Genetic Mechanisms of Immune Evasion in Colorectal Cancer.
Genetic Mechanisms of Immune Evasion in Colorectal Cancer.
复制标题
DOI：
10.1158/2159-8290.cd-17-1327
复制
发表时间：
2018-06
期刊：
影响因子：
28.2
通讯作者：
Peters U
中科院分区：
文献类型：
--
作者：
Grasso CS;Giannakis M;Wells DK;Hamada T;Mu XJ;Quist M;Nowak JA;Nishihara R;Qian ZR;Inamura K;Morikawa T;Nosho K;Abril-Rodriguez G;Connolly C;Escuin-Ordinas H;Geybels MS;Grady WM;Hsu L;Hu-Lieskovan S;Huyghe JR;Kim YJ;Krystofinski P;Leiserson MDM;Montoya DJ;Nadel BB;Pellegrini M;Pritchard CC;Puig-Saus C;Quist EH;Raphael BJ;Salipante SJ;Shin DS;Shinbrot E;Shirts B;Shukla S;Stanford JL;Sun W;Tsoi J;Upfill-Brown A;Wheeler DA;Wu CJ;Yu M;Zaidi SH;Zaretsky JM;Gabriel SB;Lander ES;Garraway LA;Hudson TJ;Fuchs CS;Ribas A;Ogino S;Peters U
为了了解结直肠癌（CRC）免疫识别和逃避的遗传驱动因素，我们分析了1，211个CRC原发性肿瘤样本，其中包括179个被归类为微卫星不稳定性高（MSI高）的样本。这一组包括癌症基因组图谱CRC队列的592个样本，在这里完成和分析。MSI-高，一种高度突变的免疫原性CRC亚型，在重要的免疫调节途径和抗原呈递机制中具有高比率的显著突变基因，包括由于拷贝数改变和拷贝中性杂合性丢失（CN-LOH）导致的B2 M和HLA基因的双等位基因丢失。WNT/β-catenin信号传导基因在所有CRC亚型中均发生显著突变，激活的WNT/β-catenin信号传导与T细胞浸润的缺乏相关。CRC的这种大规模基因组分析表明，MSI高病例经常经历免疫编辑过程，尽管突变负荷高，淋巴细胞浸润频繁，但仍为他们提供了允许免疫逃逸的遗传事件，此外，CRC肿瘤具有与激活的WNT信号传导和T细胞排斥相关的遗传和甲基化事件。
To understand the genetic drivers of immune recognition and evasion in colorectal cancer (CRC), we analyzed 1,211 CRC primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas CRC cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of CRC, had a high rate of significantly mutated genes in important immune modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy number alterations and copy-neutral loss of heterozygosity (CN-LOH). WNT/β-catenin signaling genes were significantly mutated in all CRC subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of CRC demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration, and furthermore, that CRC tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion.