Transcriptional subtyping and CD8 immunohistochemistry identifies poor prognosis stage II/III colorectal cancer patients who benefit from adjuvant chemotherapy.
Transcriptional subtyping and CD8 immunohistochemistry identifies poor prognosis stage II/III colorectal cancer patients who benefit from adjuvant chemotherapy.
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DOI：
10.1200/po.17.00241
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发表时间：
2018-06-13
影响因子：
4.6
通讯作者：
Longley DB
中科院分区：
文献类型：
--
作者：
Allen WL;Dunne PD;McDade S;Scanlon E;Loughrey M;Coleman H;McCann C;McLaughlin K;Nemeth Z;Syed N;Jithesh P;Arthur K;Wilson R;Coyle V;McArt D;Murray GI;Samuel L;Nuciforo P;Jimenez J;Argiles G;Dienstmann R;Tabernero J;Messerini L;Nobili S;Mini E;Sheahan K;Ryan E;Johnston PG;Van Schaeybroeck S;Lawler M;Longley DB
结直肠癌的转录谱分析(CRC)导致了对II期和III期疾病具有预后价值的四种共识分子亚型(CMS1至4)的鉴定。最近，结直肠癌固有亚型(CRIS)分类系统帮助定义了结直肠肿瘤上皮成分特有的生物学特性；然而，这些分类系统在预测标准护理辅助化疗疗效方面的临床价值尚不清楚。使用来自欧洲四个地点的样本，我们组装了一个新的II和III期结直肠癌患者队列(n=156个样本)，进行了转录图谱和靶向测序，并生成了一个组织微阵列，以实现集成的多组学分析。我们还获取了两个已发表的II期和III期结直肠癌患者队列的数据：GSE39582和GSE14333(分别为479个和185个样本)。富含上皮细胞的CMS2亚型结直肠癌在II期和III期疾病中均从辅助化疗中显著受益(分别为P=0.02和P&t；.001)，而CMS3亚型仅在III期中显著受益(P=.001)。在CMS2的CRIS底物化后，我们观察到只有CRIS-C亚型在II期和III期疾病的辅助化疗中显著受益(分别为P=.0081和P<；.001)，而CRIS-D亚型仅在III期显著受益(P=.0034)。我们还观察到CD8+肿瘤浸润性淋巴细胞水平低的CRIS-C患者在II期和III期疾病中复发的风险最大(对数等级P=0.0031；风险比12.18[95%CI，1.51至98.58])。结合转录亚型和CD8免疫组织化学分析进行患者分层，能够识别预后较差的II和III期疾病患者，这些患者受益于辅助标准护理化疗。这些发现与II期疾病患者尤其相关，在这些患者中，辅助化疗的总体好处微乎其微。
Transcriptomic profiling of colorectal cancer (CRC) has led to the identification of four consensus molecular subtypes (CMS1 to 4) that have prognostic value in stage II and III disease. More recently, the Colorectal Cancer Intrinsic Subtypes (CRIS) classification system has helped to define the biology specific to the epithelial component of colorectal tumors; however, the clinical value of these classification systems in the prediction of response to standard-of-care adjuvant chemotherapy remains unknown. Using samples from four European sites, we assembled a novel cohort of patients with stage II and III CRC (n = 156 samples) and performed transcriptomic profiling and targeted sequencing and generated a tissue microarray to enable integrated multiomics analyses. We also accessed data from two published cohorts of patients with stage II and III CRC: GSE39582 and GSE14333 (n = 479 and n = 185 samples, respectively). The epithelial-rich CMS2 subtype of CRC benefitted significantly from treatment with adjuvant chemotherapy in both stage II and III disease (P = .02 and P < .001, respectively), whereas the CMS3 subtype significantly benefitted in stage III only (P = .001). After CRIS substratification of CMS2, we observed that only the CRIS-C subtype significantly benefitted from treatment with adjuvant chemotherapy in stage II and III disease (P = .0081 and P < .001, respectively), whereas the CRIS-D subtype significantly benefitted in stage III only (P = .0034). We also observed that CRIS-C patients with low levels of CD8+ tumor-infiltrating lymphocytes were most at risk for relapse in both stage II and III disease (log-rank P = .0031; hazard ratio, 12.18 [95% CI, 1.51 to 98.58]). Patient stratification using a combination of transcriptional subtyping and CD8 immunohistochemistry analyses is capable of identifying patients with poor prognostic stage II and III disease who benefit from adjuvant standard-of-care chemotherapy. These findings are particularly relevant for patients with stage II disease, where the overall benefit of adjuvant chemotherapy is marginal.