Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer
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 p...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Oxford University Press
2014
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| _version_ | 1797056542694965248 |
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| author | Teo, M Dyrskjøt, L Nsengimana, J Buchwald, C Snowden, H Morgan, J Jensen, J Knowles, M Taylor, G Barrett, J Borre, M Orntoft, T Bishop, D Kiltie, A |
| author_facet | Teo, M Dyrskjøt, L Nsengimana, J Buchwald, C Snowden, H Morgan, J Jensen, J Knowles, M Taylor, G Barrett, J Borre, M Orntoft, T Bishop, D Kiltie, A |
| author_sort | Teo, M |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T19:24:08Z |
| format | Journal article |
| id | oxford-uuid:1b22cd1a-419d-4e77-a5cd-99113f73a8f9 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:24:08Z |
| publishDate | 2014 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:1b22cd1a-419d-4e77-a5cd-99113f73a8f92022-03-26T10:58:43ZNext-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancerJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:1b22cd1a-419d-4e77-a5cd-99113f73a8f9EnglishSymplectic Elements at OxfordOxford University Press2014Teo, MDyrskjøt, LNsengimana, JBuchwald, CSnowden, HMorgan, JJensen, JKnowles, MTaylor, GBarrett, JBorre, MOrntoft, TBishop, DKiltie, ABackground 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. |
| spellingShingle | Teo, M Dyrskjøt, L Nsengimana, J Buchwald, C Snowden, H Morgan, J Jensen, J Knowles, M Taylor, G Barrett, J Borre, M Orntoft, T Bishop, D Kiltie, A Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer |
| title | Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer |
| title_full | Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer |
| title_fullStr | Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer |
| title_full_unstemmed | Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer |
| title_short | Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer |
| title_sort | next generation sequencing identifies germline mre11a variants as markers of radiotherapy outcomes in muscle invasive bladder cancer |
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