APC and TP53 Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes.
APC and TP53 Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes.
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DOI：
10.3390/cancers13215394
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发表时间：
2021-10-27
期刊：
影响因子：
5.2
通讯作者：
Yeatman TJ
中科院分区：
文献类型：
--
作者：
Thota R;Yang M;Pflieger L;Schell MJ;Rajan M;Davis TB;Wang H;Presson A;Pledger WJ;Yeatman TJ
结直肠癌(CRC)是癌症死亡的主要原因。西妥昔单抗是FDA批准的、未得到充分利用的针对转移性结直肠癌表皮生长因子受体(EGFR)的治疗药物。到目前为止，尽管选择了野生型RAS患者，但仍然很难确定哪些患者可能受益于EGFR抑制剂(例如西妥昔单抗)治疗。我们的目标是对结直肠癌患者进行分子分类，以便更好地识别对EGFR靶向治疗敏感的亚群。APC和TP53是结直肠癌中两个主要的抑癌基因，它们的突变与肿瘤的发生和发展有关，可能识别西妥昔单抗敏感的肿瘤。最近，有人建议使用共识分子亚型(CMS)分类来帮助识别西妥昔单抗敏感的患者。在这里，我们报告了一项使用APC和TP53联合突变对多个结直肠癌肿瘤/PDX/细胞系数据集的分析，以完善CMS分类，以更好地预测西妥昔单抗的疗效，从而改善患者预后。最近，有研究表明，共识分子亚型(CMS)可能有助于预测EGFR抑制剂(西妥昔单抗)治疗的反应。我们最近发现，APC和TP53是两个肿瘤抑制基因，当突变时，可能会增强西妥昔单抗的敏感性，并可能是肿瘤或血液中易于测量的生物标志物。我们的研究旨在使用APC和TP53突变(AP)来改进CMS分类，以更好地预测西妥昔单抗的疗效。总共有433例结直肠癌被分为CMS1-4亚型。在每个CMS类别中确定AP与非AP肿瘤的西妥昔单抗敏感性(CTX-S)签名评分。携带联合AP突变的肿瘤主要集中在CMS2类，其次是CMS4类。另一方面，在所有CMS类别中，AP突变的CRC的CTX-S得分显著高于非AP CRC。在独立的TCGA肿瘤标本(n=531)和PDMR PDX/PDO/PDC模型(n=477)中也得到了类似的结果。此外，西妥昔单抗的体外生长抑制作用与携带A/P基因的CMS2细胞株优先相关。总而言之，AP突变特征代表了一个方便的生物标记物，它完善了CMS分类，以确定预测对EGFR靶向治疗敏感的CRC亚群。
Colorectal cancer (CRC) is a major cause of cancer deaths. Cetuximab is an FDA-approved, underutilized therapeutic targeting the epidermal growth factor receptor (EGFR) in metastatic CRC. To date, despite selection of patients with wild-type RAS, it is still difficult to identify patients who may benefit from EGFR inhibitor (e.g., cetuximab) therapy. Our aim is to molecularly classify CRC patients to better identify subpopulations sensitive to EGFR targeted therapy. APC and TP53 are two major tumor suppressor genes in CRC whose mutations contribute to tumor initiation and progression and may identify cetuximab-sensitive tumors. Recently, it has been suggested that the consensus molecular subtype (CMS) classification may be used to help identify cetuximab-sensitive patients. Here, we report an analysis of multiple CRC tumor/PDX/cell line datasets using combined APC and TP53 mutations to refine the CMS classification to better predict responses to cetuximab to improve patient outcomes. Recently, it was suggested that consensus molecular subtyping (CMS) may aide in predicting response to EGFR inhibitor (cetuximab) therapies. We recently identified that APC and TP53 as two tumor suppressor genes, when mutated, may enhance cetuximab sensitivity and may represent easily measured biomarkers in tumors or blood. Our study aimed to use APC and TP53 mutations (AP) to refine the CMS classification to better predict responses to cetuximab. In total, 433 CRC tumors were classified into CMS1-4 subtypes. The cetuximab sensitivity (CTX-S) signature scores of AP vs. non-AP tumors were determined across each of the CMS classes. Tumors harboring combined AP mutations were predominantly enriched in the CMS2 class, and to a lesser degree, in the CMS4 class. On the other hand, AP mutated CRCs had significantly higher CTX-S scores compared to non-AP CRCs across all CMS classes. Similar results were also obtained in independent TCGA tumor collections (n = 531) and in PDMR PDX/PDO/PDC models (n = 477). In addition, the in vitro cetuximab growth inhibition was preferentially associated with the CMS2 cell lines harboring A/P genotypes. In conclusion, the AP mutation signature represents a convenient biomarker that refines the CMS classification to identify CRC subpopulations predicted to be sensitive to EGFR targeted therapies.
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DOI：
10.1097/ppo.0b013e318238216e
发表时间：
2011-11
期刊：
Cancer journal (Sudbury, Mass.)
影响因子：
--
作者：
Fenstermacher DA;Wenham RM;Rollison DE;Dalton WS
通讯作者：
Dalton WS
影响因子：
5.7
作者：
Bertino EM;McMichael EL;Mo X;Trikha P;Davis M;Paul B;Grever M;Carson WE;Otterson GA
通讯作者：
Otterson GA
影响因子：
45.3
作者：
Khambata-Ford, Shirin;Garrett, Christopher R.;Mauro, David J.
通讯作者：
Mauro, David J.
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
45.3
作者：
Lenz, Heinz-Josef;Ou, Fang-Shu;Kabbarah, Omar
通讯作者：
Kabbarah, Omar