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Longitudinal change of genetic variations in cetuximab-treated metastatic colorectal cancer
Cancer Genetics ( IF 1.4 ) Pub Date : 2021-07-11 , DOI: 10.1016/j.cancergen.2021.06.007
Sun Young Kim 1 , Kwoneel Kim 2 , Su Han Cho 3 , Sung-Min Chun 4 , Eunyoung Tak 5 , Yong Sang Hong 1 , Jeong Eun Kim 1 , Tae Won Kim 1
Affiliation  

Recurrent gene mutations and copy number alterations in cancer patients are presumably associated with resistance to targeted therapy. In the present study, we assessed the gene mutations and copy number alterations that recurrently occurred in cetuximab-treated patients with metastatic colorectal cancer (mCRC). Targeted next-generation sequencing was performed in the tumor samples obtained pre- and postcetuximab treatment to assess the variations that occurred during cetuximab treatment. Moreover, we identified the emergent gene mutations (CDK6, EPHA3, ERCC2, MYC, PCMTD1, PIK3CA, PRIM2, RICTOR, and ZNRF3) and copy number alterations (ARAF, BCL2, BRCA2, EGFR, MYC, and SMAD4) that were recurrently observed only in postprogression samples and not in pretreatment or posttreatment samples from patients revealing clinical response. Furthermore, to identify the feasible candidate variations implicated in treatment resistance, we examined the variants with clonal expansion during treatment and discovered PCBP1 as a variant associated with posttreatment progression. Various recurrent mutations were enriched in the TGF-beta signaling pathway. Collectively, we identified recurrent variations in mCRC samples exhibiting post-cetuximab progression. Additionally, future studies are required to evaluate the therapeutic potential of these variations.



中文翻译:

西妥昔单抗治疗的转移性结直肠癌遗传变异的纵向变化

癌症患者的复发性基因突变和拷贝数改变可能与靶向治疗的耐药性有关。在本研究中,我们评估了在接受西妥昔单抗治疗的转移性结直肠癌 (mCRC) 患者中反复发生的基因突变和拷贝数改变。在西妥昔单抗治疗前后获得的肿瘤样本中进行了靶向下一代测序,以评估在西妥昔单抗治疗期间发生的变化。此外,我们确定了紧急基因突变(CDK6、EPHA3、ERCC2、MYC、PCMTD1、PIK3CA、PRIM2、RICTOR 和 ZNRF3)和拷贝数改变(ARAF、BCL2、BRCA2、EGFR、MYCSMAD4) 仅在进展后样本中反复观察到,而不是在来自显示临床反应的患者的治疗前或治疗后样本中反复观察到。此外,为了确定与治疗抵抗有关的可行候选变异,我们检查了治疗期间具有克隆扩增的变异,并发现PCBP1作为与治疗后进展相关的变异。TGF-β 信号通路中丰富了各种反复发生的突变。总的来说,我们确定了 mCRC 样本中表现出西妥昔单抗后进展的复发性变异。此外,未来的研究需要评估这些变异的治疗潜力。

更新日期:2021-07-24
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