B2M and JAK1/2-mutated MSI-H Colorectal Carcinomas Can Benefit From Anti-PD-1 Therapy.
B2M and JAK1/2-mutated MSI-H Colorectal Carcinomas Can Benefit From Anti-PD-1 Therapy.
复制标题
B2M 和 JAK1/2 突变的 MSI-H 结直肠癌可以受益于抗 PD-1 治疗。
DOI：
10.1097/cji.0000000000000417
复制
发表时间：
2022-05-01
期刊：
影响因子：
--
通讯作者：
Ding P
中科院分区：
文献类型：
--
作者：
Zhang C;Li D;Xiao B;Zhou C;Jiang W;Tang J;Li Y;Zhang R;Han K;Hou Z;Zhang L;Sui Q;Liao L;Pan Z;Zhang X;Ding P
β2-微球蛋白(B2M)和JAK1/2(JAK1/2)突变被认为是抗程序性细胞死亡蛋白1(PD-1)治疗免疫逃避的遗传机制。B2M和JAK1/2功能缺失突变是否会导致结直肠癌患者对抗PD-1治疗产生原发抵抗仍存在争议。在这里，我们试图比较抗PD-1治疗在伴有或不伴有B2M或JAK1/2突变的DNA错配修复缺陷/微卫星不稳定的高CRC患者中的疗效。35例接受抗PD-1治疗的结直肠癌患者进入本研究。所有的肿瘤样本都进行了下一代测序。本研究还对110例大肠癌患者的临床和分子数据进行了分析，这些数据是用纪念斯隆-凯特林-可操作癌症靶点突变分析(MSK-IMPACT)进行测序的，并通过生物门户网站获取。本中心35例结直肠癌患者中，10例(28.6%)为B2M功能缺失突变，8例(22.9%)为JAK1/2功能缺失突变。与B2M野生型相比，B2M突变的CRCs对抗PD-1治疗的耐药率并不高(P=0.71)。JAK1/2基因突变患者的抗PD-1治疗效果明显好于无突变患者(P=0.015)。在MSK-IMPACT数据集中的110例结直肠癌患者中，13例(11.8%)有B2M突变，15例(13.6%)有JAK1/2突变。在分析了这110例患者对抗PD-1治疗的反应后，我们发现了相似的结果(分别为P=0.438和0.071)。此外，具有B2M或JAK1/2突变的患者的肿瘤突变负荷评分低于无突变的患者。B2M和JAK1/2功能缺失突变在微卫星不稳定性-高CRC中频繁发生。我们的研究表明，携带B2M或JAK1/2突变的结直肠癌患者不应被排除在抗PD-1治疗之外。
β2-microglobulin (B2M) and Janus kinases 1 and 2 (JAK1/2) mutations have been suggested as genetic mechanisms of immune evasion for anti–programmed cell death protein 1 (PD-1) therapy. Whether B2M and JAK1/2 lose-of-function mutation can cause primary resistance to anti-PD-1 therapy in colorectal carcinoma (CRC) patients remains controversial. Here, we sought to compare the efficacy of anti-PD-1 therapy in DNA mismatch repair deficient/microsatellite instability–high CRC patients with or without B2M or JAK1/2 mutations. Thirty-Five CRC patients who received anti-PD-1 therapy were enrolled in this study. All tumor samples underwent next-generation sequencing. The clinical and molecular data from 110 CRC patients sequenced with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay and accessed through cBioportal were also analyzed in this study. Of the 35 CRC patients from our center, 10 (28.6%) had a B2M loss-of-function mutation, and 8 (22.9%) had a JAK1/2 loss-of-function mutation. Compared with B2M wild-type CRCs, B2M-mutated CRCs did not show a higher frequency of resistance to anti-PD-1 therapy (P=0.71). There was even better response to anti-PD-1 therapy in patients with JAK1/2 mutation than in those without (P=0.015). Of the 110 CRC patients in the MSK-IMPACT datasets, 13 (11.8%) had a B2M mutation, and 15 (13.6%) had a JAK1/2 mutation. After analyzing the response to anti-PD-1 therapy in these 110 patients, we found similar results (P=0.438 and 0.071, respectively). Moreover, patients with B2M or JAK1/2 mutation had a lower tumor mutational burden score compared with those without. B2M and JAK1/2 loss-of-function mutations occur frequently in microsatellite instability–high CRC. Our study demonstrated that patients with CRC harboring B2M or JAK1/2 mutations should not be excluded from anti-PD-1 therapy.