Do GWAS-Identified Risk Variants for Chronic Lymphocytic Leukemia Influence Overall Patient Survival and Disease Progression?

• Published in: International journal of molecular sciences Vol. 24; no. 9; p. 8005
• Main Authors: Cabrera-Serrano, Antonio José, Sánchez-Maldonado, José Manuel, Ter Horst, Rob, Macauda, Angelica, García-Martín, Paloma, Benavente, Yolanda, Landi, Stefano, Clay-Gilmour, Alyssa, Niazi, Yasmeen, Espinet, Blanca, Rodríguez-Sevilla, Juan José, Pérez, Eva María, Maffei, Rossana, Blanco, Gonzalo, Giaccherini, Matteo, Cerhan, James R, Marasca, Roberto, López-Nevot, Miguel Ángel, Chen-Liang, Tzu, Thomsen, Hauke, Gámez, Irene, Campa, Daniele, Moreno, Víctor, de Sanjosé, Silvia, Marcos-Gragera, Rafael, García-Álvarez, María, Dierssen-Sotos, Trinidad, Jerez, Andrés, Butrym, Aleksandra, Norman, Aaron D, Luppi, Mario, Slager, Susan L, Hemminki, Kari, Li, Yang, Berndt, Sonja I, Casabonne, Delphine, Alcoceba, Miguel, Puiggros, Anna, Netea, Mihai G, Försti, Asta, Canzian, Federico, Sainz, Juan
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 28.04.2023; MDPI
• Subjects: Adult; B cells; Brief Report; Cancer; Chromosomes; Chronic lymphocytic leukemia; Consortia; Development and progression; Disease Progression; Disease susceptibility; Females; Genealogy; Genetic aspects; Genetic Predisposition to Disease; genetic variants; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Hospitals; Humans; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Medical prognosis; Nucleotides; Oncology, Experimental; overall survival; Patient outcomes; Patients; polygenic risk score; Polymorphism, Single Nucleotide; Prognosis; Regression analysis; Risk; Risk Factors; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Steroids; Survival; susceptibility; TTFT; Germany; Spain; Italy; genetic variants; overall survival; TTFT; chronic lymphocytic leukemia; susceptibility; polygenic risk score
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24098005

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 ( < 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 ( < 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.