Integrative Molecular Characterization of Resistance to Neoadjuvant Chemoradiation in Rectal Cancer
Integrative Molecular Characterization of Resistance to Neoadjuvant Chemoradiation in Rectal Cancer
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DOI：
10.1158/1078-0432.ccr-19-0908
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发表时间：
2019-09-01
影响因子：
11.5
通讯作者：
Van Allen, Eliezer M.
中科院分区：
文献类型：
--
作者：
Kamran, Sophia C.;Lennerz, Jochen K.;Van Allen, Eliezer M.
目的：与同步化疗和放疗（CRT）的完全反应或获得性耐药相关的分子特性尚未完全表征。实验设计：我们在新辅助CRT（pre-CRT）之前和切除时对直肠腺癌肿瘤进行了整合的全外显子组/转录组测序和免疫浸润分析结果：CRT与肿瘤突变负荷或新抗原负荷增加无关，也不改变直肠癌中已确定的体细胞肿瘤突变的分布。并发KRAS/TP 53突变（KP）与NR肿瘤相关，并富集上皮-间充质转化转录程序。此外，NR与CD 4/CD 8 T细胞浸润减少和CRT后M2巨噬细胞表型相关。任何局部肿瘤复发的情况下，KP/NR状态预测更差的无进展生存，表明局部免疫逃逸CRT期间或之后与特定的基因组特征有助于远端progression.Conclusions：总体而言，而CRT没有影响基因组图谱，CRT影响肿瘤免疫微环境，特别是在耐药病例。
Purpose: Molecular properties associated with complete response or acquired resistance to concurrent chemotherapy and radiotherapy (CRT) are incompletely characterized.Experimental Design: We performed integrated whole-exome/transcriptome sequencing and immune infiltrate analysis on rectal adenocarcinoma tumors prior to neoadjuvant CRT (pre-CRT) and at time of resection (post-CRT) in 17 patients [8 complete/partial responders, 9 nonresponders (NR)].Results: CRT was not associated with increased tumor mutational burden or neoantigen load and did not alter the distribution of established somatic tumor mutations in rectal cancer. Concurrent KRAS/TP53 mutations (KP) associated with NR tumors and were enriched for an epithelial-mesenchymal transition transcriptional program. Furthermore, NR was associated with reduced CD4/CD8 T-cell infiltrates and a post-CRT M2 macrophage phenotype. Absence of any local tumor recurrences, KP/NR status predicted worse progression-free survival, suggesting that local immune escape during or after CRT with specific genomic features contributes to distant progression.Conclusions: Overall, while CRT did not impact genomic profiles, CRT impacted the tumor immune microenvironment, particularly in resistant cases.