8ff079ef0bf605a2d179d07c509438ce pmc_10178669.pdf e910b8c6131d2adef129303063652ad326716d6a pmc_10178669.pdf c7a829107533faca77388b6564a7c5cd793e1c0d54d96ebf365ca52d3ad622d6 pmc_10178669.pdf Title: Do GWAS-Identified Risk Variants for Chronic Lymphocytic Leukemia Influence Overall Patient Survival and Disease Progression? Subject: 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. Keywords: chronic lymphocytic leukemia; overall survival; TTFT; genetic variants; susceptibility; polygenic risk score Author: 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 Thomsen, Irene 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 and Juan Sainz Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Fri May 5 08:37:26 2023 CEST ModDate: Fri May 5 09:20:20 2023 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 11 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 789536 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- FFAYKL+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 JIHRXL+VnURWPalladioL Type 1 Custom yes yes no 15 0 YAGLTG+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 LMFYYW+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 UNDQGY+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 46 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 49 0 KXDJCR+CMSY10 Type 1 Builtin yes yes no 74 0 XBYCSB+EURB5 Type 1 Builtin yes yes no 82 0 OWGSLX+URWPalladioL-BoldItal Type 1 Custom yes yes no 86 0 BRFUXO+EURM7 Type 1 Builtin yes yes no 90 0 OKKEPF+Cambria,Bold CID TrueType Identity-H yes yes yes 99 0 OKKEIA+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 105 0 OKKEIB+PalatinoLinotype,Bold CID TrueType Identity-H yes yes yes 108 0 OKKEIC+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 114 0 OKKEID+PalatinoLinotype CID TrueType Identity-H yes yes yes 117 0 OKKEIE+PalatinoLinotype TrueType WinAnsi yes yes no 123 0 OKKEND+PalatinoLinotype TrueType MacRoman yes yes no 126 0 OKKEPE+PalatinoLinotype,BoldItalic TrueType WinAnsi yes yes no 129 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 136 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 140 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 144 0 BCDHEE+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 148 0 BCDIEE+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 155 0 BCDJEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 162 0 BCDKEE+PalatinoLinotype-BoldItalic TrueType WinAnsi yes yes no 169 0 BCDMEE+Cambria CID TrueType Identity-H yes yes yes 173 0 CKKPIN+EURM5 Type 1 Builtin yes yes no 187 0 RFECCF+EURM10 Type 1 Builtin yes yes no 200 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-02-02 02:34:59 CET RepresentationInformation: pmc_10178669.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-07-12 02:23:09 CEST Size: 789536 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 328 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Study Participants Destination: subsection.4.1 Item: Title: SNP Selection and Genotyping Destination: subsection.4.2 Item: Title: Statistical Analysis and Meta-Analysis Destination: subsection.4.3 Item: Title: Functional Effect of the GWAS-Identified Risk Variants on Immune Responses Destination: subsection.4.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.A. Info: Title: Do GWAS-Identified Risk Variants for Chronic Lymphocytic Leukemia Influence Overall Patient Survival and Disease Progression? Author: 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 Thomsen, Irene 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 and Juan Sainz Subject: 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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