Multi-omics landscape and clinical significance of a SMAD4-driven immune signature: Implications for risk stratification and frontline therapies in pancreatic cancer.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:35317237", "kind": "science-record", "revision": 4, "content_hash": "sha256:2f6b25181a0ee0863f2d9ab70fe41edc69cae1b45e289f890bd72851166e73be", "created_at": "2026-11-01T18:14:07Z", "updated_at": "2026-11-01T22:06:09Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Multi-omics landscape and clinical significance of a SMAD4-driven immune signature: Implications for risk stratification and frontline therapies in pancreatic cancer.", "doi": "10.1016/j.csbj.2022.02.031", "pmid": "35317237", "authors": ["Libo Wang", "Zaoqu Liu", "Rongtao Zhu", "Ruopeng Liang", "Weijie Wang", "Jian Li", "Yuyuan Zhang", "Chunguang Guo", "Xinwei Han", "Yuling Sun"], "journal": "Computational and structural biotechnology journal", "year": 2022, "abstract": "SMAD4 mutation was recently implicated in promoting invasion and poor prognosis of pancreatic cancer (PACA) by regulating the tumor immune microenvironment. However, SMAD4-driven immune landscape and clinical significance remain elusive. In this study, we applied the consensus clustering and weighted correlation network analysis (WGCNA) to identify two heterogeneous immune subtypes and immune genes. Combined with SMAD4-driven genes determined by SMAD4 mutation status, a SMAD4-driven immune signature (SDIS) was developed in ICGC-AU2 (microarray data) via machine learning algorithm, and then was validated by RNA-seq data (TCGA, ICGC-AU and ICGC-CA) and microarray data (GSE62452 and GSE85916). The high-risk group displayed a worse prognosis, and multivariate Cox regression indicated that SDIS was an independent prognostic factor. In six cohorts, SDIS also displayed excellent accuracy in predicting prognosis. Moreover, the high-risk group was characterized by higher frequencies of TP53/CDKN2A mutations and SMAD4 deletion, superior immune checkpoint molecules expression and more sensitive to chemotherapy and immunotherapy. Meanwhile, the low-risk group was significantly enriched in metabolism-related pathways and suggested the potential to target tumor metabolism to develop specific drugs. Overall, SDIS could robustly predict prognosis in PACA, which might serve as an attractive platform to further tailor decision-making in chemotherapy and immunotherapy in clinical settings.", "claims": [{"id": "claim-data-access", "statement": "We collected datasets meeting the study objectives from The Cancer Genome Atlas (TCGA, http://portal.gdc.cancer.gov/), International Cancer Genome Consortium (ICGC, http://dcc.icgc.org/), and Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/) databases", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:35317237", "locator": "sections[3] \"Data acquisition and processing\" paragraph 2", "quote": "We collected datasets meeting the study objectives from The Cancer Genome Atlas (TCGA, http://portal.gdc.cancer.gov/), International Cancer Genome Consortium (ICGC, http://dcc.icgc.org/), and Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/) databases"}], "state": "complete"}, {"id": "claim-target-result", "statement": "WGCNA identified the black module containing 1446 genes as having the strongest association with immune subtypes.", "kind": "quantitative", "target": {"value": 0.001, "unit": "p-value", "tolerance": null, "source": "the results of correlation analysis showed that the black module containing 1446 genes not only had the strongest association with immune subtypes (R^2 = 0.76, P < 0.001), but also had a significant correlation with OS, gender, M stage and grade (Fig. 3G)."}, "evidence": [{"asset": "source:pmid:35317237", "locator": "sections[18] \"Identification of an immune-related co-expression module based on WGCNA\" paragraph 2", "quote": "the results of correlation analysis showed that the black module containing 1446 genes not only had the strongest association with immune subtypes (R^2 = 0.76, P < 0.001), but also had a significant correlation with OS, gender, M stage and grade (Fig. 3G)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "WGCNA identified the black module containing 1446 genes as having the strongest association with immune subtypes.", "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:35317237"], "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": "blocked", "blocked_on": "data:accession_absent", "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": [], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "blocked", "blocked_on": "method:group_comparison_wilcoxon", "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": [], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": ["step:run_analysis blocked on method:group_comparison_wilcoxon", "step:obtain_source_data blocked on data:accession_absent"]}, "data": {"state": "partial", "assets": [{"id": "source:pmid:35317237", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1016/j.csbj.2022.02.031", "sha256": "sha256:becca0234c571e0d79f6316225be734124de55cd1cf6b535f8bb2094ff373421", "bytes": 55730, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1016/j.csbj.2022.02.031", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC8908051", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}], "gaps": []}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "family": "group_comparison", "specific": "wilcoxon", "label": "Group comparison", "dsl_operations": [], "missing_operations": ["group_comparison_wilcoxon"], "expressible": false, "parameters": {}, "data_shapes": ["two_or_more_groups_continuous"], "evidence": {"score": 0.8, "band": "high", "quote": "Wilcoxon"}}, {"id": "method-2", "family": "survival_analysis", "specific": "kaplan_meier", "label": "Survival analysis", "dsl_operations": ["survival_km"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 0.8, "band": "high", "quote": "Kaplan-Meier"}}, {"id": "method-3", "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": 0.7, "band": "medium", "quote": "Cox regression"}}, {"id": "method-4", "family": "diagnostic_evaluation", "specific": "roc", "label": "Diagnostic test evaluation", "dsl_operations": ["confusion_counts", "roc_curve", "sensitivity_specificity", "solve_confusion_matrix", "classification_metrics", "published_precision_envelope"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["reference_standard_and_test"], "evidence": {"score": 0.8, "band": "high", "quote": "ROC curve"}}, {"id": "method-5", "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"}}, {"id": "method-6", "family": "contingency_analysis", "specific": "fisher_exact", "label": "Categorical (contingency table) analysis", "dsl_operations": ["contingency_table", "chi_square_test"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["categorical_cross_tabulation"], "evidence": {"score": 0.8, "band": "high", "quote": "Fisher's exact"}}], "targets": [{"id": "target-published-estimate", "claim_id": "claim-target-result", "operation": "chi_square_test", "expected_value": 0.001, "unit": "p-value", "tolerance": null, "state": "complete", "note": "The threshold the paper applied to its own result, as the paper states it. A run that reproduces the effect is judged against this threshold."}], "gaps": ["method.group_comparison_wilcoxon"]}, "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": "blocked", "tier": "R4", "blocking_axis": "data", "blocked_on": "data:accession_absent", "axes": {"method": {"tier": "R1", "expressible": false, "required_operations": [], "missing_operations": ["group_comparison_wilcoxon"], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: wilcoxon."}, "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": "R4", "reachable": false, "accessions": ["GSE62452 (NCI", "GSE85916 (n = 79)"], "resolved_accessions": [], "statements": ["We collected datasets meeting the study objectives from The Cancer Genome Atlas (TCGA, http://portal.gdc.cancer.gov/), International Cancer Genome Consortium (ICGC, http://dcc.icgc.org/), and Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/) databases"], "basis": "The paper names GSE62452 (NCI, GSE85916 (n = 79), but the accession does not resolve in the repository (no reason recorded, no reason recorded), so the data cannot be reached from here. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": [], "assets": ["source:pmid:35317237"], "steps": []}, "must_build": {"dsl_operations": [{"operation": "group_comparison_wilcoxon", "unlocks_papers": null, "priority": null}], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:None"]}, "gaps": ["data:accession_absent"]}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T17:38:59Z", "independence": "single_reader"}, "evidence_check": {"method": null, "availability": null}, "calls": 5, "usage": {"prompt_tokens": 15419, "completion_tokens": 2100, "cached_tokens": 264}}, "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:35317237", "type": "paper", "label": "pmid:35317237"}, {"id": "source:pmid:35317237", "type": "manuscript", "label": "PMID 35317237 full text"}, {"id": "data:geo:None", "type": "dataset", "label": "GEO None"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:35317237", "type": "paper", "label": "pmid:35317237"}, {"id": "source:pmid:35317237", "type": "manuscript", "label": "PMID 35317237 full text"}, {"id": "data:geo:None", "type": "dataset", "label": "GEO None"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-35317237", "type": "extraction", "used": ["source:pmid:35317237"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-None", "type": "accession_resolution", "used": ["data:geo:None"], "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:35317237", "parent_hash": "sha256:e5e21f274b2847342da606676d544c8cb9c626c03a154b8f403009e706f55903", "fork_of": null, "generation": 3}, "gaps": ["execution.not_run", "method.group_comparison_wilcoxon", "review.human_critique", "review.independent_reader", "review.machine_critique", "step:obtain_source_data blocked on data:accession_absent", "step:run_analysis blocked on method:group_comparison_wilcoxon"], "assays": [{"role": "data_generation", "definition_id": "rna_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["earning algorithm, and then was validated by RNA-seq data (TCGA, ICGC-AU and ICGC-CA) and microar"], "order_basis": "paper_text_order:736", "id": "assay:1"}, {"role": "analysis", "definition_id": "group_comparison", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 0.8, "evidence": ["Wilcoxon"], "order_basis": "consumes_earlier_output", "id": "assay:2"}]}