Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults worldwide. Although genome-wide association studies (GWAS) have uncovered the germline genetic component underlying CLL susceptibility, the potential use of GWAS-identified risk variants to predict disease progression and patient survival remains unexplored. Here, we evaluated whether 41 GWAS-identified risk variants for CLL could influence overall survival (OS) and disease progression, defined as time to first treatment (TTFT) in a cohort of 1039 CLL cases ascertained through the CRuCIAL consortium. Although this is the largest study assessing the effect of GWAS-identified susceptibility variants for CLL on OS, we only found a weak association of ten single nucleotide polymorphisms (SNPs) with OS (p < 0.05) that did not remain significant after correction for multiple testing. In line with these results, polygenic risk scores (PRSs) built with these SNPs in the CRuCIAL cohort showed a modest association with OS and a low capacity to predict patient survival, with an area under the receiver operating characteristic curve (AUROC) of 0.57. Similarly, seven SNPs were associated with TTFT (p < 0.05); however, these did not reach the multiple testing significance threshold, and the meta-analysis with previous published data did not confirm any of the associations. As expected, PRSs built with these SNPs showed reduced accuracy in prediction of disease progression (AUROC = 0.62). These results suggest that susceptibility variants for CLL do not impact overall survival and disease progression in CLL patients.

Cancer Prevention and Control Program Unit of Biomarkers and Susceptibility Bellvitge Biomedical Research Institute Catalan Institute of Oncology 08907 Barcelona Spain

Catalan Institute of Oncology Bellvitge Biomedical Research Institute 08908 Barcelona Spain

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences 1090 Vienna Austria

Centre for Individualised Infection Medicine 30625 Hannover Germany

CIBER Epidemiología y Salud Pública 28029 Madrid Spain

Consortium for Biomedical Research in Epidemiology and Public Health University of Barcelona 08908 Barcelona Spain

Department for Immunology and Metabolism Life and Medical Sciences Institute University of Bonn 53115 Bonn Germany

Department of Biochemistry and Molecular Biology 1 Faculty of Sciences University of Granada 18012 Granada Spain

Department of Biology University of Pisa 56126 Pisa Italy

Department of Cancer Prevention and Therapy Medical University of Wrocław 50 556 Wrocław Poland

Department of Clinical Sciences Faculty of Medicine University of Barcelona 08907 Barcelona Spain

Department of Epidemiology and Biostatistics Arnold School of Public Health University of South Carolina Greenville SC 29208 USA

Department of Hematology Experimental Hematology Unit Vall d'Hebron Institute of Oncology University Hospital Vall d'Hebron 08035 Barcelona Spain

Department of Hematology University Hospital of Salamanca 37007 Salamanca Spain

Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center 6525 GA Nijmegen The Netherlands

Department of Leukemia The University of Texas MD Anderson Cancer Center Houston TX 77030 USA

Department of Medical and Surgical Sciences University of Modena and Reggio Emilia AOU Policlinico 41124 Modena Italy

Department of Nursing Universitat de Girona 17007 Girona Spain

Department of Quantitative Health Sciences Mayo Clinic Rochester MN 55905 USA

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda MD 20814 USA

Division of Cancer Epidemiology German Cancer Research Center Im Neuenheimer Feld 280 69120 Heidelberg Germany

Division of Computational Genomics Mayo Clinic Rochester MN 85054 USA

Division of Hematology Mayo Clinic Rochester MN 55905 USA

Division of Pediatric Neurooncology German Cancer Research Center 69120 Heidelberg Germany

Epidemiology Unit and Girona Cancer Registry Oncology Coordination Plan Department of Health Autonomous Government of Catalonia Catalan Institute of Oncology Girona Biomedical Research Institute 17190 Girona Spain

Faculty of Medicine and Biomedical Center in Pilsen Charles University Prague 30605 Pilsen Czech Republic

Faculty of Medicine University of Cantabria 39011 Santander Spain

Genomic Epidemiology Group German Cancer Research Center 69120 Heidelberg Germany

Genomic Oncology Area GENYO Centre for Genomics and Oncological Research Pfizer University of Granada Andalusian Regional Government PTS 18016 Granada Spain

Hematology Department Morales Meseguer University Hospital 30008 Murcia Spain

Hopp Children's Cancer Center 69120 Heidelberg Germany

Hospital Campus de la Salud PTS 18016 Granada Spain

Immunology Department Virgen de las Nieves University Hospital 18014 Granada Spain

Instituto de Investigación Biosanitaria IBs Granada 18012 Granada Spain

Josep Carreras Leukemia Research Institute 08916 Girona Spain

Molecular Cytogenetics Laboratory Pathology Department Hospital del Mar 08003 Barcelona Spain

MSB Medical School Berlin D 14197 Berlin Germany

Translational Research on Hematological Neoplasms Group Cancer Research Program Institut Hospital del Mar d'Investigacions Mèdiques 08003 Barcelona Spain

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