预测氟嘧啶类新辅助放化疗治疗Ⅱ期和Ⅲ期直肠癌的反应的遗传特征。
A Predictive Genetic Signature for Response to Fluoropyrimidine-Based Neoadjuvant Chemoradiation in Clinical Stage II and III Rectal Cancer.
机构信息
Department of Radiation Oncology, Brown University , Providence, RI , USA.
出版信息
Front Oncol. 2013 Nov 25;3:288. doi: 10.3389/fonc.2013.00288. eCollection 2013.
PURPOSE
Pre-operative chemoradiation (CRT) is currently the standard of care for patients with clinical stage II and III rectal cancer but only about 45% of patients achieve tumor downstaging and <20% of patients achieve a pathologic complete response. Better methods to stratify patients according to potential neoadjuvant treatment response are needed. We used microarray analysis to identify a genetic signature that correlates with a pathological complete response (pCR) to neoadjuvant CRT. We performed a gene network analysis to identify potential signaling pathways involved in determining response to neoadjuvant treatment.
PATIENTS AND METHODS
We identified 31 T3-4 N0-1 rectal cancer patients who were treated with neoadjuvant fluorouracil-based CRT. Eight patients were identified to have achieved a pCR to treatment while 23 patients did not. mRNA expression was analyzed using cDNA microarrays. The correlation between mRNA expression and pCR from pre-treatment tumor biopsies was determined. Gene network analysis was performed for the genes represented by the predictive signature.
RESULTS
A genetic signature represented by expression levels of the three genes EHBP1, STAT1, and GAPDH was found to correlate with a pCR to neoadjuvant treatment. The difference in expression levels between patients who achieved a pCR and those who did not was greatest for EHBP1. Gene network analysis showed that the three genes can be connected by the gene ubiquitin C (UBC).
CONCLUSION
This study identifies a 3-gene signature expressed in pre-treatment tumor biopsies that correlates with a pCR to neoadjuvant CRT in patients with clinical stage II and III rectal cancer. These three genes can be connected by the gene UBC, suggesting that ubiquitination is a molecular mechanism involved in determining response to treatment. Validating this genetic signature in a larger number of patients is proposed.
目的
术前放化疗（CRT）目前是临床 II 期和 III 期直肠癌患者的标准治疗方法，但只有约 45%的患者实现肿瘤降期，<20%的患者实现病理完全缓解。需要更好的方法根据潜在的新辅助治疗反应对患者进行分层。我们使用微阵列分析来识别与新辅助 CRT 病理完全缓解（pCR）相关的遗传特征。我们进行了基因网络分析，以确定参与决定新辅助治疗反应的潜在信号通路。
患者和方法
我们鉴定了 31 例接受新辅助氟尿嘧啶为基础的 CRT 的 T3-4 N0-1 直肠癌症患者。8 例患者被鉴定为对治疗有 pCR，而 23 例患者没有。使用 cDNA 微阵列分析 mRNA 表达。确定来自预处理肿瘤活检的 mRNA 表达与 pCR 之间的相关性。对预测特征代表的基因进行基因网络分析。
结果
发现表达水平为 EHBP1、STAT1 和 GAPDH 的三个基因的遗传特征与新辅助治疗的 pCR 相关。在实现 pCR 的患者和未实现 pCR 的患者之间，EHBP1 的表达水平差异最大。基因网络分析表明，这三个基因可以通过基因泛素 C（UBC）连接。
结论
本研究鉴定了一个在临床 II 期和 III 期直肠癌症患者的预处理肿瘤活检中表达的 3 个基因特征，与新辅助 CRT 的 pCR 相关。这三个基因可以通过基因 UBC 连接，表明泛素化是决定治疗反应的分子机制之一。建议在更多患者中验证该遗传特征。
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