Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:23836465", "kind": "science-record", "revision": 8, "content_hash": "sha256:dde8273e84f4f31018b6fa6f12be482de5041b75a7cb280ae78ca58e5ca124d3", "created_at": "2026-11-01T15:40:03Z", "updated_at": "2026-11-01T22:41:58Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer.", "doi": "10.1002/path.4212", "pmid": "23836465", "authors": ["Eva Budinska", "Vlad Popovici", "Sabine Tejpar", "Giovanni D'Ario", "Nicolas Lapique", "Katarzyna Otylia Sikora", "Antonio Fabio Di Narzo", "Pu Yan", "John Graeme Hodgson", "Scott Weinrich", "Fred Bosman", "Arnaud Roth", "Mauro Delorenzi"], "journal": "The Journal of pathology", "year": 2013, "abstract": "The recognition that colorectal cancer (CRC) is a heterogeneous disease in terms of clinical behaviour and response to therapy translates into an urgent need for robust molecular disease subclassifiers that can explain this heterogeneity beyond current parameters (MSI, KRAS, BRAF). Attempts to fill this gap are emerging. The Cancer Genome Atlas (TGCA) reported two main CRC groups, based on the incidence and spectrum of mutated genes, and another paper reported an EMT expression signature defined subgroup. We performed a prior free analysis of CRC heterogeneity on 1113 CRC gene expression profiles and confronted our findings to established molecular determinants and clinical, histopathological and survival data. Unsupervised clustering based on gene modules allowed us to distinguish at least five different gene expression CRC subtypes, which we call surface crypt-like, lower crypt-like, CIMP-H-like, mesenchymal and mixed. A gene set enrichment analysis combined with literature search of gene module members identified distinct biological motifs in different subtypes. The subtypes, which were not derived based on outcome, nonetheless showed differences in prognosis. Known gene copy number variations and mutations in key cancer-associated genes differed between subtypes, but the subtypes provided molecular information beyond that contained in these variables. Morphological features significantly differed between subtypes. The objective existence of the subtypes and their clinical and molecular characteristics were validated in an independent set of 720 CRC expression profiles. Our subtypes provide a novel perspective on the heterogeneity of CRC. The proposed subtypes should be further explored retrospectively on existing clinical trial datasets and, when sufficiently robust, be prospectively assessed for clinical relevance in terms of prognosis and treatment response predictive capacity. Original microarray data were uploaded to the ArrayExpress database (http://www.ebi.ac.uk/arrayexpress/) under Accession Nos E-MTAB-990 and E-MTAB-1026.", "claims": [{"id": "claim-method", "statement": "Hierarchical clustering (complete linkage, Pearson correlation similarity measure) and dynamic cut tree 20 were used to produce gene modules (groups of genes with correlated expression)", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:23836465", "locator": "sections[4] \"Subtype definition and validation\" paragraph 2", "quote": "Hierarchical clustering (complete linkage, Pearson correlation similarity measure) and dynamic cut tree 20 were used to produce gene modules (groups of genes with correlated expression)"}], "state": "complete"}, {"id": "claim-data-access", "statement": "which were uploaded to ArrayExpress (http://www.ebi.ac.uk/arrayexpress/), under Accession Nos E-MTAB-990 and E-MTAB-1026, respectively.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:23836465", "locator": "sections[3] \"Data acquisition and processing\" paragraph 3", "quote": "which were uploaded to ArrayExpress (http://www.ebi.ac.uk/arrayexpress/), under Accession Nos E-MTAB-990 and E-MTAB-1026, respectively."}], "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:23836465"], "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-1026"], "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-1026"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:23836465", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1002/path.4212", "sha256": "sha256:e086752af1e5b6d5e4638c26d5e388eab161e1fab138b67a08fcc3b697009d96", "bytes": 57477, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1002/path.4212", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC3840702", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:E-MTAB-1026", "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-1026", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "E-MTAB-1026", "version": null, "note": "which were uploaded to ArrayExpress (http://www.ebi.ac.uk/arrayexpress/), under Accession Nos E-MTAB-990 and E-MTAB-1026, respectively.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "which were uploaded to ArrayExpress (http://www.ebi.ac.uk/arrayexpress/), under Accession Nos E-MTAB-990 and E-MTAB-1026, respectively.", "access_statement_kind": "repository_route_statement", "sample_accessions": [], "sample_count": null, "group_sizes": null, "group_sizes_basis": null, "platform": null, "taxon": null, "title": null, "resolution_checked_at": "2026-10-31T18:28:56Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "data:geo:E-MTAB-990", "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-990", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "E-MTAB-990", "version": null, "note": "which were uploaded to ArrayExpress (http://www.ebi.ac.uk/arrayexpress/), under Accession Nos E-MTAB-990 and E-MTAB-1026, respectively.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "which were uploaded to ArrayExpress (http://www.ebi.ac.uk/arrayexpress/), under Accession Nos E-MTAB-990 and E-MTAB-1026, respectively.", "access_statement_kind": "repository_route_statement", "sample_accessions": [], "sample_count": null, "group_sizes": null, "group_sizes_basis": null, "platform": null, "taxon": null, "title": null, "resolution_checked_at": "2026-10-31T18:29:04Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "asset:table:pmid:23836465:1", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:b4efe29cf828373c1cab58dbb8fdd717230565f666e6d9201b4d0f6b41f828bf", "bytes": 4504, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[10]/table-wrap[1]#tbl1", "version": null, "note": "Biological identification of gene modules", "structure": {"pmcid": "PMC3840702", "section_index": 10, "section_title": "Subtypes are characterized by distinct biological components", "row_count": 24, "column_count": 4}, "table": {"label": "Table 1", "caption": "Biological identification of gene modules", "rows": [["Cluster name", "Number of genes", "Pathway analysis result (number of overlapping genes, p value) OR description based on literature search", "Selected genes"], ["1. GDC", "27", "Genes involved in differentiation of colon crypt and/or whose expression was reported to be affected in colorectal cancer and/or with prognostic effect in CRC", "Intestinal differentiation genes: CDX245, IHH46, VAV347, ASCL235, PLAGL248 Genes reported altered in colorectal cancer with prognostic effect: PITX249, DDC50, PRLR51, SPINK152 Other genes connected to CRC: GGH–connected to CIMP+ phenotype 53 NR1I2–connected to chemoresistance 54"], ["2. Chromosome 20q genes", "33", "Chromosome 20 (26 genes, 9.2E-34)", "Other, non-20q genes: TP53RK, ANO9, NEU1, CLDN3, PRSS8"], ["3. Proliferation", "83", "Cell cycle (36 genes, 3.0E-33) Mitosis (26 genes, 1.4E-29) Chromosome (26 genes, 2.5E-17) DNA metabolic process (20 genes, 4.9E-10) Lipid synthesis (4 genes, 5.0E-2)", "Mitotic checkpoint kinases: BUB1, BUB1B Cyclins: CCNA2, CCNB2 Centromere proteins: CENPA, CENPE, CENPN Kinesins: KIF11, KIF23, KIF4A Topoisomerase II (TOP2A) Cell division cycle 2 CDC2"], ["4. Colon crypt markers (secretory cells)", "16", "", "AGR255, AGR3, MUC2, SPINK456, RETNLB57, REG458"], ["5. EMT/stroma", "310", "Extracellular region part (90 genes) 2.7E-36 Cell adhesion (57 genes) 1.2E-17 Extracellular matrix (44 genes) 5.3E-30 Collagen (16 genes) 1.2E-15 EGF-like domain (26 genes) 1.6E-12 Cell motion (33 genes) 7.2E-8 Blood vessel development (25 genes) 1.1E-8 Growth factor binding (6 genes) 6.0E-5 Frizzled related (5 genes) 6.7E-3 Cell junction organization (7 genes) 1.8E-2 WNT receptor signalling pathway (8 genes) 1.4E-1", "Inhibitors of β-catenin-dependent canonical WNT: SFRP1, SFRP2, SFRP4, DKK3, FZD1,7, PRICKLE1, NXN Mesenchymal markers: N-cadherin, OB cadherin, SPARC, DDR2 EMT inducers(TFs): SNAI2, ZEB1, ZEB2, TWIST1, CDH11 ECM remodelling and invasion: MMP14, VIM ECM proteins: fibronectin 1, collagens Angiogenesis: PLAT, PLAU, NRP1, NRP2, THBS1, THBS2, THBS4 TGFs, their receptors and binding proteins: IGF1, IGFBP5, IGFBP7,TGFB, LTBP1, LTBP2, PDGFRA, PDGFRB"], ["6. Unidentified", "14", "", "DUSP1, EGR2, SERPINE1"], ["7 and 8. Immune response", "103", "Immune response (42 genes) 2.0E-28 Positive regulation of immune system process (16 genes) 4.0E-9 Antigen processing and presentation via MHC class II (6 genes) 7.5E-5 Defence response (31 genes) 3.3E-17 Chemokine signalling pathway (9 genes) 2.2E-3 Lymphocyte activation (11 genes) 2.1E-5 Regulation of programmed cell death (14 genes) 2.1E-2", "Cytokines: CCL3, CXCL5, CXCL9,CXCL10, CXCL11, SPP1, LTB MHC class II: HLA-DMB, HLA-DPA1, HLA-DRA, CD74 MHC class I: HLA-F, TAP1, TAP2 Anti-apoptotic: BCL2A1, CD74, BIRC3, IFI6, TNFAIP3, TNFAIP3 Apoptotic: STAT1, XAF1 Interferon-induced proteins: IFI30, IFI16, IFI44, IFI16, IFIH1, IFIT3"], ["Cluster-unassigned meta-genes with colon crypt cell markers (enterocytes/top of the crypt)"], ["Meta-gene 105", "6", "Top of the crypt genes", "FAM55A, FAM55D, MUC12 and CEACAM759, SLC26A259, SLC26A359"], ["Meta-gene 144", "5", "Enterocytes, goblet cells markers", "LOC644844, NGEF, HEPH, KRT2059, MUC2059"], ["Cluster-unassigned meta-genes associated with chromosomal location 0"], ["Meta-gene 81", "7", "Chromosome X (7 genes) 1.1E-8", "CXorf15, EIF1AX, HDHD1A, MED14, PNPLA4, SCML1, SMC1A"], ["Meta-gene 97", "6", "Chromosome 20p (5 genes) 5.0E-11", "CDC25B, CSNK2A1, MRPS26, PTPRA, RP5-1022P6.2, SNRPB"], ["Meta-gene 84", "7", "Chromosome 8 (7 genes) 5.4E-9", "AGPAT5, FDFT1, GTF2E2, LONRF1, MTUS1, VPS37A, ZNF395"], ["Other cluster-unassigned meta-genes"], ["Meta-gene 141", "5", "EREG", "AK3L1, ARID3A, EREG, LDLRAD3, ZBTB10"], ["Meta-gene 112", "6", "Lipid synthesis (4 genes) 5.0E-2", "DHCR7, FASN, FGFBP1, HMGCS1, IDI1, PCSK9"], ["Meta-gene 95", "6", "Homeobox genes", "HOXA10, HOXA11, HOXA13, HOXA5, HOXA7, HOXA9"], ["Meta-gene 124", "5", "Metallothioneins", "MT1E, MT1F, MT1G, MT1M, MT1X"], ["Meta-gene 131", "5", "Disulphide bonds (5 genes) 1.7E-02", "CXCL5, IL6, MMP1, MMP3, PTGS2"], ["Meta-gene 143", "5", "Unidentified", "DUSP5, ERRFI1, KLF6, MXD1, PLAUR"], ["Meta-gene 80", "7", "Regulation of RNA metabolic process (6 genes) 4.9E-2", "ATF3, C8orf4, FOS, JUNB, NR4A1, SIK1, ZFP36"], ["Meta-gene 71", "8", "Gut development (3 genes) 3.5E-2", "CCL11, CH25H, EDNRB, F2RL2, FOXF1, FOXF2, PCDH18, WNT5A"]], "row_count": 24, "column_count": 4, "numeric_cells": 67, "header_rows": 1, "locator": "section[10]/table-wrap[1]#tbl1"}}, {"id": "asset:table:pmid:23836465:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:72b55ee671557f292c8468f3a705d04592828f1ae2feb1acafbf39d3448bb92a", "bytes": 1057, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[10]/table-wrap[2]#tbl2", "version": null, "note": "Subtype-specific minimal gene set as identified by Elastic net", "structure": {"pmcid": "PMC3840702", "section_index": 10, "section_title": "Subtypes are characterized by distinct biological components", "row_count": 7, "column_count": 3}, "table": {"label": "Table 2", "caption": "Subtype-specific minimal gene set as identified by Elastic net", "rows": [["", "Minimal gene sets specifying a subtype"], ["Subtype", "Up-regulated from population mean", "Down-regulated from population mean"], ["A. Surface crypt-like", "ADTRP, B3GNT7, CLCA1, MUC2, NR3C2, PADI2, RETNLB, STYK1", "CHI3L1, FNDC1, TIMP3, SULF1"], ["B. Lower crypt-like", "CCDC113, CDHR1, FARP1, GPSM2, GRM8, HNF4A, IHH, KCNK5, KIAA0226L, MYRIP, PLAGL2, PRR15, QPRT, RNF43, RPS6KA3, SLC5A6, TP53RK, TSPAN6, VAV3, YAE1D1", "ALOX5, BASP1, CREB3L1, CXCR4, EPB41L3, FSCN1, GFPT2, GPX8, ITPRIP, KCNMA1, KCTD12,MT1E, RARRES3, RNASE1, SGK1, SOCS3"], ["C. CIMP-H-like", "ANP32E, EGLN3, IDO1, PLK2, RAB27B, RARRES3, RPL22L1, TFAP2A", "ATP9A, C10orf99, CXCL14, KIAA0226L"], ["D. Mesenchymal", "ANK2, BOC, C7, CRYAB, DCHS1, DDR2, GEM, PRICKLE1, TAGLN", "HOOK1, RBM47"], ["E. Mixed", "CEACAM6, CXCL5, HSD11B1, IL1B, IL6, MRPS31, PI15, RAP2A, UQCC", "AGR3, RAB27B, REG4"]], "row_count": 7, "column_count": 3, "numeric_cells": 7, "header_rows": 2, "locator": "section[10]/table-wrap[2]#tbl2"}}, {"id": "asset:table:pmid:23836465:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:d5d8b1960d6a07f7b5eae7fe656da88293176601370213d216fdc3cac20547fa", "bytes": 715, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[12]/table-wrap[1]#tbl3", "version": null, "note": "Result of additive multivariate Cox proportional hazards model, with subtype, BRAF mutation, MSI and stagea", "structure": {"pmcid": "PMC3840702", "section_index": 12, "section_title": "Subtypes and patient survival", "row_count": 8, "column_count": 7}, "table": {"label": "Table 3", "caption": "Result of additive multivariate Cox proportional hazards model, with subtype, BRAF mutation, MSI and stagea", "rows": [["Variable", "RFS HR", "p", "OS HR", "p", "SAR HR", "p"], ["A", "0.906", "0.760", "1.381", "0.390", "1.726", "0.180"], ["C", "0.940", "0.850", "1.560", "0.220", "3.675", "0.0022*"], ["D", "1.688", "0.0055*", "2.161", "0.0011*", "1.906", "0.014*"], ["E", "1.506", "0.210", "2.201", "0.035*", "2.046", "0.075"], ["BRAFm", "1.633", "0.085", "2.472", "0.0034*", "3.361", "0.00072*"], ["MSI", "0.478", "0.044*", "0.275", "0.004*", "0.356", "0.036*"], ["Stage 3", "0.770", "0.190", "0.943", "0.820", "1.780", "0.062*"]], "row_count": 8, "column_count": 7, "numeric_cells": 43, "header_rows": 1, "locator": "section[12]/table-wrap[1]#tbl3"}}, {"id": "asset:table:pmid:23836465:4", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:425086c01239994e5ee2e11a1eafd440a26eb1526918e3659f88c9c6aa530e8b", "bytes": 1292, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[16]/table-wrap[1]#tbl4", "version": null, "note": "Summary of subtype characteristics", "structure": {"pmcid": "PMC3840702", "section_index": 16, "section_title": "Discussion", "row_count": 7, "column_count": 14}, "table": {"label": "Table 4", "caption": "Summary of subtype characteristics", "rows": [["Subtype", "CRC markers and mutations", "Histopathology", "IHC", "Median survival (months)", "Clinical", "Gene expression"], ["MSI", "BRAF", "KRAS", "P53", "Dominant", "Nuclear β-catenin at IF", "OS", "RFS", "SAR", "Site", "Grade", "Up-regulated", "Down-regulated"], ["A: Surface crypt-like", "", "–", "+", "", "Papillary or serrated", "–", "NA", "NA", "28.9", "", "", "Top colon crypt, secretory cell, metallothioneins", "EMT/stroma, Wnt, CSC, Chr20q, proliferation"], ["B: Lower crypt-like", "–", "–", "", "", "Complex tubular", "+", "NA", "NA", "50.4", "Left", "2", "Top colon crypt, proliferation, Wnt", "EMT/stroma, immune, secretory cell"], ["C: CIMP-H-like", "+", "+", "", "–", "Solid/trabecular or mucinous", "–", "NA", "NA", "6.9", "Right", "3", "Proliferation, immune, metallothioneins", "GDC, top colon crypt, Chr20q"], ["D: Mesenchymal", "", "", "", "", "Desmoplastic", "–", "NA", "79.5", "19.8", "", "", "EMT/stroma, CSC, immune", "Proliferation, secretory cell, top colon crypt, GDC, Wnt, Chr20q"], ["E: Mixed", "–", "–", "", "+", "Complex tubular", "+", "NA", "NA", "19.6", "Left", "", "EMT/stroma, immune, top colon crypt, Chr20q, GDC, CSC", "Secretory cell"]], "row_count": 7, "column_count": 14, "numeric_cells": 13, "header_rows": 2, "locator": "section[16]/table-wrap[1]#tbl4"}}], "gaps": ["asset:data:geo:E-MTAB-1026 not downloaded", "asset:data:geo:E-MTAB-1026 licence not read", "asset:data:geo:E-MTAB-990 not downloaded", "asset:data:geo:E-MTAB-990 licence not read"]}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "family": "correlation_analysis", "specific": "pearson", "label": "Correlation analysis", 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