Aim: DNA repair has an important role in malignant pleural mesothelioma (MPM) tumorigenesis and progression. Prognostic/predictive biomarkers for better management of MPM patients are needed. In the present manuscript, we analyzed the expression of more than 700 genes in a cohort of MPM patients to possibly find biomarkers correlated with survival. Methods: A total of 54 MPM patients, all with epithelioid histology, whose survival follow-up and formalin-fixed paraffin-embedded tumors were available, were included in the study. Gene expression profiles were evaluated using a Nanostring platform analyzing 760 genes involved in different cellular pathways. The percentages of proliferating tumor cells positive for RAD51 and BRCA1 foci were evaluated using an immunofluorescence assay, as a readout of homologous recombination repair status. Results: Patient median survival time was 16.9 months, and based on this value, they were classified as long and short survivors (LS/SS) with, respectively, an overall survival ≥ and <16.9 months as well as very long and very short survivors (VLS/VSS) with an overall survival ≥ than 33.8 and < than 8.45 months. A down-regulation in the DNA damage/repair expression score was observed in LS and VLS as compared to SS and VSS. These findings were validated by the lower number of both RAD51 and BRCA1-positive tumor cells in VLS as compared to VSS. Conclusions: The down-regulation of DNA repair signature in VLS was functionally validated by a lower % of RAD51 and BRCA1-positive tumor cells. If these data can be corroborated in a prospective trial, an easy, cost-effective test could be routinely used to better manage treatment in MPM patients.
目的：DNA修复在恶性胸膜间皮瘤（MPM）的肿瘤发生与进展中具有重要作用。目前亟需能够改善MPM患者管理的预后/预测性生物标志物。本研究通过分析一组MPM患者中700多个基因的表达情况，旨在寻找与生存期相关的潜在生物标志物。 方法：本研究纳入54例经组织学证实为上皮型MPM的患者，所有患者均具备完整的生存随访资料及福尔马林固定石蜡包埋肿瘤样本。采用Nanostring平台评估760个涉及不同细胞通路的基因表达谱，并通过免疫荧光法检测RAD51和BRCA1灶阳性增殖肿瘤细胞百分比，以此作为同源重组修复状态的读数。 结果：患者中位生存期为16.9个月。基于该数值，将患者分为长生存期（LS）与短生存期（SS）组（总生存期分别≥和<16.9个月），以及超长生存期（VLS）与超短生存期（VSS）组（总生存期分别≥33.8个月和<8.45个月）。与SS和VSS组相比，LS和VLS组显示出DNA损伤/修复表达评分的下调。这一发现在VLS组中通过较低的RAD51和BRCA1阳性肿瘤细胞数量得到验证。 结论：VLS组中DNA修复特征的下调通过较低的RAD51和BRCA1阳性肿瘤细胞百分比得到功能验证。若能在前瞻性试验中证实这些发现，未来或可常规采用简便、经济高效的检测方法，以优化MPM患者的治疗管理。
Epithelioid Mesothelioma Patients with Very Long Survival Display Defects in DNA Repair
肿瘤(癌症)患者之家