Saito Shinta, Kato Shingo, Arai Usaki, En Atsuki, Tsunezumi Jun, Mizushima Taichi, Tateishi Kensuke, Adachi Noritaka
Department of Life and Environmental System Science, Graduate School of Nanobioscience, Yokohama City University, Yokohama, 236-0027, Japan.
Department of Clinical Cancer Genomics, Yokohama City University Hospital, Yokohama, 236-0004, Japan.
Nat Commun. 2025 May 12;16(1):4239. doi: 10.1038/s41467-025-59462-2.
Homologous recombination (HR) and mismatch repair (MMR) act as guardians of the human genome, and defects in HR or MMR are causative in at least a quarter of all malignant tumors. Although these DNA repair-deficient tumors are eligible for effective targeted therapies, fully reliable diagnostic strategies based on functional assay have yet to be established, potentially limiting safe and proper application of the molecular targeted drugs. Here we show that transient transfection of artificial DNA substrates enables ultrarapid detection of HR and MMR. This finding led us to develop a diagnostic strategy that can determine the cellular HR/MMR status within one day without the need for control cells or tissues. Notably, the accuracy of this method allowed the discovery of a pathogenic RAD51D mutation, which was missed by existing companion diagnostic tests. Our methods, termed HR eye and MMR eye, are applicable to frozen tumor tissues and roughly predict the response to therapy. Overall, the findings presented here could pave the way for accurately assessing malignant tumors with functional defects in HR or MMR, a step forward in accelerating precision medicine.
同源重组（HR）和错配修复（MMR）是人类基因组的守护者，HR或MMR缺陷在至少四分之一的所有恶性肿瘤中起致病作用。尽管这些DNA修复缺陷型肿瘤适合接受有效的靶向治疗，但基于功能测定的完全可靠的诊断策略尚未建立，这可能会限制分子靶向药物的安全和正确应用。在这里，我们表明人工DNA底物的瞬时转染能够超快速检测HR和MMR。这一发现促使我们开发出一种诊断策略，该策略可以在一天内确定细胞的HR/MMR状态，而无需对照细胞或组织。值得注意的是，这种方法的准确性使得发现了一种致病性RAD51D突变，而现有伴随诊断测试却遗漏了该突变。我们的方法，称为HR眼和MMR眼，适用于冷冻肿瘤组织，并大致预测对治疗的反应。总体而言，此处呈现的研究结果可为准确评估具有HR或MMR功能缺陷的恶性肿瘤铺平道路，这是在加速精准医学方面向前迈出的一步。
