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From Germline Variants to Tumor Outcome: GWAS-Based Functional Genomics Prioritizes Colorectal Cancer Susceptibility Genes and Links SMAD9 to Prognosis.

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Τίτλος: From Germline Variants to Tumor Outcome: GWAS-Based Functional Genomics Prioritizes Colorectal Cancer Susceptibility Genes and Links SMAD9 to Prognosis.
Συγγραφείς: Hu C; Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China, fimmu.com.; Department of Gastroenterology, Guangzhou Medical University Affiliated Women and Children's Medical Center, Guangzhou, China., Yang G; Department of General Surgery, Guangzhou Twelfth People's Hospital, Guangzhou Medical University, Guangzhou, China, gzhmc.edu.cn., Xiong H; Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com.; Department of Rheumatology and Immunology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com., Xie Y; The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com., Yuan Z; The second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China, glmc.edu.cn., Liu J; Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com.; Department of Rheumatology and Immunology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com., Wang P; The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com., Li M; Department of Rheumatology and Immunology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com., Xu J; Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com.; Department of Rheumatology and Immunology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com., Li Q; Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com.; Department of Rheumatology and Immunology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com., Li C; The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com., Han W; The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com., Peng X; Department of Rheumatology and Immunology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com.; The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com., Zhang L; Department of Nursing, Jiuquan Hospital of Shanghai General Hospital (Jiuquan People's Hospital), Jiuquan, China., Cai S; Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, Lancashire, UK, lancs.ac.uk., Zhong F; Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com.; Department of Rheumatology and Immunology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com.; The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com., Dai L; Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China, fimmu.com., Liu S; Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China, fimmu.com.; The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China, fimmu.com.
Πηγή: Human mutation [Hum Mutat] 2026 Aug 20; Vol. 2026, pp. 5617762. Date of Electronic Publication: 2026 Aug 20 (Print Publication: 2026).
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Wiley-Liss Country of Publication: United States NLM ID: 9215429 Publication Model: eCollection Cited Medium: Internet ISSN: 1098-1004 (Electronic) Linking ISSN: 10597794 NLM ISO Abbreviation: Hum Mutat Subsets: MEDLINE
Imprint Name(s): Original Publication: New York : Wiley-Liss, c1992-
Ιατρικοί όροι (MeSH): Colorectal Neoplasms*/genetics , Colorectal Neoplasms*/pathology , Genomics*/methods , Genome-Wide Association Study* , Genetic Predisposition to Disease* , Germ-Line Mutation*, Humans ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Prognosis ; Gene Expression Regulation, Neoplastic ; Delta-5 Fatty Acid Desaturase
Περίληψη: Introduction: Genome-wide association studies (GWAS) have identified over 200 germline risk loci for colorectal cancer (CRC), yet the causal variants and genes behind most GWAS signals remain unknown and the link between inherited risk and tumor outcome is largely unexplored. Connecting germline single nucleotide polymorphisms (SNPs) to gene expression through expression quantitative trait loci (eQTL) and to clinical outcome is needed to interpret this inherited risk.
Methods: We combined CRC GWAS summary data (73,149 cases and 112,467 controls of European ancestry) with GTEx v8 eQTL from colon sigmoid, colon transverse, small intestine terminal ileum, and whole blood, integrating causal transcriptome-wide association study (cTWAS) with SuSiE fine-mapping, Bayesian colocalization, MAGMA SNP-to-gene analysis, and AlphaGenome variant-effect prediction. Prioritized proteins were assessed by western blot. Four experimentally selected regulatory variants were genotyped in HCT116, SW480, RKO, and NCM460 cells; genotype-protein associations were tested across cell-line means, and cis-regulatory effects were assessed by allele-specific expression (ASE) and reference-versus-alternate dual-luciferase assays. Prognostic relevance was evaluated in TCGA colorectal tumors.
Results: cTWAS identified seven genes with posterior inclusion probability (PIP) > 0.50, and colocalization across 78 gene-tissue pairs revealed 20 associations with PP.H4 > 0.80. Four genes showed convergent evidence: SMAD9 (PIP = 0.916, PP.H4 = 0.981), MAP3K2 (PIP = 0.762, PP.H4 = 0.827), FADS1 (PIP = 0.632, PP.H4 = 0.942), and ACTR1B (PIP = 0.566, PP.H4 = 0.994). All four proteins were reduced in CRC cells. Alt-allele dosage was inversely associated with SMAD9 (Pearson r = -0.985, BH-adjusted p = 0.029) and FADS1 protein abundance (r = -0.995, BH-adjusted p = 0.020), but not with MAP3K2 or ACTR1B. Reporter and ASE assays detected the clearest allele-specific effects at SMAD9 and FADS1, whereas MAP3K2 and ACTR1B were null in the tested systems. Lower SMAD9 expression was nominally associated with poorer survival (log - rank p = 0.022 to 0.050), but these associations did not survive Benjamini-Hochberg correction across 12 tests.
Conclusions: Integrating statistical genetics, regulatory prediction, and locus-directed experiments prioritized SMAD9, MAP3K2, FADS1, and ACTR1B as CRC susceptibility genes. Functional evidence was strongest and most directionally coherent for SMAD9, demonstrated allele-specific but context-dependent regulation at FADS1, and placed experimental bounds on the proposed MAP3K2 and ACTR1B mechanisms.
(Copyright © 2026 Chengguang Hu et al. Human Mutation published by John Wiley & Sons Ltd.)
Competing Interests: The authors declare no conflicts of interest.
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Contributed Indexing: Keywords: AlphaGenome; causal transcriptome-wide association study; colorectal cancer; expression quantitative trait locus (eQTL); genome-wide association study (GWAS); germline variants; single nucleotide polymorphism (SNP)
Substance Nomenclature: EC 1.14.19.3 (FADS1 protein, human)
0 (Delta-5 Fatty Acid Desaturase)
Entry Date(s): Date Created: 20260821 Date Completed: 20260821 Latest Revision: 20260926
Update Code: 20260926
PubMed Central ID: PMC13492055
DOI: 10.1155/humu/5617762
PMID: 42626603
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1098-1004
DOI:10.1155/humu/5617762