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Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer

Lookup NU author(s): Dr Jérémie Nsengimana

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


Abstract

Background: Muscle-invasive bladder cancer (MIBC) can be cured by radical radiotherapy (RT). We previously found tumour MRE11 expression to be predictive of survival following RT in MIBC, and this was independently validated in a separate institute.Here, we investigated germline MRE11A variants as possible predictors of RT outcomes in MIBC,using next-generation sequencing (NGS).Patients and methods: The MRE11A gene was amplified in germline DNA from 186 prospectively recruited MIBC patients treated with RT and sequenced using bar-coded multiplexed NGS.Germline variants were analysed for associations with cancer-specific survival (CSS).For validation as a prognostic or predictive marker, rs1805363 was then genotyped in a cystectomy-treated MIBC cohort of 256 individuals.MRE11A mRNA isoform expression was measured in bladder cancer cell lines and primary tumour samples. Results: Carriage of at least one of six (five novel) rare variants was associated with the worse RT outcome (hazard ratio [HR] 4.04, 95% confidence interval [95% CI] 1.42-11.51, P = 0.009).The single-nucleotide polymorphism (SNP), rs1805363 (minor allele frequency 11%), was also associated with worse CSS ( per-allele HR 2.10, 95% CI 1.34-3.28, Ptrend = 0.001) following RT in MIBC, with a gene-dosage effect observed, but no effect seen on CSS in the cystectomy cohort (Ptrend = 0.89).Furthermore, rs1805363 influenced relative MRE11A isoform expression, with increased isoform 2 expression with carriage of the rs1805363 minor A allele. Conclusions: Germline MRE11A SNP rs1805363 was predictive of RT, but not of cystectomy outcome in MIBC.If successfully validated in an independent RT-treated cohort, this SNP could be a useful clinical tool for selecting patients for bladder-conserving treatment. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Publication metadata

Author(s): Teo MTW, Dyrskjøt L, Nsengimana J, Buchwald C, Snowden H, Morgan J, Jensen JB, Knowles MA, Taylor G, Barrett JH, Borre M, Ørntoft TF, Bishop DT, Kiltie AE

Publication type: Article

Publication status: Published

Journal: Annals of Oncology

Year: 2014

Volume: 25

Issue: 4

Pages: 877-883

Print publication date: 01/04/2014

Online publication date: 06/01/2020

Acceptance date: 31/12/2013

Date deposited: 10/06/2020

ISSN (print): 0923-7534

ISSN (electronic): 1569-8041

Publisher: Oxford University Press

URL: https://doi.org/10.1093/annonc/mdu014

DOI: 10.1093/annonc/mdu014

PubMed id: 24623370


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