Tímár József, Ladányi Andrea
II. Sz. Patológiai Intézet, Semmelweis Egyetem, Budapest, Hungary.
Sebészeti és Molekuláris Patológiai Osztály, Országos Onkológiai Intézet, Budapest, Hungary.
Magy Onkol. 2019 Sep 18;63(3):173-182. Epub 2019 Aug 13.
Genomic instability is a hallmark of cancer therefore of the metastatic disease as well. High tumor mutation burden is due to deficiencies of the DNA repair systems and leads to immunosensitivity due to generation of neoantigens. However, APOBEC activation of that system, though increases mutation rate, but causes immunoresistance. Deficient antigen presentation due to HLA class I defects is another major cause of immunoresistance. The contemporary immunotherapies may exploit gene amplification of PD-L1 but if the affected chromosome is damaged IFN activation can be lost, again causing immunoresistance. Since these genetic changes can be generated continuously during tumor progression (the entire metastatic process), it would be necessary to monitor them continuously. On the other hand, since tumors are genetically and phenotypically heterogeneous, multiple sampling would be necessary to obtain a more realistic picture of biomarker expressions.
基因组不稳定是癌症的一个标志，因此也是转移性疾病的标志。高肿瘤突变负荷是由于DNA修复系统缺陷所致，并因新抗原的产生而导致免疫敏感性。然而，该系统的载脂蛋白B mRNA编辑酶催化多肽样3（APOBEC）激活虽然会增加突变率，但会导致免疫抗性。由于人类白细胞抗原（HLA）I类缺陷导致的抗原呈递不足是免疫抗性的另一个主要原因。当代免疫疗法可能利用程序性死亡受体配体1（PD-L1）的基因扩增，但如果受影响的染色体受损，干扰素激活可能会丧失，再次导致免疫抗性。由于这些基因变化可在肿瘤进展（整个转移过程）中持续产生，因此有必要对其进行持续监测。另一方面，由于肿瘤在基因和表型上具有异质性，因此需要进行多次采样，以更真实地了解生物标志物的表达情况。
