CHD7 expression predicts survival outcomes in patients with resected pancreatic cancer.
CHD7 expression predicts survival outcomes in patients with resected pancreatic cancer.
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DOI：
10.1158/0008-5472.can-13-1996
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发表时间：
2014-05-15
期刊：
影响因子：
11.2
通讯作者：
Yu DS
中科院分区：
文献类型：
--
作者：
Colbert LE;Petrova AV;Fisher SB;Pantazides BG;Madden MZ;Hardy CW;Warren MD;Pan Y;Nagaraju GP;Liu EA;Saka B;Hall WA;Shelton JW;Gandhi K;Pauly R;Kowalski J;Kooby DA;El-Rayes BF;Staley CA 3rd;Adsay NV;Curran WJ Jr;Landry JC;Maithel SK;Yu DS
胰腺导管腺癌(PDAC)是一种破坏性疾病，目前的治疗效果很差。吉西他滨是临床上使用的主要辅助药物，但其疗效有限。在这项研究中，我们的目标是利用一种原理驱动的方法来确定早期切除的PDAC患者使用吉西他滨治疗的结果的新的生物标记物。利用人PDAC细胞中的合成致死筛选，我们鉴定了93个基因，其中包括55个与DNA损伤反应(DDR)相关的基因，这些基因在沉默时表现出吉西他滨的敏感性，包括在染色质重塑中发挥作用的CHD7。CHD7缺失可使PDAC细胞对吉西他滨增敏，并延缓其在肿瘤移植瘤中的生长。此外，CHD7沉默减弱了依赖ATR的CHK1的磷酸化，并增加了吉西他滨诱导的DNA损伤。CHD7表达失调，在一组PDAC临床标本中的差异表达高于90%，突显了它作为生物标志物的潜力。在单因素和多因素分析中，59例接受吉西他滨辅助治疗的PDAC切除标本的免疫组织化学分析显示，CHD7低表达与无复发生存期(RFS)和总生存期(OS)的增加有关。值得注意的是，CHD7的表达与未接受吉西他滨治疗的患者的RFS或OS无关。因此，在该患者群体中，CHD7的低表达与吉西他滨敏感性有选择性地相关。这些结果支持了我们的理论驱动的策略，即利用PDAC中失调的DDR通路来确定吉西他滨敏感性的遗传决定因素，将CHD7确定为进一步评估PDAC个体化治疗的新的生物标志物候选。
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor outcomes with current therapies. Gemcitabine is the primary adjuvant drug used clinically, but its effectiveness is limited. In this study, our objective was to utilize a rationale-driven approach to identify novel biomarkers for outcome in patients with early-stage resected PDAC treated with adjuvant gemcitabine. Using a synthetic lethal screen in human PDAC cells, we identified 93 genes including 55 genes linked to DNA damage responses (DDR) that demonstrated gemcitabine sensitization when silenced, including CHD7 which functions in chromatin remodeling. CHD7 depletion sensitized PDAC cells to gemcitabine and delayed their growth in tumor xenografts. Moreover, CHD7 silencing impaired ATR-dependent phosphorylation of CHK1 and increased DNA damage induced by gemcitabine. CHD7 was dysregulated, ranking above the 90th percentile in differential expression in a panel of PDAC clinical specimens, highlighting its potential as a biomarker. Immunohistochemical analysis of specimens from 59 resected PDAC patients receiving adjuvant gemcitabine revealed that low CHD7 expression was associated with increased recurrence-free survival (RFS) and overall survival (OS), in univariate and multivariate analyses. Notably, CHD7 expression was not associated with RFS or OS for patients not receiving gemcitabine. Thus, low CHD7 expression was correlated selectively with gemcitabine sensitivity in this patient population. These results supported our rationale-driven strategy to exploit dysregulated DDR pathways in PDAC to identify genetic determinants of gemcitabine sensitivity, identifying CHD7 as a novel biomarker candidate to evaluate further for individualizing PDAC treatment.