| Title: | Genomic structural equation modelling of 12 cancers identifies a latent pan-cancer susceptibility factor and shared determinants of carcinogenesis |
| Journal: | EBioMedicine |
| Published: | 26 Jun 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42361404/ |
| DOI: | https://doi.org/10.1016/j.ebiom.2026.106356 |
Publication 20524
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Abstract
BACKGROUND: Common cancers share germline susceptibility, yet the genetic architecture of a truly pan-cancer component of carcinogenesis remains incompletely resolved.</p>
METHODS: We applied genomic structural equation modelling (gSEM) to genome-wide association studies (GWAS) summary statistics for 12 cancers (>600,000 European-ancestry cases) to separate a latent pan-cancer genetic factor from cancer-specific components, and then performed a multivariate GWAS of that factor. We conducted comprehensive downstream genetic, predictive, and functional analyses to characterise the resulting pan-cancer factor.</p>
FINDINGS: We identified 133 LD-independent loci associated with the pan-cancer factor, including eight loci not previously associated with any cancer phenotype. Pan-cancer genetic risk was concentrated in evolutionarily conserved regulatory DNA, with enrichment in promoter and enhancer annotations and tissue-relevant signals in mammary and uterine contexts. A pan-cancer polygenic risk score (PRS) derived from the latent-factor GWAS improved prediction of overall cancer in UK Biobank (Royston-Sauerbrei R2 = 2.97%), showed significant predictive value for most assessed cancers (R2 up to 8.66%), and retained predictive signal in an independent East Asian validation dataset (Nagelkerke R2 = 0.56%), outperforming a previous meta-analysis-based cross-cancer PRS and all site-specific PRSs. Gene and pathway prioritisation identified 132 putative risk genes across 106 loci, including 21 genes with little or no prior cancer annotation, and implicated canonical genome maintenance and cell cycle programmes alongside less emphasised processes involving organelle organisation, vesicle trafficking, and protein post-translational modification. Finally, proteome-wide Mendelian randomisation identified 23 blood proteins with putative causal effects on pan-cancer risk, including six druggable targets.</p>
INTERPRETATION: Together, these results delineate a gSEM-derived pan-cancer genetic architecture, provide a cross-site PRS for overall cancer susceptibility, and nominate genes and circulating proteins for functional follow-up and prevention-oriented target discovery.</p>
FUNDING: Noncommunicable Chronic Diseases-National Science and Technology Major Project, National Natural Science Foundation of China, and National Key Research and Development Program of China.</p>
11 Keywords
- Carcinogenesis
- Genetic Predisposition to Disease
- Genetic Risk Score
- Genome-Wide Association Study
- Genomics
- Humans
- Models, Genetic
- Multifactorial Inheritance
- Neoplasms
- Phenotype
- Polymorphism, Single Nucleotide
12 Authors
- Qian Xu
- Lu Niu
- Zian Cao
- Jiwen Geng
- Huazhen Yang
- Yu Zeng
- Yanan Zhang
- Qian Li
- Chen Suo
- Gang Yuan
- Huan Song
- Can Hou
1 Application
| Application ID | Title |
|---|---|
| 54803 | Deciphering complex traits - phenotypic and genetic associations between traits in the UK Biobank Cohort |
Enabling scientific discoveries that improve human health