Neoadjuvant chemotherapy affects molecular classification of colorectal tumors.
Neoadjuvant chemotherapy affects molecular classification of colorectal tumors.
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DOI：
10.1038/oncsis.2017.48
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发表时间：
2017-07-10
期刊：
影响因子：
6.2
通讯作者：
Kranenburg O
中科院分区：
文献类型：
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作者：
Trumpi K;Ubink I;Trinh A;Djafarihamedani M;Jongen JM;Govaert KM;Elias SG;van Hooff SR;Medema JP;Lacle MM;Vermeulen L;Borel Rinkes IHM;Kranenburg O
最近在人类原发结直肠癌中发现的‘分子亚型’揭示了亚型、转移倾向和治疗反应之间的相关性。目前尚不清楚分子肿瘤亚型在远距离扩散后是否保持不变。如果是这样的话，原发肿瘤的分子分型可以指导转移性疾病的亚型靶向治疗。在这项研究中，我们使用最近开发的基于免疫组织化学的分类工具，将配对的原发性结直肠癌及其相应的肝转移瘤(n=129)样本分类为上皮样或间叶样。我们观察到在原发肿瘤及其肝转移的分类上有相当大的不一致(45%)。不一致的分类与新辅助化疗的使用显著相关。此外，化疗暴露的肝转移与化疗未治疗的肝转移的基因表达分析显示，在治疗前的肿瘤中有间充质程序的表达。为了探索化疗是否会导致影响分子亚型的基因表达变化，我们将患者来源的结肠球暴露于5-氟尿嘧啶的六个短周期。基因表达谱分析和信号浓缩分析随后显示，在化疗暴露的肿瘤培养中，识别间充质样瘤的信号的表达显著增加。使用化疗诱导的基因表达程序对大量的人类结肠肿瘤进行无监督的分组，发现预后较差的间充质样亚群。我们的结论是，新辅助化疗诱导残留肿瘤细胞的间质表型，这可能影响结直肠肿瘤的分子分类。
The recent discovery of ‘molecular subtypes’ in human primary colorectal cancer has revealed correlations between subtype, propensity to metastasize and response to therapy. It is currently not known whether the molecular tumor subtype is maintained after distant spread. If this is the case, molecular subtyping of the primary tumor could guide subtype-targeted therapy of metastatic disease. In this study, we classified paired samples of primary colorectal carcinomas and their corresponding liver metastases (n=129) as epithelial-like or mesenchymal-like, using a recently developed immunohistochemistry-based classification tool. We observed considerable discordance (45%) in the classification of primary tumors and their liver metastases. Discordant classification was significantly associated with the use of neoadjuvant chemotherapy. Furthermore, gene expression analysis of chemotherapy-exposed versus chemotherapy naive liver metastases revealed expression of a mesenchymal program in pre-treated tumors. To explore whether chemotherapy could cause gene expression changes influencing molecular subtyping, we exposed patient-derived colonospheres to six short cycles of 5-fluorouracil. Gene expression profiling and signature enrichment analysis subsequently revealed that the expression of signatures identifying mesenchymal-like tumors was strongly increased in chemotherapy-exposed tumor cultures. Unsupervised clustering of large cohorts of human colon tumors with the chemotherapy-induced gene expression program identified a poor prognosis mesenchymal-like subgroup. We conclude that neoadjuvant chemotherapy induces a mesenchymal phenotype in residual tumor cells and that this may influence the molecular classification of colorectal tumors.
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影响因子：
168.9
作者：
Midgley, R;Kerr, D
通讯作者：
Kerr, D
影响因子：
2.4
作者：
Han, Cheng-Bo;Li, Fan;Zou, Hua-Wei
通讯作者：
Zou, Hua-Wei
影响因子：
45.3
作者：
Khambata-Ford, Shirin;Garrett, Christopher R.;Mauro, David J.
通讯作者：
Mauro, David J.
影响因子：
3.7
作者：
Snoeren N;van Hooff SR;Adam R;van Hillegersberg R;Voest EE;Guettier C;van Diest PJ;Nijkamp MW;Brok MO;van Leenen D;Koerkamp MJ;Holstege FC;Rinkes IH
通讯作者：
Rinkes IH
影响因子：
82.9
作者：
通讯作者：
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