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DNA mismatch repair in cancer
Pharmacology & Therapeutics ( IF 12.0 ) Pub Date : 2018-04-15 , DOI: 10.1016/j.pharmthera.2018.04.004
Marina Baretti , Dung T. Le

Microsatellite instability (MSI) refers to the hypermutator phenotype secondary to frequent polymorphism in short repetitive DNA sequences and single nucleotide substitution, as consequence of DNA mismatch repair (MMR) deficiency. MSI secondary to germline mutation in DNA MMR proteins is the molecular fingerprint of Lynch syndrome (LS), while epigenetic inactivation of these genes is more commonly found in sporadic MSI tumors. MSI occurs at different frequencies across malignancies, although original methods to assess MSI or MMR deficiency have been developed mostly in LS related cancers. Here we will discuss the current methods to detect MSI/MMR deficiency with a focus of new tools which are emerging as highly sensitive detector for MSI across multiple tumor types.

Due to high frequencies of non-synonymous mutations, the presence of frameshift-mutated neoantigens, which can trigger a more robust and long-lasting immune response and strong TIL infiltration with tumor eradication, MSI has emerged as an important predictor of sensitivity for immunotherapy-based strategies, as showed by the recent FDA's first histology agnostic-accelerated approval to immune checkpoint inhibitors for refractory, adult and pediatric, MMR deficient (dMMR) or MSI high (MSI-H) tumors. Moreover, it is known that MSI status may predict cancer response/resistance to certain chemotherapies.

Here we will describe the complex interplay between the genetic and clinical-pathological features of MSI/dMMR tumors and the cancer immunotherapy, with a focus on the predictive and prognostic role of MMR status for immune checkpoint inhibitors (ICIs) and providing some suggestions on how to conceive better predictive markers for immunotherapy in the next future.



中文翻译:

DNA错配修复在癌症中

微卫星不稳定性(MSI)是指由于DNA错配修复(MMR)缺乏而在短的重复DNA序列和单核苷酸取代中多态性继发于多态性的超突变体表型。DNA MMR蛋白中继生殖系突变后的MSI是Lynch综合征(LS)的分子指纹,而这些基因的表观遗传失活更常见于散发MSI肿瘤中。尽管大多数在LS相关的癌症中已经开发出了评估MSI或MMR缺乏症的原始方法,但MSI在整个恶性肿瘤中的发生频率不同。在这里,我们将讨论以新工具为重点的当前检测MSI / MMR缺陷的方法,这些新工具正在成为跨多种肿瘤类型的MSI的高度灵敏检测器。

由于非同义突变的频率很高,存在移码突变的新抗原,可以触发更强效和持久的免疫反应,并能在肿瘤根除中引发强大的TIL浸润,因此,MSI已成为免疫疗法敏感性的重要预测指标,基于FDA的策略,如最近FDA首次组织学上加速批准使用免疫检查点抑制剂治疗难治性,成年和小儿,MMR缺陷(dMMR)或MSI高(MSI-H)肿瘤。此外,已知MSI状态可以预测癌症对某些化学疗法的反应/耐药性。

在这里,我们将描述MSI / dMMR肿瘤的遗传和临床病理特征与癌症免疫疗法之间的复杂相互作用,重点是MMR状况对免疫检查点抑制剂(ICI)的预测和预后作用,并提供一些建议为未来的免疫疗法设计更好的预测标记。

更新日期:2018-04-15
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