To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability–high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, 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. WNT/β-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of colorectal cancer 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 colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion.

Significance: This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. Cancer Discov; 8(6); 730–49. ©2018 AACR.

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为了了解结直肠癌免疫识别和逃避的遗传驱动因素，我们分析了1,211例结直肠癌原发性肿瘤样本，包括179个分类为微卫星不稳定性高（MSI高）的样本。该组包括592个样本的“癌症基因组图集”大肠直肠癌队列，已在此处完成并进行了分析。MSI高，一种大突变的免疫原性结直肠癌亚型，在重要的免疫调节途径和抗原呈递机制中，包括B2M和HLA的双等位基因丢失，具有很高的显着突变基因基因由于拷贝数改变和杂合性的拷贝中性丧失而引起。WNT /β-catenin信号转导基因在所有大肠癌亚型中均发生了显着突变，并且活化的WNT /β-catenin信号转导与T细胞浸润不相关。结直肠癌的大规模基因组分析表明，MSI高的病例经常经历免疫编辑过程，从而为他们提供遗传事件，尽管突变负荷高且淋巴细胞浸润频繁，但免疫逃逸；此外，结直肠癌肿瘤也具有遗传和甲基化事件与激活的WNT信号传导和T细胞排斥相关。

启示：这项对1,211例大肠癌原发肿瘤的多组学分析表明，应该有可能在15％的对免疫阻断疗法有反应的病例中更好地监测耐药性，并在85％的病例中使用WNT信号抑制剂逆转免疫排斥目前尚不存在的情况。巨蟹座Discov; 8（6）; 730–49。©2018 AACR。

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