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.

Do GWAS-Identified Risk Variants for Chronic Lymphocytic Leukemia Influence Overall Patient Survival and Disease Progression? / 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. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 24:9(2023), pp. 8005-1-8005-11. [10.3390/ijms24098005]

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

Marasca, Roberto;Luppi, Mario;
2023

Abstract

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.
2023
24
9
8005-1
8005-11
Do GWAS-Identified Risk Variants for Chronic Lymphocytic Leukemia Influence Overall Patient Survival and Disease Progression? / 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. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 24:9(2023), pp. 8005-1-8005-11. [10.3390/ijms24098005]
Cabrera-Serrano, Antonio José; Sánchez-Maldonado, José Manuel; Ter Horst, Rob; Macauda, Angelica; García-Martín, Paloma; Benavente, Yolanda; Landi, St...espandi
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