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. 2023 Mar 31;9(1):59-71.
doi: 10.3233/BLC-220076. eCollection 2023.

An Association Study of Germline Variants in Bladder Cancer-Related Genes with the Prognosis of Non-Muscle Invasive Bladder Cancer

Jasper P Hof  1 , Sita H Vermeulen  1 , Antoine G van der Heijden  2 , Gerald W Verhaegh  2 , Lars Dyrskjøt  3   4 , James W F Catto  5 , Lourdes Mengual  6 , Richard T Bryan  7 , Neil E Fleshner  8 , Lambertus A L M Kiemeney  1   2 , Tessel E Galesloot  1
Affiliations

An Association Study of Germline Variants in Bladder Cancer-Related Genes with the Prognosis of Non-Muscle Invasive Bladder Cancer

Jasper P Hof et al. Bladder Cancer. .

Abstract

Background: Various germline genetic variants are associated with the prognosis of non-muscle invasive bladder cancer (NMIBC). Germline variants in genes frequently somatically mutated in bladder cancer have not been studied thoroughly in relation to risk of recurrence or progression in NMIBC.

Objective: To identify germline DNA variants in bladder carcinogenesis-related genes associated with recurrence or progression in NMIBC.

Methods: We analysed associations between single-nucleotide polymorphisms (SNPs) and NMIBC recurrence and progression using data from the Nijmegen Bladder Cancer Study (NBCS, 1,443 patients). We included 5,053 SNPs within 46 genes known to have mutation, overexpression or amplification in bladder cancer. We included all recurrences in the statistical analysis and performed both single variant analysis and gene-based analysis. SNPs and genes that showed significant or suggestive association (false discovery rate P value < 20%) were followed-up in independent cohorts for replication analysis, through eQTL analysis and tests for association of tumour expression levels with NMIBC recurrence and progression.

Results: Single variant analysis showed no statistically significant associations with recurrence or progression. In gene-based analysis, the aggregate effect of the 25 SNPs in the Cyclin D1 gene (CCND1) was statistically significantly associated with NMIBC recurrence (Punadj = 0.001, PFDR = 0.046), but not with progression (Punadj = 0.17, PFDR = 0.54). Validation analysis in independent cohorts did not confirm the association of CCND1 with NMIBC recurrence.

Conclusions: We could not identify reproducible associations between common germline variants in bladder carcinogenesis-related genes and NMIBC recurrence or progression.

Keywords: Bladder cancer; candidate gene analysis; genetic association study; progression; recurrence.

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Conflict of interest statement

Jasper P. Hof J. Hof has no conflict of interest to report. Sita H. Vermeulen S. Vermeulen has no conflict of interest to report. Antoine G. van der Heijden Consultant: MSD, Astellas, MerckPfizer, MML Honoraria: MerckPfizer, Astellas Gerald W. Verhaegh G. Verhaegh has no conflict of interest to report. Lars Dyrskjøt Grants: C2i genomics, Natera, Photocure, Ferring Consultant: Ferring Honoraria: Roche L. Dyrskjøt is an Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. James W.F. Catto Grants: Roche Consultant or advisory board: Astra Zeneca, BMS, Gilead, QED Therapeutics, Roche, Ferring, Steba biotech, UroGen, Janssen, Photocure Honoraria: BMS, Astra Zeneca, Roche Board member: Fight Bladder Cancer UK J. Catto is an Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Lourdes Mengual Honoraria: Fundación Investigación Urología (AEU) Receipt of material or service: Nucleix Richard T. Bryan Funding: Cancer Research UK Grants: Urogen Pharma, QED Therapeutics, Janssen Royalties: Nonacus Limited Board member: The Lichfield Science and Engineering Society Trustee: Action Bladder Cancer UK Neil E. Fleshner Grants: Janssen, Astellas, Bayer, Sanofi, Nucleix, Progenix, SpectraCure AB, Bavarian Nordic Consultant: Amgen, Janssen, Astellas, Bayer, Sanofi, Abbvie, Ferring Board member: Verity Pharmaceuticals, POINT Biopharma Stock: POINT Biopharma, Verity Pharamceuticals Lambertus A.L.M. Kiemeney L.A.L.M. Kiemeney is an Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Tessel E. Galesloot Tessel E. Galesloot has no conflict of interest to report.

Figures

Fig. 1
Fig. 1
Recurrence patterns in individuals per prognostic group in the Nijmegen Bladder Cancer Study. Every layer away from the centre represents a new recurrence, the circle in the middle represents the characteristics of the primary tumour. Prognostic risk groups were assessed using a modified version of EAU prognostic risk categories, as not all clinical data were available [2]. Risk groups are defined in supplemental document 1.
Fig. 2
Fig. 2
Regional association plot of SNPs in and nearby CCND1 constructed in LocusZoom. The SNP in CCND1 that shows the strongest association with NMIBC recurrences, rs655089, is marked by the purple diamond.
Fig. 3
Fig. 3
Expression levels of CCND1 in tumours from different transcriptomic classes in publicly available data from UROMOL [9]. The black horizontal lines mark the mean expression levels per class.
See this image and copyright information in PMC

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