Sequential gene expression analysis of cervical malignant transformation identifies RFC4 as a novel diagnostic and prognostic biomarker.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:36352434", "kind": "science-record", "revision": 5, "content_hash": "sha256:dc9f65a2b1220df9aedc9b59367602d508d4611f0e33e1450da7a1da4fd808e5", "created_at": "2026-11-01T18:15:48Z", "updated_at": "2026-11-01T22:50:34Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Sequential gene expression analysis of cervical malignant transformation identifies RFC4 as a novel diagnostic and prognostic biomarker.", "doi": "10.1186/s12916-022-02630-8", "pmid": "36352434", "authors": ["Jianwei Zhang", "Silu Meng", "Xiaoyan Wang", "Jun Wang", "Xinran Fan", "Haiying Sun", "Ruoqi Ning", "Bing Xiao", "Xiangqin Li", "Yao Jia", "Dongli Kong", "Ruqi Chen", "Changyu Wang", "Ding Ma", "Shuang Li"], "journal": "BMC medicine", "year": 2022, "abstract": "BACKGROUND: Cervical squamous cell carcinoma (SCC) is known to arise through increasingly higher-grade squamous intraepithelial lesions (SILs) or cervical intraepithelial neoplasias (CINs). This study aimed to describe sequential molecular changes and identify biomarkers in cervical malignant transformation.\nMETHODS: Multidimensional data from five publicly available microarray and TCGA-CESC datasets were analyzed. Immunohistochemistry was carried out on 354 cervical tissues (42 normal, 62 CIN1, 26 CIN2, 47 CIN3, and 177 SCC) to determine the potential diagnostic and prognostic value of identified biomarkers.\nRESULTS: We demonstrated that normal epithelium and SILs presented higher molecular homogeneity than SCC. Genes in the region (e.g., 3q, 12q13) with copy number alteration or HPV integration were more likely to lose or gain expression. The IL-17 signaling pathway was enriched throughout disease progression with downregulation of IL17C and decreased Th17 cells at late stage. Furthermore, we identified AURKA, TOP2A, RFC4, and CEP55 as potential causative genes gradually upregulated during the normal-SILs-SCC transition. For detecting high-grade SIL (HSIL), TOP2A and RFC4 showed balanced sensitivity (both 88.2%) and specificity (87.1 and 90.1%), with high AUC (0.88 and 0.89). They had equivalent diagnostic performance alone to the combination of p16INK4a and Ki-67. Meanwhile, increased expression of RFC4 significantly and independently predicted favorable outcomes in multi-institutional cohorts of SCC patients.\nCONCLUSIONS: Our comprehensive study of gene expression profiling has identified dysregulated genes and biological processes during cervical carcinogenesis. RFC4 is proposed as a novel surrogate biomarker for determining HSIL and HSIL+, and an independent prognostic biomarker for SCC.", "claims": [{"id": "claim-method", "statement": "Survival curves were plotted using the Kaplan-Meier method and compared using the log-rank test. Multivariate Cox regression analysis was performed to determine the prognostic value of the selected gene with considering clinical factors.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:36352434", "locator": "sections[8] \"Survival analysis\" paragraph 3", "quote": "Survival curves were plotted using the Kaplan-Meier method and compared using the log-rank test. Multivariate Cox regression analysis was performed to determine the prognostic value of the selected gene with considering clinical factors."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Publicly available datasets were analyzed in this study. These can be found in The Cancer Genome Atlas (https://portal.gdc.cancer.gov/) and the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/). The tissue microarrays were obtained from Fanpu Biotech. Co., Ltd. (Guilin, China; Product code: CIN1021 and CIN1022) and Outdo Biotech. Co., Ltd. (Shanghai, China; Product Code: HUteS154Su01). The raw experimental data and analysis codes supporting the conclusions of this article will be made available by the corresponding author.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:36352434", "locator": "sections[25] \"Availability of data and materials\" paragraph 2", "quote": "Publicly available datasets were analyzed in this study. These can be found in The Cancer Genome Atlas (https://portal.gdc.cancer.gov/) and the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/). The tissue microarrays were obtained from Fanpu Biotech. Co., Ltd. (Guilin, China; Product code: CIN1021 and CIN1022) and Outdo Biotech. Co., Ltd. (Shanghai, China; Product Code: HUteS154Su01). The raw experimental data and analysis codes supporting the conclusions of this article will be made available by the corresponding author."}], "state": "complete"}, {"id": "claim-target-result", "statement": "For detecting high-grade SIL (HSIL), TOP2A and RFC4 showed balanced sensitivity (both 88.2%) and specificity (87.1 and 90.1%), with high AUC (0.88 and 0.89).", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:36352434", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "For detecting high-grade SIL (HSIL), TOP2A and RFC4 showed balanced sensitivity (both 88.2%) and specificity (87.1 and 90.1%), with high AUC (0.88 and 0.89)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "For detecting high-grade SIL (HSIL), TOP2A and RFC4 showed balanced sensitivity (both 88.2%) and specificity (87.1 and 90.1%), with high AUC (0.88 and 0.89).", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:36352434"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE138080"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE138080"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:36352434", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1186/s12916-022-02630-8", "sha256": "sha256:ca47d0ed218262c33275f0bac09ffdb064257e8019fde2b2743f355f688dfa18", "bytes": 73284, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1186/s12916-022-02630-8", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC9648022", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE138080", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE138080", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE138080", "version": null, "note": "Publicly available datasets were analyzed in this study. These can be found in The Cancer Genome Atlas (https://portal.gdc.cancer.gov/) and the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/). The tissue microarrays were obtained from Fanpu Biotech. Co., Ltd. (Guilin, China; Product code: CIN1021 and CIN1022) and Outdo Biotech. Co., Ltd. (Shanghai, China; Product Code: HUteS154Su01). The raw experimental data and analysis codes supporting the conclusions of this article will be made available by the corresponding author.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Publicly available datasets were analyzed in this study. These can be found in The Cancer Genome Atlas (https://portal.gdc.cancer.gov/) and the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/). The tissue microarrays were obtained from Fanpu Biotech. Co., Ltd. (Guilin, China; Product code: CIN1021 and CIN1022) and Outdo Biotech. Co., Ltd. (Shanghai, China; Product Code: HUteS154Su01). The raw experimental data and analysis codes supporting the conclusions of this article will be made available by the corresponding author.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM4098861", "GSM4098862", "GSM4098863", "GSM4098864", "GSM4098865", "GSM4098866", "GSM4098867", "GSM4098868", "GSM4098869", "GSM4098870", "GSM4098871", "GSM4098872", "GSM4098873", "GSM4098874", "GSM4098875", "GSM4098876", "GSM4098877", "GSM4098878", "GSM4098879", "GSM4098880", "GSM4098881", "GSM4098882", "GSM4098883", "GSM4098884", "GSM4098885", "GSM4098886", "GSM4098887", "GSM4098888", "GSM4098889", "GSM4098890", "GSM4098891", "GSM4098892", "GSM4098893", "GSM4098894", "GSM4098895"], "sample_count": 35, "group_sizes": null, "group_sizes_basis": null, "platform": "4133", "taxon": "Homo sapiens", "title": "Identification of deregulated pathways, key regulators, and novel miRNA-mRNA interactions in HPV-mediated transformation. 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These can be found in The Cancer Genome Atlas (https://portal.gdc.cancer.gov/) and the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/). The tissue microarrays were obtained from Fanpu Biotech. Co., Ltd. (Guilin, China; Product code: CIN1021 and CIN1022) and Outdo Biotech. Co., Ltd. (Shanghai, China; Product Code: HUteS154Su01). The raw experimental data and analysis codes supporting the conclusions of this article will be made available by the corresponding author.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Publicly available datasets were analyzed in this study. These can be found in The Cancer Genome Atlas (https://portal.gdc.cancer.gov/) and the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/). The tissue microarrays were obtained from Fanpu Biotech. Co., Ltd. (Guilin, China; Product code: CIN1021 and CIN1022) and Outdo Biotech. Co., Ltd. (Shanghai, China; Product Code: HUteS154Su01). 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These can be found in The Cancer Genome Atlas (https://portal.gdc.cancer.gov/) and the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/). The tissue microarrays were obtained from Fanpu Biotech. Co., Ltd. (Guilin, China; Product code: CIN1021 and CIN1022) and Outdo Biotech. Co., Ltd. (Shanghai, China; Product Code: HUteS154Su01). The raw experimental data and analysis codes supporting the conclusions of this article will be made available by the corresponding author.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Publicly available datasets were analyzed in this study. These can be found in The Cancer Genome Atlas (https://portal.gdc.cancer.gov/) and the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/). The tissue microarrays were obtained from Fanpu Biotech. Co., Ltd. (Guilin, China; Product code: CIN1021 and CIN1022) and Outdo Biotech. Co., Ltd. (Shanghai, China; Product Code: HUteS154Su01). The raw experimental data and analysis codes supporting the conclusions of this article will be made available by the corresponding author.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM1943705", "GSM1943706", "GSM1943707", "GSM1943708", "GSM1943709", "GSM1943710", "GSM1943711", "GSM1943712", "GSM1943713", "GSM1943714", "GSM1943715", "GSM1943716", "GSM1943717", "GSM1943718", "GSM1943719", "GSM1943720", "GSM1943721", "GSM1943722", "GSM1943723", "GSM1943724", "GSM1943725", "GSM1943726", "GSM1943727", "GSM1943728", "GSM1943729", "GSM1943730", "GSM1943731", "GSM1943732", "GSM1943733", "GSM1943734", "GSM1943735", "GSM1943736", "GSM1943737", "GSM1943738", "GSM1943739", "GSM1943740", "GSM1943741", "GSM1943742", "GSM1943743", "GSM1943744", "GSM1943745"], "sample_count": 41, "group_sizes": null, "group_sizes_basis": null, "platform": "570", "taxon": "Homo sapiens", "title": "TMEM45A, SERPINB5 and p16INK4A transcript levels are predictive for development of high-grade cervical lesions", "resolution_checked_at": "2026-11-01T18:46:34Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "data:geo:GSE7803", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE7803", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE7803", "version": null, "note": "Publicly available datasets were analyzed in this study. These can be found in The Cancer Genome Atlas (https://portal.gdc.cancer.gov/) and the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/). The tissue microarrays were obtained from Fanpu Biotech. Co., Ltd. (Guilin, China; Product code: CIN1021 and CIN1022) and Outdo Biotech. Co., Ltd. (Shanghai, China; Product Code: HUteS154Su01). The raw experimental data and analysis codes supporting the conclusions of this article will be made available by the corresponding author.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Publicly available datasets were analyzed in this study. These can be found in The Cancer Genome Atlas (https://portal.gdc.cancer.gov/) and the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/). The tissue microarrays were obtained from Fanpu Biotech. Co., Ltd. (Guilin, China; Product code: CIN1021 and CIN1022) and Outdo Biotech. Co., Ltd. (Shanghai, China; Product Code: HUteS154Su01). 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Immuno", "ve bioinformatic analysis of gene expression microarray datasets was conducted to identify molecular", ". Figure S10. The illustration of the tissue microarray (HUteS154Su01; TMA) from Outdo Biotech. Co.,", "TMA) from Outdo Biotech. Co., Ltd. Table S1. Microarray datasets analyzed in this study. Table S2. H"], "order_basis": "paper_text_order:462", "id": "assay:1"}, {"role": "data_generation", "definition_id": "ihc", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["oarray and TCGA-CESC datasets were analyzed. Immunohistochemistry was carried out on 354 cervical tissues (42", "nce alone to the combination of p16INK4a and Ki-67. Meanwhile, increased expression of RFC4 sig", "Figure S2. The flow of sample selection and immunohistochemistry (IHC), related to Table S2. Figure S3. Pathw", "Gene Sets1&2. Table S4. Antibodies used for immunohistochemical staining. Table S5. Immunohistochemical scor"], "order_basis": "paper_text_order:511", "id": "assay:2"}, {"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["survival_km"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["Survival curves were plotted using the Kaplan-Meier method and compared using the log-rank test. Multivariate Cox regression analysis was performed to determine the prognostic value of the selected gene with considering clinical factors."], "order_basis": "consumes_earlier_output", "id": "assay:3"}]}