MTAP作为胸腔恶性肿瘤的新兴生物标志物
MTAP as an emerging biomarker in thoracic malignancies
影响因子:4.40000
分区:医学2区 / 肿瘤学3区 呼吸系统3区
发表日期:2024 Nov
作者:
Magdalena M Brune, Spasenija Savic Prince, Tatjana Vlajnic, Obinna Chijioke, Luca Roma, David König, Lukas Bubendorf
摘要
S-甲基-5'-硫代腺苷磷酸化酶（MTAP）缺乏是非小细胞肺癌（NSCLC）及以后的新兴生物标志物。 MTAP基因位于染色体区域9P21.3中，该区域显示了所有人类癌症中最常见的纯合缺失之一（9p21损失）。在大多数胸膜间皮瘤中发现了9p21的损失，在那里它是已建立的诊断标记。直到最近，荧光原位杂交（FISH）还是检测9P21损失的金标准，但是免疫组织化学（IHC）通过易于应用和具有成本效益的诊断替代标记而获得的MTAP表达损失越来越重要。此外，在NSCLC和其他癌症类型的两种不同的情况下，NSCLC中有13％的MTAP损失正在成为一种新兴的预测生物标志物：1）MTAP损失似乎对免疫检查点抑制剂（ICI）的反应负面预测，通过对肿瘤微型环境的沉默和2）的策略进行了预测，以及对型号损失进行预测。 MTAP缺乏导致蛋白质精氨酸甲基转移酶5（PRMT5）的功能受损，这是由于其由MTAP积累的底物甲基甲基腺苷（MTA）的部分抑制作用。该过程使MTAP缺乏肿瘤细胞在很大程度上取决于PRMT5的剩余功能，从而使其成为合成致死性的理想目标。实际上，现在在几项临床试验中测试了MTA合作性PRMT5抑制剂，并在固体恶性肿瘤中具有有希望的早期结果。随着其作为预测性生物标志物的出现，将MTAP IHC实施到NSCLC和其他肿瘤的诊断常规中很快就会很快发生。在这篇评论文章中，我们总结了有关MTAP在胸部肿瘤中作用的当前文献，并评估包括IHC，FISH和下一代测序在内的不同测试方法。
Abstract
S-methyl-5'-thioadenosine phosphorylase (MTAP) deficiency is an emerging biomarker in non-small cell lung cancer (NSCLC) and beyond. The MTAP gene is located in the chromosomal region 9p21.3, which shows one of the most common homozygous deletions across all human cancers (9p21 loss). Loss of 9p21 is found in the majority of pleural mesotheliomas, where it serves as an established diagnostic marker. Until recently, fluorescence in situ hybridization (FISH) was the gold standard for the detection of 9p21 losses, but loss of MTAP expression by immunohistochemistry (IHC) gains increasing importance as an easy to apply and cost-effective diagnostic surrogate marker. Besides, MTAP loss, which has been reported in 13% of NSCLC, is becoming an emerging predictive biomarker in two different scenarios in NSCLC and other cancer types: 1) MTAP loss seems to negatively predict the response to immune checkpoint inhibitor (ICI) treatment via silencing of the tumor microenvironment, and 2) MTAP loss serves as a predictive biomarker for novel targeted treatment strategies. MTAP deficiency leads to an impaired function of the protein arginine methyltransferase 5 (PRMT5) due to its partial inhibition by MTAP's accumulating substrate methylthioadenosine (MTA). This process leaves MTAP deficient tumor cells heavily dependent on the remaining function of PRMT5, making it a perfect target for synthetic lethality. Indeed, MTA-cooperative PRMT5-inhibitors are now tested in several clinical trials with promising early results in solid malignancies. With its emergence as a predictive biomarker, the implementation of MTAP IHC into diagnostic routine for NSCLC and other tumors is likely to take place soon. In this review article, we summarize the current literature on the role of MTAP in thoracic tumors and evaluate different testing methods, including IHC, FISH and next generation sequencing.