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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 and Espinet, Blanca , et al. (2023) In International Journal of Molecular Sciences 24(9).
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
chronic lymphocytic leukemia, genetic variants, overall survival, polygenic risk score, susceptibility, TTFT
in
International Journal of Molecular Sciences
volume
24
issue
9
article number
8005
publisher
MDPI AG
external identifiers
  • scopus:85159295515
  • pmid:37175717
ISSN
1661-6596
DOI
10.3390/ijms24098005
language
English
LU publication?
no
additional info
Funding Information: This work was supported by the European Union’s Horizon 2020 research and innovation program, N° 856620 and by grants from the Instituto de Salud Carlos III and FEDER (Madrid, Spain; PI17/02256 and PI20/01845) and from the Consejería de Transformación Económica, Industria, Conocimiento y Universidades y FEDER (PY20/01282). “The Mayo studies in InterLymph were supported in part by the US National Cancer Institute grants P50 CA97274 and R01 CA92153.” Publisher Copyright: © 2023 by the authors.
id
e47e4ef5-29ce-482b-b9bf-a390cf0c8531
date added to LUP
2023-07-27 21:00:31
date last changed
2024-11-02 19:42:45
@article{e47e4ef5-29ce-482b-b9bf-a390cf0c8531,
  abstract     = {{<p>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 &lt; 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 &lt; 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.</p>}},
  author       = {{Cabrera-Serrano, Antonio José and Sánchez-Maldonado, José Manuel and ter Horst, Rob and Macauda, Angelica and García-Martín, Paloma and Benavente, Yolanda and Landi, Stefano and Clay-Gilmour, Alyssa and Niazi, Yasmeen and Espinet, Blanca and Rodríguez-Sevilla, Juan José and Pérez, Eva María and Maffei, Rossana and Blanco, Gonzalo and Giaccherini, Matteo and Cerhan, James R. and Marasca, Roberto and López-Nevot, Miguel Ángel and Chen-Liang, Tzu and Thomsen, Hauke and Gámez, Irene and Campa, Daniele and Moreno, Víctor and de Sanjosé, Silvia and Marcos-Gragera, Rafael and García-Álvarez, María and Dierssen-Sotos, Trinidad and Jerez, Andrés and Butrym, Aleksandra and Norman, Aaron D. and Luppi, Mario and Slager, Susan L. and Hemminki, Kari and Li, Yang and Berndt, Sonja I. and Casabonne, Delphine and Alcoceba, Miguel and Puiggros, Anna and Netea, Mihai G. and Försti, Asta and Canzian, Federico and Sainz, Juan}},
  issn         = {{1661-6596}},
  keywords     = {{chronic lymphocytic leukemia; genetic variants; overall survival; polygenic risk score; susceptibility; TTFT}},
  language     = {{eng}},
  number       = {{9}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{Do GWAS-Identified Risk Variants for Chronic Lymphocytic Leukemia Influence Overall Patient Survival and Disease Progression?}},
  url          = {{http://dx.doi.org/10.3390/ijms24098005}},
  doi          = {{10.3390/ijms24098005}},
  volume       = {{24}},
  year         = {{2023}},
}