Alblihy Adel, Shoqafi Ahmed, Toss Michael S, Algethami Mashael, Harris Anna E, Jeyapalan Jennie N, Abdel-Fatah Tarek, Servante Juliette, Chan Stephen Y T, Green Andrew, Mongan Nigel P, Rakha Emad A, Madhusudan Srinivasan
Nottingham Biodiscovery Institute, School of Medicine, University of Nottingham, University Park, Nottingham, NG7 3RD, UK.
Medical Center, King Fahad Security College (KFSC), Riyadh, 11461, Saudi Arabia.
NPJ Breast Cancer. 2021 Nov 15;7(1):143. doi: 10.1038/s41523-021-00350-5.
The MRE11-RAD50-NBS1 (MRN) complex is critical for genomic stability. Although germline mutations in MRN may increase breast cancer susceptibility, such mutations are extremely rare. Here, we have conducted a comprehensive clinicopathological study of MRN in sporadic breast cancers. We have protein expression profiled for MRN and a panel of DNA repair factors involved in double-strand break repair (BRCA1, BRCA2, ATM, CHK2, ATR, Chk1, pChk1, RAD51, γH2AX, RPA1, RPA2, DNA-PKcs), RECQ DNA helicases (BLM, WRN, RECQ1, RECQL4, RECQ5), nucleotide excision repair (ERCC1) and base excision repair (SMUG1, APE1, FEN1, PARP1, XRCC1, Pol β) in 1650 clinical breast cancers. The prognostic significance of MRE11, RAD50 and NBS1 transcripts and their microRNA regulators (hsa-miR-494 and hsa-miR-99b) were evaluated in large clinical datasets. Expression of MRN components was analysed in The Cancer Genome Atlas breast cancer cohort. We show that low nuclear MRN is linked to aggressive histopathological phenotypes such as high tumour grade, high mitotic index, oestrogen receptor- and high-risk Nottingham Prognostic Index. In univariate analysis, low nuclear MRE11 and low nuclear RAD50 were associated with poor survival. In multivariate analysis, low nuclear RAD50 remained independently linked with adverse clinical outcomes. Low RAD50 transcripts were also linked with reduced survival. In contrast, overexpression of hsa-miR-494 and hsa-miR-99b microRNAs was associated with poor survival. We observed large-scale genome-wide alterations in MRN-deficient tumours contributing to aggressive behaviour. We conclude that MRN status may be a useful tool to stratify tumours for precision medicine strategies.
MRE11-RAD50-NBS1（MRN）复合物对基因组稳定性至关重要。尽管MRN的种系突变可能会增加患乳腺癌的易感性，但此类突变极为罕见。在此，我们对散发性乳腺癌中的MRN进行了全面的临床病理研究。我们对1650例临床乳腺癌中的MRN以及一组参与双链断裂修复的DNA修复因子（BRCA1、BRCA2、ATM、CHK2、ATR、Chk1、pChk1、RAD51、γH2AX、RPA1、RPA2、DNA-PKcs）、RECQ DNA解旋酶（BLM、WRN、RECQ1、RECQ4、RECQ5）、核苷酸切除修复（ERCC1）和碱基切除修复（SMUG1、APE1、FEN1、PARP1、XRCC1、Pol β）进行了蛋白质表达分析。在大型临床数据集中评估了MRE11、RAD50和NBS1转录本及其微小RNA调节因子（hsa-miR-494和hsa-miR-99b）的预后意义。在癌症基因组图谱乳腺癌队列中分析了MRN组分的表达。我们发现低核MRN与侵袭性组织病理学表型相关，如高肿瘤分级、高有丝分裂指数、雌激素受体阴性以及高风险诺丁汉预后指数。在单变量分析中，低核MRE11和低核RAD50与不良生存相关。在多变量分析中，低核RAD50仍独立与不良临床结局相关。低RAD50转录本也与生存率降低相关。相反，hsa-miR-494和hsa-miR-99b微小RNA的过表达与不良生存相关。我们在MRN缺陷肿瘤中观察到大规模全基因组改变，这导致了侵袭性行为。我们得出结论，MRN状态可能是用于精准医学策略对肿瘤进行分层的有用工具。
