Biological basis of extensive pleiotropy between blood traits and cancer risk

Miguel Angel Pardo-Cea, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Xavier Farré, Genomes for Life - GCAT Lab Group, Institut Germans Trias i Pujol (IGTP), Badalona, 08916, Barcelona, Catalonia, Spain.
Anna Esteve, Badalona Applied Research Group in Oncology (B-ARGO), Catalan Institute of Oncology, Institut Germans Trias i Pujol (IGTP), Badalona, 08916, Barcelona, Catalonia, Spain.
Joanna Palade, Cancer and Cell Biology, Translational Genomics Research Institute (TGen), Arizona, Phoenix, AZ, 85004, USA.
Roderic Espín, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Francesca Mateo, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Eric Alsop, Cancer and Cell Biology, Translational Genomics Research Institute (TGen), Arizona, Phoenix, AZ, 85004, USA.
Marc Alorda, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Natalia Blay, Genomes for Life - GCAT Lab Group, Institut Germans Trias i Pujol (IGTP), Badalona, 08916, Barcelona, Catalonia, Spain.
Alexandra Baiges, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Arzoo Shabbir, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Francesc Comellas, Department of Mathematics, Technical University of Catalonia, Castelldefels, 08860, Barcelona, Catalonia, Spain.
Antonio Gómez, Department of Biosciences, Faculty of Sciences and Technology (FCT), University of Vic - Central University of Catalonia (UVic-UCC), Vic, 08500, Barcelona, Catalonia, Spain.
Montserrat Arnan, Department of Hematology, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Alex Teulé, Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Monica Salinas, Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Laura Berrocal, OncoGir, Catalan Institute of Oncology, Girona Biomedical Research Institute (IDIBGI), 17190, Salt, Catalonia, Spain.
Joan Brunet, Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Paula Rofes, Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Conxi Lázaro, Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Miquel Conesa, 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.
Juan Jose Rojas, 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.
Lars Velten, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), 08003, Barcelona, Spain.
Wojciech Fendler, Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215, Lodz, Poland.
Urszula Smyczynska, Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215, Lodz, Poland.
Dipanjan Chowdhury, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
Yong Zeng, Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2C4, Canada.
Housheng Hansen He, Princess Margaret Cancer Center, University Health Network, Toronto, ON, M5G 2C4, Canada.
Rong Li, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, 20052, USA.
Kendall Van Keuren-Jensen, Cancer and Cell Biology, Translational Genomics Research Institute (TGen), Arizona, Phoenix, AZ, 85004, USA. kjensen@tgen.org.
Rafael de Cid, Genomes for Life - GCAT Lab Group, Institut Germans Trias i Pujol (IGTP), Badalona, 08916, Barcelona, Catalonia, Spain. rdecid@igtp.cat.
Miquel Angel Pujana, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain. mapujana@iconcologia.net.

Document Type

Journal Article

Publication Date

2-2-2024

Journal

Genome medicine

Volume

16

Issue

1

DOI

10.1186/s13073-024-01294-8

Keywords

Blood trait; Cancer; Eosinophil; Hematopoiesis; Myeloid; Pleiotropy; Telomere; Y-RNA

Abstract

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.

Department

Biochemistry and Molecular Medicine

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