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| Pàgina inicial > Articles > Articles publicats > Biological basis of extensive pleiotropy between blood traits and cancer risk |
(Institut Germans Trias i Pujol) (Institut Germans Trias i Pujol) (Institut d'Investigació Biomèdica de Bellvitge) (Institut Germans Trias i Pujol) (Universitat Politècnica de Catalunya. Departament de Matemàtiques) (Institut d'Investigació Biomèdica de Bellvitge) (Institut d'Investigació Biomèdica de Bellvitge) (Institut d'Investigació Biomèdica de Bellvitge) (Institut d'Investigació Biomèdica de Bellvitge) (Institut Germans Trias i Pujol)| Data: | 2024 |
| Resum: | Background: The immune system has a central role in preventing carcinogenesis. Alteration of systemic immune cell levels may increase cancer risk. However, the extent to which common genetic variation influences blood traits and cancer risk remains largely undetermined. Here, we identify pleiotropic variants and predict their underlying molecular and cellular alterations. Methods: Multivariate Cox regression was used to evaluate associations between blood traits and cancer diagnosis in cases in the UK Biobank. Shared genetic variants were identified from the summary statistics of the genome-wide association studies of 27 blood traits and 27 cancer types and subtypes, applying the conditional/conjunctional false-discovery rate approach. Analysis of genomic positions, expression quantitative trait loci, enhancers, regulatory marks, functionally defined gene sets, and bulk- and single-cell expression profiles predicted the biological impact of pleiotropic variants. Plasma small RNAs were sequenced to assess association with cancer diagnosis. Results: The study identified 4093 common genetic variants, involving 1248 gene loci, that contributed to blood-cancer pleiotropism. Genomic hotspots of pleiotropism include chromosomal regions 5p15-TERT and 6p21-HLA. Genes whose products are involved in regulating telomere length are found to be enriched in pleiotropic variants. Pleiotropic gene candidates are frequently linked to transcriptional programs that regulate hematopoiesis and define progenitor cell states of immune system development. Perturbation of the myeloid lineage is indicated by pleiotropic associations with defined master regulators and cell alterations. Eosinophil count is inversely associated with cancer risk. A high frequency of pleiotropic associations is also centered on the regulation of small noncoding Y-RNAs. Predicted pleiotropic Y-RNAs show specific regulatory marks and are overabundant in the normal tissue and blood of cancer patients. Analysis of plasma small RNAs in women who developed breast cancer indicates there is an overabundance of Y-RNA preceding neoplasm diagnosis. Conclusions: This study reveals extensive pleiotropism between blood traits and cancer risk. Pleiotropism is linked to factors and processes involved in hematopoietic development and immune system function, including components of the major histocompatibility complexes, and regulators of telomere length and myeloid lineage. Deregulation of Y-RNAs is also associated with pleiotropism. Overexpression of these elements might indicate increased cancer risk. |
| Ajuts: | Instituto de Salud Carlos III PI21/01306 Instituto de Salud Carlos III PI18/01512 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-449 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-1282 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-184 Ministerio de Ciencia e Innovación ADE10/00026 Generalitat de Catalunya SLT017-20-000076 Generalitat de Catalunya SLT017-20-000072 |
| Nota: | Altres ajuts: GINKGO Apac del Berguedà; Toca-te-les; NIH, CA282303; VEIS project (001-P-001647) |
| Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | Blood trait ; Cancer ; Eosinophil ; Hematopoiesis ; Myeloid ; Pleiotropy ; Telomere ; Y-RNA |
| Publicat a: | Genome medicine, Vol. 16 Núm. 1 (feb. 2024) , art. 21, ISSN 1756-994X |
