MRE11 and ATM Expression Levels Predict Rectal Cancer Survival and Their Association with Radiotherapy Response

<div><p>Background</p><p>Aberrant expression of DNA repair proteins is associated with poor survival in cancer patients. We investigated the combined expression of MRE11 and ATM as a predictive marker of response to radiotherapy in rectal cancer.</p><p>Methods</p><p>MRE11 and ATM expression were examined in tumor samples from 262 rectal cancer patients who underwent surgery for rectal cancer, including a sub-cohort of 54 patients who were treated with neoadjuvant radiotherapy. The relationship between expression of the two-protein panel and tumor regression grade (TRG) was assessed by Mann–Whitney U test and receiver operating characteristics area under curve (ROC-AUC) analysis. The association between expression of the two-protein panel and clinicopathologic variables and survival was examined by Kaplan-Meier methods and Cox regression analysis.</p><p>Results</p><p>A high score for two-protein combined expression in the tumor center (TC) was significantly associated with worse disease-free survival (DFS) (<i>P</i> = 0.035) and overall survival (OS) (<i>P</i> = 0.003) in the whole cohort, and with DFS (<i>P</i> = 0.028) and OS (<i>P</i> = 0.024) in the neoadjuvant subgroup (n = 54). In multivariate analysis, the two-protein combination panel (HR = 2.178, 95% CI 1.115–4.256, <i>P</i> = 0.023) and perineural invasion (HR = 2.183, 95% CI 1.222–3.899, <i>P</i> = 0.008) were significantly associated with DFS. Using ROC-AUC analysis of good versus poor histological tumor response among patients treated preoperatively with radiotherapy, the average ROC-AUC was 0.745 for the combined panel, 0.618 for ATM alone, and 0.711 for MRE11 alone.</p><p>Conclusions</p><p>The MRE11/ATM two-protein panel developed in this study may have clinical value as a predictive marker of tumor response to neoadjuvant radiotherapy, and a prognostic marker for disease-free and overall survival.</p></div

Kaplan-Meier survival analysis.

<p>(A) and (B) respectively show survival curves of high (green line) and low (blue line) ATM/MRE11 two-protein expression groups in lymph node (LN) negative and LN positive rectal cancers. These show the effect of LN status on the association between expression levels and disease-free survival (DFS). (C) and (D) respectively show overall survival (OS) and DFS survival curves of 54 patients who received preoperative radiotherapy in terms of high (green line) and low (blue line) two protein expression groups. Worse OS (<i>P</i> = 0.024) and DFS (<i>P</i> = 0.028) were seen with high expression.</p

ROC-AUC analysis of ATM, MRE11, and combined protein panel expressions with tumour regression grade (TRG).

<p>(A−C) Box plots show levels of ATM, MRE11, and their combined expression in the TC categorized by TRG as 0–2 (good response) or 3 (poor response). The association between protein expression with TRG was examined by Mann−Whitney U test (ATM, <i>P</i> = 0.27; MRE11, <i>P</i> = 0.015; and combined proteins, <i>P</i> = 0.011). (D) Receiver operating characteristic (ROC) curve analysis comparing the performance of ATM and MRE11 alone with the combined 2-protein panel.</p

Cox regression analyses of combined TC expression level with clinicopathologic variables and DFS.

<p>Cox regression analyses of combined TC expression level with clinicopathologic variables and DFS.</p

Patient characteristics.

<p>Patient characteristics.</p

Associations between the combined expression of ATM and MRE11 in the tumor center and tumor periphery and clinicohistopathological data.

<p>Associations between the combined expression of ATM and MRE11 in the tumor center and tumor periphery and clinicohistopathological data.</p

Association between combined protein expression levels of ATM and MRE11 in rectal cancer tissues and survival.

<p>(A) Representative immunohistochemical staining of ATM and MRE11 in rectal cancer tissues. Bar = 200 μm. Staining for each protein was scored as high or low, as described in the Materials and Methods. (B) Overall survival according to combined protein expression levels of ATM and MRE11 was determined by Kaplan−Meier survival analyses and compared using the log-rank test. Patients with high combined protein expression levels of ATM and MRE11 in the TC (green line) showed significantly worse OS than those with low expression (blue line; <i>P</i> = 0.003). (C) Similarly, patients with high expression levels in the TC (green line) exhibited worse disease-free survival than those with low expression (blue line; <i>P</i> = 0.035). (D and E) When measured in the TP, no significant survival difference was seen between the high- and low-expression groups for overall survival (<i>P</i> = 0.208) or disease-free survival (<i>P</i> = 0.748).</p