A specific mode of microsatellite instability is a crucial biomarker in adult T-cell leukaemia/lymphoma patients.
A specific mode of microsatellite instability is a crucial biomarker in adult T-cell leukaemia/lymphoma patients.
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DOI：
10.1007/s00432-016-2294-1
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发表时间：
2017-03
影响因子：
3.6
通讯作者：
Uike N
中科院分区：
文献类型：
--
作者：
Miyashita K;Fujii K;Taguchi K;Shimokawa M;Yoshida MA;Abe Y;Okamura J;Oda S;Uike N
微卫星不稳定性（MSI）一直是肿瘤细胞耐药性的长期生物标志物候选者。尽管有大量的临床研究，但文献中的数据并不是结论性的。在某些恶性肿瘤中MSI现象的复杂性可能，至少部分地，解释了这种差异。此外，还指出了测定技术中存在的方法学问题。我们以前建立了一个独特的荧光技术，在传统的测定中的主要方法学问题被克服。该技术的应用揭示了两种不同的微卫星改变模式，即A型和B型。更重要的是，我们证明了A型MSI是缺陷DNA错配修复（MMR）的直接结果，该缺陷DNA错配修复（MMR）导致细胞对药物的耐药性。我们首先将这项技术应用于成人T细胞白血病/淋巴瘤（ATLL）。在ATLL中确实观察到MSI现象（4/20，20%）。有趣的是，观察到的微卫星改变总是A型，这意味着肿瘤是MMR缺陷的。事实上，这些MSI+肿瘤患者的临床结局明显更差。多因素分析显示A型MSI是独立的预后因素。这些观察结果强烈表明A型MSI作为ATLL预后和潜在预测生物标志物的可能性。
Microsatellite instability (MSI) has been a long-standing biomarker candidate for drug resistance in tumour cells. Despite numerous clinical studies, the data in the literature are not conclusive. The complexity of the MSI phenomenon in some malignancies may, at least partly, account for the discrepancy. In addition, methodological problems are also pointed out in the assay techniques. We previously established a unique fluorescent technique in which the major methodological problems in conventional assays are overcome. Application of this technique has revealed two distinct modes of microsatellite alterations, i.e. Type A and Type B. More importantly, we demonstrated that Type A MSI is the direct consequence of defective DNA mismatch repair (MMR) that causes cellular resistance against antineoplastic agents. We first applied this technique to adult T-cell leukaemia/lymphoma (ATLL). The MSI phenomenon was indeed observed in ATLLs (4/20, 20%). Intriguingly, the observed microsatellite alterations were invariably Type A, which implies that the tumours were MMR-defective. Indeed, clinical outcomes of patients with these MSI+ tumours were significantly worse. Furthermore, multivariate analysis revealed that Type A MSI is an independent prognostic factor. These observations strongly suggest the possibility of Type A MSI as a prognostic and potentially predictive biomarker in ATLL.