence and structure analysis (CCPII) was established to foster bioinformatics in the broad community and the UK research community in particular. A World-Wide Web site called 'The Bioinformatics Resource' has been created containing a comprehensive set of information resources of use to the bioinformatician. The activities of CCPII are complementary to other providers of molecular biology information such as the BIOSCI electronic communication forum, which was established to facilitate communication between professionals in the biological sciences.

Computational Biology↗

Extracting transcriptional events from temporal gene expression patterns during Dictyostelium development.

MOTIVATION: The DNA microarray technology can generate a large amount of data describing the time-course of gene expression. These data, when properly interpreted, can yield a great deal of information concerning differential gene expression during development. Much current effort in bioinformatics has been devoted to the analysis of gene expression data, usually via some 'clustering analysis' on the raw data in some abstract high dimensional space. Here, we describe a method where we first 'process' the raw time-course data using a simple biologically based kinetic model of gene expression. This allows us to reduce the vast data to a few vital attributes characterizing each expression profile, e.g. the times of the onset and cessation of the expression of the developmentally regulated genes. These vital attributes can then be trivially clustered by visual inspection to reveal biologically significant effects. RESULTS: We have applied this approach to microarray expression data from samples isolated every 2 h throughout the 24 h developmental program of Dictyostelium discoideum. mRNA accumulation patterns for 50 developmental genes were found to fit the kinetic model with a p-value of 0.05 or better. Transcription of these genes appears to be initiated in bursts at well-defined periods during development, in a manner suggestive of a dependent sequence. This approach can be applied to analyses of other temporal gene expression patterns, including those of the cell cycle.

Algorithms↗

TriosCompass: a snakemake workflow for integrated detection of SNVs, indels, STRs, and structural de novo variants in parent-child trios.

MOTIVATION: The accurate and sensitive identification of de novo variants, which are unique to an individual and not found in the parents' germlines, is critical for understanding the genetic basis of rare diseases, developmental disorders, and evolutionary processes. Existing de novo variant detection pipelines often lack the flexibility to handle multiple variant types, struggle with speed and reproducibility across computational environments, demand extensive manual configuration, or require bioinformatics expertise for downstream curation and analysis, limiting their scalability and usability for large genomic studies. Accordingly, there is a pressing need to better address these challenges. RESULTS: We introduce TriosCompass, an open-source Snakemake workflow that addresses these challenges by providing a modular, accelerated, and environmentally-configurable end-to-end solution for comprehensive de novo variant discovery. It integrates state-of-the-art tools into a reproducible framework, empowering researchers to discover novel genetic insights with greater efficiency and reliability. AVAILABILITY: TriosCompass is implemented as a Snakemake workflow and is freely available at https://github.com/NCI-CGR/TriosCompass_v2 or on Zenodo (10.5281/zenodo.17981062). SUPPLEMENTARY INFORMATION: Supplementary data is available on GitHub at https://github.com/NCI-CGR/TriosCompass_v2/tree/manuscript/report_dashboards. Supplementary methods on DeepTrio benchmark runs can be viewed at: https://github.com/NCI-CGR/TriosCompass_v2/blob/manuscript/TriosCompass_Supp_Methods_deeptrio_benchmark.md.

Software↗

Whole-genome expression profiling defines the HrpL regulon of Pseudomonas syringae pv. tomato DC3000, allows de novo reconstruction of the Hrp cis clement, and identifies novel coregulated genes.

Pseudomonas syringae pv. tomato DC3000 is a model pathogen of tomato and Arabidopsis that uses a hypersensitive response and pathogenicity (Hrp) type III secretion system (T3SS) to deliver virulence effector proteins into host cells. Expression of the Hrp system and many effector genes is activated by the HrpL alternative sigma factor. Here, an open reading frame-specific whole-genome microarray was constructed for DC3000 and used to comprehensively identify genes that are differentially expressed in wild-type and deltahrpL strains. Among the genes whose differential regulation was statistically significant, 119 were upregulated and 76 were downregulated in the wild-type compared with the deltahrpL strain. Hierarchical clustering revealed a subset of eight genes that were upregulated particularly rapidly. Gibbs sampling of regions upstream of HrpL-activated operons revealed the Hrp promoter as the only identifiable regulatory motif and supported an iterative refinement involving real-time polymerase chain reaction testing of additional HrpL-activated genes and refinements in a hidden Markov model that can be used to predict Hrp promoters in P. syringae strains. This iterative bioinformatic-experimental approach to a comprehensive analysis of the HrpL regulon revealed a mix of genes controlled by HrpL, including those encoding most type III effectors, twin-arginine transport (TAT) substrates, other regulatory proteins, and proteins involved in the synthesis or metabolism of phytohormones, phytotoxins, and myo-inositol. This analysis provides an extensively verified, robust method for predicting Hrp promoters in P. syringae genomes, and it supports subsequent identification of effectors and other factors that likely are important to the host-specific virulence of P. syringae.

Bacterial Proteins↗

Large-scale identification of protein-protein interaction of Escherichia coli K-12.

Protein-protein interactions play key roles in protein function and the structural organization of a cell. A thorough description of these interactions should facilitate elucidation of cellular activities, targeted-drug design, and whole cell engineering. A large-scale comprehensive pull-down assay was performed using a His-tagged Escherichia coli ORF clone library. Of 4339 bait proteins tested, partners were found for 2667, including 779 of unknown function. Proteins copurifying with hexahistidine-tagged baits on a Ni2+-NTA column were identified by MALDI-TOF MS (matrix-assisted laser desorption ionization time of flight mass spectrometry). An extended analysis of these interacting networks by bioinformatics and experimentation should provide new insights and novel strategies for E. coli systems biology.

Escherichia coli K12↗

From genes to proteins: in vitro expression of rickettsial proteins.

The availability of the complete genome sequences of several organisms allows the comparative analysis of genomes, a branch of bioinformatics known as genomics. With this approach, much can be learned about the biology of organisms that are difficult to culture, even when few, if any, of their proteins have been isolated and studied directly. We have focused our interest on Rickettsia conorii, an obligate intracellular bacterium responsible for Mediterranean spotted fever, a disease endemic in southern Europe. While bioinformatic annotation of the complete genome of this bacteria has allowed identification of 1,374 genes, a large number of them remain functionally uncharacterized. The final goal of many experiments in molecular biology is to use biological systems to synthesize the protein encoded by the gene being studied. Because three-dimensional structures are more resilient to evolution and change than amino acid sequences, structure determination of some open reading frames should also exhibit structural similarity to previously described protein families. We have thus initiated a systematic expression and structure determination program for the proteins encoded by rickettsial genes of interest. We have cloned different genes of R. conorii by recombinational cloning (GATEWAY), Invitrogen) a method that uses in vitro site-specific recombination to accomplish a directional cloning of PCR products and the subsequent automatic subcloning of the DNA segment into new vector backbones at high efficiency. The constructions in p-Dest17 yielded several clones able to express recombinant proteins with a C-terminal histidine tag. Expression of corresponding proteins was then performed using a cell-free protein expression system (Rapid Translation System, RTS, Roche Diagnostics). The recombinational cloning approach coupled to RTS provides an approach to rapid optimization of protein expression and is very useful to express rickettsial proteins. Moreover, this system is able to overcome some of the limitations encountered with rickettsial proteins highly toxic for E. coli or insect cells.

Bacterial Proteins↗

Boudicca, a retrovirus-like long terminal repeat retrotransposon from the genome of the human blood fluke Schistosoma mansoni.

The genome of Schistosoma mansoni contains a proviral form of a retrovirus-like long terminal repeat (LTR) retrotransposon, designated BOUDICCA: Sequence and structural characterization of the new mobile genetic element, which was found in bacterial artificial chromosomes prepared from S. mansoni genomic DNA, revealed the presence of three putative open reading frames (ORFs) bounded by direct LTRs of 328 bp in length. ORF1 encoded a retrovirus-like major homology region and a Cys/His box motif, also present in Gag polyproteins of related retrotransposons and retroviruses. ORF2 encoded enzymatic domains and motifs characteristic of a retrovirus-like polyprotein, including aspartic protease, reverse transcriptase, RNase H, and integrase, in that order, a domain order similar to that of the gypsy/Ty3 retrotransposons. An additional ORF at the 3' end of the retrotransposon may encode an envelope protein. Phylogenetic comparison based on the reverse transcriptase domain of ORF2 confirmed that Boudicca was a gypsy-like retrotransposon and showed that it was most closely related to CsRn1 from the Oriental liver fluke Clonorchis sinensis and to kabuki from Bombyx mori. Bioinformatics approaches together with Southern hybridization analysis of genomic DNA of S. mansoni and the screening of a bacterial artificial chromosome library representing approximately 8-fold coverage of the S. mansoni genome revealed that numerous copies of Boudicca were interspersed throughout the schistosome genome. By reverse transcription-PCR, mRNA transcripts were detected in the sporocyst, cercaria, and adult developmental stages of S. mansoni, indicating that Boudicca is actively transcribed in this trematode.

Amino Acid Sequence↗

Evolving strategies for the incorporation of bioinformatics within the undergraduate cell biology curriculum.

Recent advances in genomics and structural biology have resulted in an unprecedented increase in biological data available from Internet-accessible databases. In order to help students effectively use this vast repository of information, undergraduate biology students at Drake University were introduced to bioinformatics software and databases in three courses, beginning with an introductory course in cell biology. The exercises and projects that were used to help students develop literacy in bioinformatics are described. In a recently offered course in bioinformatics, students developed their own simple sequence analysis tool using the Perl programming language. These experiences are described from the point of view of the instructor as well as the students. A preliminary assessment has been made of the degree to which students had developed a working knowledge of bioinformatics concepts and methods. Finally, some conclusions have been drawn from these courses that may be helpful to instructors wishing to introduce bioinformatics within the undergraduate biology curriculum.

Biology↗

A GPI-linked carbonic anhydrase expressed in the larval mosquito midgut.

We have previously described the first cloning and partial characterization of carbonic anhydrase from larval Aedes aegypti mosquitoes. Larval mosquitoes utilize an alkaline digestive environment in the lumen of their anterior midgut, and we have also demonstrated a critical link between alkalization of the gut and carbonic anhydrase(s). In this report we further examine the nature of the previously described carbonic anhydrase and test the hypothesis that its pattern of expression is consistent with a role in gut alkalization. Additionally we take advantage of the recently published genome of the mosquito Anopheles gambiae to assess the complexity of the carbonic anhydrase gene family in these insects. We report here that the previously described carbonic anhydrase from Aedes aegypti is similar to mammalian CA IV in that it is a GPI-linked peripheral membrane protein. In situ hybridization analyses identify multiple locations of carbonic anhydrase expression in the larval mosquito. An antibody prepared against a peptide sequence specific to the Aedes aegypti GPI-linked carbonic anhydrase labels plasma membranes of a number of cell types including neuronal cells and muscles. A previously undescribed subset of gut muscles is specifically identified by carbonic anhydrase immunohistochemistry. Bioinformatic analyses using the Ensembl automatic analysis pipeline show that there are at least 14 carbonic anhydrase genes in the Anopheles gambiae genome, including a homologue to the GPI-linked gene product described herein. Therefore, as in mammals which similarly possess numerous carbonic anhydrase genes, insects require a large family of these genes to handle the complex metabolic pathways influenced by carbonic anhydrases and their substrates.

Amino Acid Sequence↗

[A new approach to pharmacogenomics].

The medicine in the 21st century will be so called "evidence based medicine" or "personalized medicine," based on the principle of "right drug to right patient." Pharmacogenomics covers the entire spectrum of genes that determines drug behavior and sensitivity, and we anticipate it will bring major impact on the healthcare system as well as the drug discovery process in the near future. Three waves of genomic impact are predicted to arise as follows: The first wave will hit on existing drugs and late-phase development candidates within the next 2-3 years, aiming to minimize the risks in clinical trials (adverse events, resistance, etc.). The wave will then affect the candidate selection process in the early pre-development stage, and finally the disease gene finding to target discovery process. The driving force will be technologies such as SNPs database, differential gene expression (DGE) analysis, proteomics, serial analysis of gene expression (SAGE) and bioinformatics. This new approach of genomic discovery (so called "integrated approach") requires knowledge on how to implement and integrate new valuable technologies from an early stage of the discovery process. The implication of SNPs, high throughput proteomics and application of structural genomics will be the key issues in the pharmacogenomics era.

Genome↗

[Cloning and characterization of three novel genes encoding transmembrane proteins of Schistosoma japonicum].

OBJECTIVE: To clone and analyze novel antigen molecules of Schistosoma japonicum (Sj), and to provide effective vaccine candidate antigens against schistosomiasis japonica. METHODS: Sj adult cDNA library was screened using sera of mice infected with Trichinella spiralis (Ts) and the inserts of positive clones were specifically amplified by PCR. The positive clones were sequenced and the sequence data were analyzed using Nucleotide BLAST software of NCBI and Expert Protein Analysis System of Swiss Institute of Bioinformatics. RESULTS: Nine positive clones were obtained after three rounds of immunoscreening. The size of these inserts ranged from 0.6 kb to 2.1 kb. Among five novel genes, Sj-Ts1, Sj-Ts3 and Sj-Ts5 (GenBank accession number: AY005816, AF299080 and AY024352, respectively) encode trans-membrane proteins with 83, 83 and 233 amino acids, respectively. Sj-Ts1 protein predicted contains one possible trans-membrance helix, one N-myristoylation site, two phosphorylation sites for protein kinase C and one for tyrosine kinase, Sj-Ts3 protein contains two possible transmembrance helices and one casein kinase II phosphorylation site, whereas Sj-Ts5 protein has five possible transmembrance helices, one N-glycosylation site, one N-myristoylation site, two phosphorylation sites for cAMP- and cGMP-dependent protein kinase and four for protein kinase C and one for casein kinase II. CONCLUSION: Three novel genes encoding three transmembrane proteins might be developed as new vaccine candidates against Sj infection.

Amino Acid Sequence↗

Reflections on an arranged marriage between bioinformatics and health informatics.

OBJECTIVE: To compare the discussions of two workshops held during 2001 by two Canadian organisations, HEALNet, a Network of Centres of Excellence for research in health information applications, and Genome Canada, a national research funding agency for genomics and proteomics, in collaboration with the Institute of Genetics of the Canadian Institutes of Health Research, to examine strategic research development in Health Informatics and Bioinformatics respectively. METHODS: Invited workshops with structured debate. Concept analysis of preparative material and debates. RESULTS: A predominantly common set of concepts was discerned from both workshops. Analysis of published definitions showed an inability to distinguish a definition that would suggest that health informatics and bioinformatics are separate disciplines. In both workshops there was evidence of deep concerns of identity, the lack of clear structures to support research funding as well as uncertainty in distinguishing between service and research. CONCLUSIONS: Many deep issues currently inhibit the recognition and funding of research in health and bioinformatics in Canada and elsewhere. Some of these issues are common to both health and bioinformatics. The overlap in prevailing definitions, research concerns and methodological content in the respective domains suggest that common research needs should be better identified and reinforced for the benefit of both.

Biomedical Research↗

[Immunoscreening of Schistosoma japonicum adult worm cDNA library with sera vaccinated with cercaria antigen and analysis of novel genes].

OBJECTIVE: To explore antigens possessing common immunogenicity with Schistosoma japonicum (Sj) cercariae antigens, and to find out new candidate antigens for schistosomiasis diagnosis and vaccine. METHODS: Sj adult cDNA library was screened using sera from rabbits vaccinated with Sj cercariae antigen, the inserts of positive clones were amplified by PCR, all positive clones were sequenced and the data were analysed using Nucleotide BLAST software of NCBI and Expert Protein Analysis System of Swiss Institute of Bioinformatics. RESULTS: Thirteen positive clones were obtained after three rounds of immunoscreening, and all amplified by PCR. Among four novel genes, SjCAI, SjCA, SjCAI-2 and SjCAI-3 (GenBank accession number: AF495883, AF515834, AY118086 and AY129303, respectively) encoded proteins with 353, 161, 137 and 72 animo acids respectively. Sj CAI protein contained six DNA-binding zinc fingers and showed some homology to gastrula zinc finger protein XLCGF48.2; proteins encoded by SjCA, SjCAI-2 and SjCAI-3 respectively contained N-glycosylation sites and phosphorylation sites. CONCLUSION: Novel genes were obtained by immunoscreening Sj adult cDNA library.

Amino Acid Sequence↗

Statistical, computational and visualization methodologies to unveil gene primary structure features.

OBJECTIVES: Gene sequence features such as codon bias, codon context, and codon expansion (e.g. trinucleotide repeats) can be better understood at the genomic scale level by combining statistical methodologies with advanced computer algorithms and data visualization through sophisticated graphical interfaces. This paper presents the ANACONDA system, a bioinformatics application for gene primary structure analysis. METHODS: Codon usage tables using absolute metrics and software for multivariate analysis of codon and amino acid usage are available in public databases. However, they do not provide easy computational and statistical tools to carry out detailed gene primary structure analysis on a genomic scale. We propose the usage of several statistical methods--contingency table analysis, residual analysis, multivariate analysis (cluster analysis)--to analyze the codon bias under various aspects (degree of association, contexts and clustering). RESULTS: The developed solution is a software application that provides a user-guided analysis of codon sequences considering several contexts and codon usage on a genomic scale. The utilization of this tool in our molecular biology laboratory is focused on particular genomes, especially those from Saccharomyces cerevisiae, Candida albicans and Escherichia coli. In order to illustrate the applicability and output layouts of the software these species are herein used as examples. CONCLUSIONS: The statistical tools incorporated in the system are allowing to obtain global views of important sequence features. It is expected that the results obtained will permit identification of general rules that govern codon context and codon usage in any genome. Additionally, identification of genes containing expanded codons that arise as a consequence of erroneous DNA replication events will permit uncovering new genes associated with human disease.

Algorithms↗

Blast2GO goes grid: developing a grid-enabled prototype for functional genomics analysis.

The vast amount in complexity of data generated in Genomic Research implies that new dedicated and powerful computational tools need to be developed to meet their analysis requirements. Blast2GO (B2G) is a bioinformatics tool for Gene Ontology-based DNA or protein sequence annotation and function-based data mining. The application has been developed with the aim of affering an easy-to-use tool for functional genomics research. Typical B2G users are middle size genomics labs carrying out sequencing, ETS and microarray projects, handling datasets up to several thousand sequences. In the current version of B2G. The power and analytical potential of both annotation and function data-mining is somehow restricted to the computational power behind each particular installation. In order to be able to offer the possibility of an enhanced computational capacity within this bioinformatics application, a Grid component is being developed. A prototype has been conceived for the particular problem of speeding up the Blast searches to obtain fast results for large datasets. Many efforts have been done in the literature concerning the speeding up of Blast searches, but few of them deal with the use of large heterogeneous production Grid Infrastructures. These are the infrastructures that could reach the largest number of resources and the best load balancing for data access. The Grid Service under development will analyse requests based on the number of sequences, splitting them accordingly to the available resources. Lower-level computation will be performed through MPIBLAST. The software architecture is based on the WSRF standard.

Computational Biology↗

Analysis of structure and function of putative surface-exposed proteins encoded in the Streptococcus pneumoniae genome: a bioinformatics-based approach to vaccine and drug design.

Streptococcus pneumoniae is the most common cause of fatal community-acquired pneumonia, middle ear infection, and meningitis. The prevention and treatment of this infection have become a top priority for the medical-scientific community. The present polysaccharide-based vaccine used to immunize susceptible hosts is only approximately 60% effective and is ineffective in children younger than 2 years of age. The new conjugate vaccine, based on the engineered diphtheria toxin coupled to polysaccharide antigens. is approved only for use in children under 2 years of age to treat invasive disease. While penicillin is the drug of choice to treat infections secondary to S. pneumoniae, increasing numbers of bacterial strains are resistant to penicillin as well as to broad spectrum antibiotics such as vancomycin. Thus, there is a need to identify new strategies to prevent and treat diseases caused by to S. pneumoniae. In this article, we summarize the utilization of the recently available S. pneumoniae genomic information in order to identify and characterize novel proteins likely located on the surface of this Gram-positive pathogenic bacterium. Because only a limited number of surface proteins of S. pneumoniae have been characterized to date, this information provides new insights into the pathogenesis of this organism as well as highlights possible avenues for its treatment and/or prevention in the future. The review is divided into two sections. First, we brietly summarize current information about known surface-exposed proteins of S. pneumoniae. This is followed by the illustration of procedures for the identification of new putative surface-exposed proteins. These have signal peptides required for their extra-cytoplasmic transport and/or additional signature sequences. Some of these will be S. pneumoniae virulence factors. The signature sequences we have chosen are those leading to protein binding to choline present on the bacterial surface, attachment to peptidoglycan of the cell wall, or anchoring to lipids of the cytoplasmic membrane. All these signatures are indicative of binding of proteins to the surface of this organism. Secondly, we illustrate the application of bioinformatics and modeling tools to these selected proteins in order to provide information about their likely functions and preliminary three-dimensional structure models. The focal point of the analysis of these proteins, their sequences, and structures is the evaluation of their antigenic properties and possible roles in pathogenicity. The information obtained from the genome analysis will be instrumental in the development of a more effective prophylactic and/or therapeutic agents to prevent and to treat infections due to S. pneumoniae.

Amino Acid Sequence↗

The iProClass integrated database for protein functional analysis.

Increasingly, scientists have begun to tackle gene functions and other complex regulatory processes by studying organisms at the global scales for various levels of biological organization, ranging from genomes to metabolomes and physiomes. Meanwhile, new bioinformatics methods have been developed for inferring protein function using associative analysis of functional properties to complement the traditional sequence homology-based methods. To fully exploit the value of the high-throughput system biology data and to facilitate protein functional studies requires bioinformatics infrastructures that support both data integration and associative analysis. The iProClass database, designed to serve as a framework for data integration in a distributed networking environment, provides comprehensive descriptions of all proteins, with rich links to over 50 databases of protein family, function, pathway, interaction, modification, structure, genome, ontology, literature, and taxonomy. In particular, the database is organized with PIRSF family classification and maps to other family, function, and structure classification schemes. Coupled with the underlying taxonomic information for complete genomes, the iProClass system (http://pir.georgetown.edu/iproclass/) supports associative studies of protein family, domain, function, and structure. A case study of the phosphoglycerate mutases illustrates a systematic approach for protein family and phylogenetic analysis. Such studies may serve as a basis for further analysis of protein functional evolution, and its relationship to the co-evolution of metabolic pathways, cellular networks, and organisms.

Amino Acid Sequence↗

The role of KIAA1467 in breast cancer: insights from pan-cancer and single-cell sequencing analysis.

BACKGROUND: Improving the response rate of single-agent immune checkpoint blockade (ICB) urgently requires the discovery of new therapeutic targets for combinatorial regimens. Analyses of tumor microenvironment (TME)-associated biomarkers have verified that KIAA1467 drives the formation of an immune-excluded, non-inflamed TME in breast cancer (BRCA). This study systematically explores the expression pattern, prognostic value, immune regulatory function, biological effects, and drug resistance relevance of FAM234B (also known as KIAA1467) in BRCA. METHODS: We performed pan-cancer survival analysis using The Cancer Genome Atlas (TCGA) datasets. Multi-omics bioinformatics analyses were conducted to evaluate KIAA1467 expression across malignancies. Single-cell RNA sequencing (scRNA-seq) data from GSE176078 was utilized to localize KIAA1467 expression at the cellular level. Immunohistochemistry and western blot assays validated KIAA1467 expression in BRCA clinical specimens. Correlation analyses were implemented to assess relationships between KIAA1467 expression, clinicopathological features, immune modulators, tumor-infiltrating immune cells, and p53 mutation status. Functional enrichment analysis uncovered relevant signaling pathways. Bioinformatic half maximal inhibitory concentration (IC50) prediction and in vitro cellular experiments were applied to evaluate associations between KIAA1467 and chemotherapeutic drug sensitivity. RESULTS: TCGA pan-cancer survival analysis demonstrated that elevated KIAA1467 expression significantly predicted shortened overall survival in BRCA and multiple other tumor types. KIAA1467 displayed distinct expression patterns across cancers, with prominent upregulation in BRCA. scRNA-seq confirmed enriched KIAA1467 expression within BRCA cells, and its upregulation in BRCA tissues was further verified by immunohistochemistry and western blot. High KIAA1467 expression was positively correlated with advanced tumor grade and lymphatic metastasis. KIAA1467 showed negative correlations with most immune modulators and core immune checkpoint molecules, as well as tumor-infiltrating immune cells in the TME, implying its potential function in tumor immune evasion. Low KIAA1467 expression was tightly linked to p53 mutations. Enrichment analysis indicated participation of KIAA1467 in epithelial-mesenchymal transition, apoptosis and cell cycle arrest. Furthermore, high KIAA1467 expression corresponded to higher estimated IC50 values of cisplatin, gefitinib, paclitaxel and gemcitabine, consistent with reduced chemosensitivity observed in vitro. CONCLUSIONS: This study reveals the multifaceted oncogenic role of KIAA1467 in BRCA. KIAA1467 participates in remodeling an immunosuppressive TME, correlates with malignant progression and chemoresistance, and may serve as a promising candidate target to optimize ICB-based combination therapy for BRCA. These findings offer new perspectives for the clinical treatment and comprehensive management of BRCA.

KIAA1467↗