MRE11 Expression Is Predictive of Cause-Specific Survival following Radical Radiotherapy for Muscle-Invasive Bladder Cancer

Choudhury, Ananya; Nelson, Louisa D.; Teo, Mark; Chilka, Sameer; Bhattarai, Selina; Johnston, C.F.; Elliott, Faye; Lowery, Johanna; Taylor, Claire; Churchman, Michael; Bentley, Johanne; Knowles, Margaret A.; Harnden, Patricia; Bristow, Robert G.; Bishop, D. Timothy; Kiltie, Anne E.

doi:10.1158/0008-5472.can-10-1202

Cited by 183 publications

(149 citation statements)

References 37 publications

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“…Full-slide sections were scored under the microscope. Thresholds used: p16 > 10% was considered positive [ 14 ] ; Rb was negative when no staining of carcinoma cell nuclei was observed (positive control staining of stromal cell nuclei) [ 15,16 ] ; Ki67 > 20% positive carcinoma cell nuclei was considered high [ 16,17 ] ; p53 > 20% was considered positive [ 9,16,17 ] ; TIP60 and MRE11 were scored on a continuous scale and the lowest quartile considered ' low ' [ 18 ] . pATM-positive carcinoma cell nuclei were scored on a continuous scale and the optimal threshold value defi ned by receiver operating characteristic curve.…”

Section: Methodsmentioning

confidence: 99%

Expression of TIP60 (tat‐interactive protein) and MRE11 (meiotic recombination 11 homolog) predict treatment‐specific outcome of localised invasive bladder cancer

Laurberg¹,

Brems-Eskildsen²,

Nordentoft³

et al. 2012

BJU International

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What's known on the subject? and What does the study add?Several studies have shown that defects in DNA‐damage response are associated with good survival after chemotherapy and radiotherapy. Furthermore, loss of cell cycle regulators may be prognostic indicators of poor survival after cystectomy. However, the potential clinical impact of previous findings is hampered by insufficient validation of significant results in suitable cystectomy and radiotherapy cohorts.Here we use a large cohort of patients receiving radiotherapy to successfully validate the importance of MRE11 as a predictive marker of disease‐specific survival (DSS). Furthermore, using two independent patient cohorts we show for the first time that TIP60 is a predictive marker of DSS after cystectomy. We show that combined use of TIP60 and MRE11 may hold the potential to guide treatment decisions.OBJECTIVE To determine the association between the proteins: tat‐interactive protein 60 kDa (TIP60), p16, meiotic recombination 11 homolog (MRE11), phosphorylated ataxia telangiectasia mutated (ATM), retinoblastoma protein (Rb), Ki67, and p53 and clinical outcome in invasive lymph node‐negative bladder cancer. PATIENTS AND METHODS Protein expression was measured by immunohistochemistry in cancer specimens from two independent cohorts of patients with bladder cancer treated with cystectomy (162 patients and 273) and one cohort of patients receiving radiotherapy (148). Disease‐specific survival (DSS) was used as the outcome measure, and patients with no disease‐specific death were followed for a minimum of 36 months. RESULTS TIP60 was significantly correlated with DSS in both cystectomy cohorts (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.26–0.68, P < 0.001 and HR 0.45, 95% CI 0.28–0.72, P= 0.001). MRE11 was significantly correlated with DSS in the cohort receiving radiotherapy (HR 0.64, 95% CI 0.47–0.86, P= 0.005). P16 was significantly correlated with DSS in all three cohorts (HR 0.46, 95% CI 0.30–0.75, P= 0.032; HR 0.60, 95% CI 0.37–0.97, P= 0.032; HR 0.52, 95% CI 0.28–0.96, P= 0.001). Rb was significantly correlated with DSS in one cystectomy cohort (HR 1.71, 95% CI 1.13–2.75, P= 0.017). Ki67, p53, and pATM were not significantly correlated with DSS in any of the cohorts. CONCLUSIONS TIP60 protein expression was a predictive marker for DSS after cystectomy in two independent cohorts. This novel marker was the strongest predictive factor in multivariate analysis in patients receiving cystectomy. MRE11 was shown to be a predictive marker for DSS after radiotherapy. We have shown that TIP60 and MRE11 hold the potential to guide patients with invasive bladder cancer to either cystectomy or radiotherapy. This study was based on retrospective material and consequently we suggest that these markers should be validated in a prospective study.

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Section: Methodsmentioning

confidence: 99%

Expression of TIP60 (tat‐interactive protein) and MRE11 (meiotic recombination 11 homolog) predict treatment‐specific outcome of localised invasive bladder cancer

Laurberg¹,

Brems-Eskildsen²,

Nordentoft³

et al. 2012

BJU International

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“…Expression of DNA damage signalling proteins may also correlate with disease specific survival. High expression of MRE11 in bladder tumors was found to be associated with improved disease-specific survival in patients undergoing radiotherapy compared to those undergoing radical cystectomy [60]. The association between high MRE11 expression and improved disease specific survival was also validated in a study in which the majority of patients undergoing radiotherapy received concurrent chemotherapy [61].…”

Section: Pol Scientificmentioning

confidence: 87%

Bladder preservation in the treatment of muscle-invasive bladder cancer

Prado

Gollapudi

King

et al. 2014

Bladder

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Organ preserving strategies are being increasingly utilized in the treatment of solid malignancies with the intent of reducing surgical morbidity and maintaining quality of life. Organ preservation becomes a viable approach only when cancer outcomes are not compromised when compared to radical resection. We reviewed the current literature on bladder preservation for muscle-invasive bladder cancer, focusing on trimodality therapy consisting of complete transurethral resection, radiation therapy, and chemotherapy. Acknowledging the absence of randomized clinical trials, differences in patient selection, and variation in study protocols, trimodality therapy may yield similar 5-and 10-year overall survival rates compared to radical cystectomy alone. This includes the approximately 30% of patients who enter a bladder preservation protocol and undergo salvage radical cystectomy for failure of local control. Currently, bladder preservation appears to be an alternative to radical cystectomy in select patients who have appropriate rigorous surveillance.

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“…Interestingly, the muscle invasive tumours display reduced Ku DNA binding activity [97]. Provocatively, muscle invasive bladder tumours also display altered regulation of MRE11 expression, although it is unclear whether this correlates with alterations in resection and pathway usage [98].…”

Section: Modulation Of End-joining In Cancer Cellsmentioning

confidence: 99%

“…In the case of CML, ATM-deficient tumours have a severe prognosis. Other components required for the DDR are also frequently down-regulated or mutated in cancers (for example [98,104,105]). The difficulty in assessing the impact of these changes is that they likely affect multiple endpoints, including the activation of apoptosis and cell cycle checkpoint arrest.…”

Section: Changes In Ddr Signalling Proteins and Chromatin Modifying Fmentioning

confidence: 99%

How cancer cells hijack DNA double-strand break repair pathways to gain genomic instability

Jeggo

Löbrich

2015

Biochemical Journal

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DNA DSBs (double-strand breaks) are a significant threat to the viability of a normal cell, since they can result in loss of genetic material if mitosis or replication is attempted in their presence. Consequently, evolutionary pressure has resulted in multiple pathways and responses to enable DSBs to be repaired efficiently and faithfully. Cancer cells, which are under pressure to gain genomic instability, have a striking ability to avoid the elegant mechanisms by which normal cells maintain genomic stability. Current models suggest that, in normal cells, DSB repair occurs in a hierarchical manner that promotes rapid and efficient rejoining first, with the utilization of additional steps or pathways of diminished accuracy if rejoining is unsuccessful or delayed. In the present review, we evaluate the fidelity of DSB repair pathways and discuss how cancer cells promote the utilization of less accurate processes. Homologous recombination serves to promote accuracy and stability during replication, providing a battlefield for cancer to gain instability. Non-homologous end-joining, a major DSB repair pathway in mammalian cells, usually operates with high fidelity and only switches to less faithful modes if timely repair fails. The transition step is finely tuned and provides another point of attack during tumour progression. In addition to DSB repair, a DSB signalling response activates processes such as cell cycle checkpoint arrest, which enhance the possibility of accurate DSB repair. We consider the ways by which cancers modify and hijack these processes to gain genomic instability.

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MRE11 Expression Is Predictive of Cause-Specific Survival following Radical Radiotherapy for Muscle-Invasive Bladder Cancer

Cited by 183 publications

References 37 publications

Expression of TIP60 (tat‐interactive protein) and MRE11 (meiotic recombination 11 homolog) predict treatment‐specific outcome of localised invasive bladder cancer

Expression of TIP60 (tat‐interactive protein) and MRE11 (meiotic recombination 11 homolog) predict treatment‐specific outcome of localised invasive bladder cancer

Bladder preservation in the treatment of muscle-invasive bladder cancer

How cancer cells hijack DNA double-strand break repair pathways to gain genomic instability

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