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

Antonio José Cabrera-Serrano, José Manuel Sánchez-Maldonado, Rob ter Horst, Angelica Macauda, Paloma García-Martín, Yolanda Benavente, Stefano Landi, Alyssa Clay-Gilmour, Yasmeen Niazi, Blanca Espinet, Juan José Rodríguez-Sevilla, Eva María Pérez, Rossana Maffei, Gonzalo Blanco, Matteo Giaccherini, James R. Cerhan, Roberto Marasca, Miguel Ángel López-Nevot, Tzu Chen-Liang, Hauke ThomsenIrene Gámez, Daniele Campa, Víctor Moreno, Silvia de Sanjosé, Rafael Marcos-Gragera, María García-Álvarez, Trinidad Dierssen-Sotos, Andrés Jerez, Aleksandra Butrym, Aaron D. Norman, Mario Luppi, Susan L. Slager, Kari Hemminki, Yang Li, Sonja I. Berndt, Delphine Casabonne, Miguel Alcoceba, Anna Puiggros, Mihai G. Netea, Asta Försti, Federico Canzian, Juan Sainz

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number8005
JournalInternational Journal of Molecular Sciences
Volume24
Issue number9
DOIs
Publication statusPublished - 2023 May
Externally publishedYes

Bibliographical note

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.

Subject classification (UKÄ)

  • Cancer and Oncology
  • Medical Genetics

Free keywords

  • chronic lymphocytic leukemia
  • genetic variants
  • overall survival
  • polygenic risk score
  • susceptibility
  • TTFT

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