Biological basis of extensive pleiotropy between blood traits and cancer risk.

Autor: Pardo-Cea MA; ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain., Farré X; Genomes for Life - GCAT Lab Group, Institut Germans Trias i Pujol (IGTP), Badalona, 08916, Barcelona, Catalonia, Spain., Esteve A; Badalona Applied Research Group in Oncology (B-ARGO), Catalan Institute of Oncology, Institut Germans Trias i Pujol (IGTP), Badalona, 08916, Barcelona, Catalonia, Spain., Palade J; Cancer and Cell Biology, Translational Genomics Research Institute (TGen), Arizona, Phoenix, AZ, 85004, USA., Espín R; ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain., Mateo F; ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain., Alsop E; Cancer and Cell Biology, Translational Genomics Research Institute (TGen), Arizona, Phoenix, AZ, 85004, USA., Alorda M; ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain., Blay N; Genomes for Life - GCAT Lab Group, Institut Germans Trias i Pujol (IGTP), Badalona, 08916, Barcelona, Catalonia, Spain., Baiges A; ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain., Shabbir A; ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain., Comellas F; Department of Mathematics, Technical University of Catalonia, Castelldefels, 08860, Barcelona, Catalonia, Spain., Gómez A; Department of Biosciences, Faculty of Sciences and Technology (FCT), University of Vic - Central University of Catalonia (UVic-UCC), Vic, 08500, Barcelona, Catalonia, Spain., Arnan M; Department of Hematology, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain., Teulé A; Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain., Salinas M; Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain., Berrocal L; OncoGir, Catalan Institute of Oncology, Girona Biomedical Research Institute (IDIBGI), 17190, Salt, Catalonia, Spain., Brunet J; Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.; OncoGir, Catalan Institute of Oncology, Girona Biomedical Research Institute (IDIBGI), 17190, Salt, Catalonia, Spain.; Biomedical Research Network Centre in Cancer (CIBERONC), Instituto de Salud Carlos III, 28222, Madrid, Spain., Rofes P; Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.; Biomedical Research Network Centre in Cancer (CIBERONC), Instituto de Salud Carlos III, 28222, Madrid, Spain., Lázaro C; Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.; Biomedical Research Network Centre in Cancer (CIBERONC), Instituto de Salud Carlos III, 28222, Madrid, Spain., Conesa M; Department of Pathology and Experimental Therapies, University of Barcelona (UB), Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain., Rojas JJ; Department of Pathology and Experimental Therapies, University of Barcelona (UB), Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain., Velten L; Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), 08003, Barcelona, Spain.; University Pompeu Fabra (UPF), 08002, Barcelona, Spain., Fendler W; Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215, Lodz, Poland., Smyczynska U; Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215, Lodz, Poland., Chowdhury D; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.; Center for BRCA and Related Genes, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.; Harvard Medical School, Boston, MA, 02115, USA., Zeng Y; Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2C4, Canada., He HH; Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2C4, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada., Li R; Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, 20052, USA., Van Keuren-Jensen K; Cancer and Cell Biology, Translational Genomics Research Institute (TGen), Arizona, Phoenix, AZ, 85004, USA. kjensen@tgen.org., de Cid R; Genomes for Life - GCAT Lab Group, Institut Germans Trias i Pujol (IGTP), Badalona, 08916, Barcelona, Catalonia, Spain. rdecid@igtp.cat., Pujana MA; ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain. mapujana@iconcologia.net.; Biomedical Research Network Centre in Respiratory Diseases (CIBERES), Instituto de Salud Carlos III, 28222, Madrid, Spain. mapujana@iconcologia.net.
Jazyk: angličtina
Zdroj: Genome medicine [Genome Med] 2024 Feb 02; Vol. 16 (1), pp. 21. Date of Electronic Publication: 2024 Feb 02.
DOI: 10.1186/s13073-024-01294-8
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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