Multi-omics analysis of tumor angiogenesis characteristics and potential epigenetic regulation mechanisms in renal clear cell carcinoma.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:33761933", "kind": "science-record", "revision": 6, "content_hash": "sha256:120632948ed8d66fafe177bd3eb78c6a709c10c01f3f4953d4d7fd7772eefcd2", "created_at": "2026-11-01T15:41:30Z", "updated_at": "2026-11-01T21:24:58Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Multi-omics analysis of tumor angiogenesis characteristics and potential epigenetic regulation mechanisms in renal clear cell carcinoma.", "doi": "10.1186/s12964-021-00728-9", "pmid": "33761933", "authors": ["Wenzhong Zheng", "Shiqiang Zhang", "Huan Guo", "Xiaobao Chen", "Zhangcheng Huang", "Shaoqin Jiang", "Mengqiang Li"], "journal": "Cell communication and signaling : CCS", "year": 2021, "abstract": "BACKGROUND: Tumor angiogenesis, an essential process for cancer proliferation and metastasis, has a critical role in prognostic of kidney renal clear cell carcinoma (KIRC), as well as a target in guiding treatment with antiangiogenic agents. However, tumor angiogenesis subtypes and potential epigenetic regulation mechanisms in KIRC patient remains poorly characterized. System evaluation of angiogenesis subtypes in KIRC patient might help to reveal the mechanisms of KIRC and develop more target treatments for patients.\nMETHOD: Ten independent tumor angiogenesis signatures were obtained from molecular signatures database (MSigDB) and gene set variation analysis was performed to calculate the angiogenesis score in silico using the Cancer Genome Atlas (TCGA) KIRC dataset. Tumor angiogenesis subtypes in 539 TCGA-KIRC patients were identified using consensus clustering analysis. The potential regulation mechanisms was studied using gene mutation, copy number variation, and differential methylation analysis (DMA). The master transcription factors (MTF) that cause the difference in tumor angiogenesis signals were completed by transcription factor enrichment analysis.\nRESULTS: The angiogenesis score of a prognosis related angiogenesis signature including 189 genes was significantly correlated with immune score, stroma score, hypoxia score, and vascular endothelial growth factor (VEGF) signal score in 539 TCGA KIRC patients. MMRN2, CLEC14A, ACVRL1, EFNB2, and TEK in candidate gene set showed highest correlation coefficient with angiogenesis score in TCGA-KIRC patients. In addition, all of them were associated with overall survival in both TCGA-KIRC and E-MTAB-1980 KIRC data. Clustering analysis based on 183 genes in angiogenesis signature identified two prognosis related angiogenesis subtypes in TCGA KIRC patients. Two clusters also showed different angiogenesis score, immune score, stroma score, hypoxia score, VEGF signal score, and microenvironment score. DMA identified 59,654 differential methylation sites between two clusters and part of these sites were correlated with tumor angiogenesis genes including CDH13, COL4A3, and RHOB. In addition, RFX2, SOX13, and THRA were identified as top three MTF in regulating angiogenesis signature in KIRC patients.\nCONCLUSION: Our study indicate that evaluation the angiogenesis subtypes of KIRC based on angiogenesis signature with 183 genes and potential epigenetic mechanisms may help to develop more target treatments for KIRC patients. Video Abstract.", "claims": [{"id": "claim-data-access", "statement": "The data generated are included in the manuscript and supplementary data.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33761933", "locator": "sections[27] \"notes\" paragraph 1", "quote": "The data generated are included in the manuscript and supplementary data."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": null, "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:33761933"], "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:E-MTAB-1980"], "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:E-MTAB-1980"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:33761933", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1186/s12964-021-00728-9", "sha256": "sha256:8e9d3d2952a5b0dc2d4523f5a26bc61aeb5dbc8f2c21e4b9c7ac27da9074d6ab", "bytes": 55156, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1186/s12964-021-00728-9", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC7992844", "source": "europe_pmc_fulltext", "coverage": "whole_body_without_references", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:E-MTAB-1980", "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=E-MTAB-1980", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "E-MTAB-1980", "version": null, "note": "The data generated are included in the manuscript and supplementary data.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The data generated are included in the manuscript and supplementary data.", "access_statement_kind": "data_availability_statement", "sample_accessions": [], "sample_count": null, "group_sizes": null, "group_sizes_basis": null, "platform": null, "taxon": null, "title": null, "resolution_checked_at": "2026-10-31T18:28:57Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "asset:table:pmid:33761933:1", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:2bd8e7c73fb16d85931080772fce9d5ff83408078f22ab1061bcdf04048515ed", "bytes": 1398, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[16]/table-wrap[1]#Tab1", "version": null, "note": "Angiogenesis related genes in No. 7 reference gene set were significantly correlated with the methylation level of corresponding enhancer", "structure": {"pmcid": "PMC7992844", "section_index": 16, "section_title": "Differential methylation sites in two angiogenesis subgroups of TCGA KIRC patients", "row_count": 18, "column_count": 5}, "table": {"label": "Table 1", "caption": "Angiogenesis related genes in No. 7 reference gene set were significantly correlated with the methylation level of corresponding enhancer", "rows": [["Symbol", "Probe", "Distance", "Raw.p", "Pe"], ["ANG", "cg24162781", "63,309", "4.1017E-19", "0.000999001"], ["CDH13", "cg08344351", "1,153,078", "7.57956E-13", "0.000999001"], ["CDH13", "cg00864293", "1,073,606", "8.19426E-14", "0.000999001"], ["CDH13", "cg03031932", "1,113,268", "5.77968E-09", "0.000999001"], ["CDH13", "cg16583186", "1,134,045", "4.70367E-10", "0.000999001"], ["COL4A3", "cg18018313", "372,087", "1.44211E-16", "0.000999001"], ["COL4A3", "cg12302987", "2,752,319", "1.52068E-16", "0.000999001"], ["HTATIP2", "cg09118558", "252,588", "1.75087E-11", "0.000999001"], ["PLG", "cg22008851", "22,694", "1.39688E-09", "0.000999001"], ["RHOB", "cg11426800", "− 3,060,799", "1.49831E-09", "0.000999001"], ["RHOB", "cg01227744", "2462", "1.11331E-10", "0.000999001"], ["RHOB", "cg02153681", "− 65,617", "7.00899E-10", "0.000999001"], ["RHOB", "cg07493834", "− 1,465,071", "7.00899E-10", "0.000999001"], ["SPHK1", "cg10616974", "− 127,777", "2.17239E-11", "0.000999001"], ["SPINK5", "cg02154084", "1,220,880", "1.65585E-08", "0.000999001"], ["VEGFA", "cg23906612", "− 204,454", "3.21951E-14", "0.000999001"], ["VEGFA", "cg26464586", "− 167,487", "6.50071E-13", "0.000999001"]], "row_count": 18, "column_count": 5, "numeric_cells": 72, "header_rows": 1, "locator": "section[16]/table-wrap[1]#Tab1"}}], "gaps": ["asset:data:geo:E-MTAB-1980 not downloaded", "asset:data:geo:E-MTAB-1980 licence not read"]}, "analysis": {"state": "complete", "methods": [{"id": "method-1", "family": "survival_analysis", "specific": "cox_proportional_hazards", "label": "Survival analysis", "dsl_operations": ["cox_ph"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 0.8, "band": "high", "quote": "Cox regression"}}, {"id": "method-2", "family": "survival_analysis", "specific": "log_rank_test", "label": "Survival analysis", "dsl_operations": ["logrank_test"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 0.8, "band": "high", "quote": "log-rank"}}, {"id": "method-3", "family": "contingency_analysis", "specific": "chi_square", "label": "Categorical (contingency table) analysis", "dsl_operations": ["chi_square_test"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["categorical_cross_tabulation"], "evidence": {"score": 0.8, "band": "high", "quote": "Chi-square"}}], "targets": [], "gaps": []}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "complete", "tier": "R1", "blocking_axis": "none", "blocked_on": "nothing:replicable_now", "axes": {"method": {"tier": "R1", "expressible": true, "required_operations": ["cox_ph"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: cox_proportional_hazards."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["E-MTAB-1980"], "resolved_accessions": ["E-MTAB-1980"], "statements": ["The data generated are included in the manuscript and supplementary data."], "basis": "The paper names E-MTAB-1980 in EMBL-EBI and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["cox_ph"], "assets": ["source:pmid:33761933", "data:geo:E-MTAB-1980", "asset:table:pmid:33761933:1"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:E-MTAB-1980"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-10-31T19:29:10Z", "independence": "single_reader"}, "evidence_check": {"method": null, "availability": "verbatim"}, "calls": 3, "usage": {"prompt_tokens": 38729, "completion_tokens": 2527, "cached_tokens": 792}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:33761933", "type": "paper", "label": "pmid:33761933"}, {"id": "source:pmid:33761933", "type": "manuscript", "label": "PMID 33761933 full text"}, {"id": "data:geo:E-MTAB-1980", "type": "dataset", "label": "GEO E-MTAB-1980"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:33761933", "type": "paper", "label": "pmid:33761933"}, {"id": "source:pmid:33761933", "type": "manuscript", "label": "PMID 33761933 full text"}, {"id": "data:geo:E-MTAB-1980", "type": "dataset", "label": "GEO E-MTAB-1980"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-33761933", "type": "extraction", "used": ["source:pmid:33761933"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-E-MTAB-1980", "type": "accession_resolution", "used": ["data:geo:E-MTAB-1980"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:33761933", "parent_hash": "sha256:cbc02e2bc5cd45d62e45280781f84d9be96db87980b3424bedb101c03f30c36b", "fork_of": null, "generation": 5}, "gaps": ["asset:data:geo:E-MTAB-1980 licence not read", "asset:data:geo:E-MTAB-1980 not downloaded", "execution.not_run", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["cox_ph"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 0.8, "evidence": ["Cox regression"], "order_basis": "analysis_only", "id": "assay:1"}]}