Significant association of oncogene YAP1 with poor prognosis and cetuximab resistance in colorectal cancer patients.
Significant association of oncogene YAP1 with poor prognosis and cetuximab resistance in colorectal cancer patients.
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癌基因 YAP1 与结直肠癌患者的不良预后和西妥昔单抗耐药性显着相关。
DOI：
10.1158/1078-0432.ccr-14-1374
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发表时间：
2015-01-15
期刊：
影响因子：
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通讯作者：
Lee JS
中科院分区：
文献类型：
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作者：
Lee KW;Lee SS;Kim SB;Sohn BH;Lee HS;Jang HJ;Park YY;Kopetz S;Kim SS;Oh SC;Lee JS
Hippo通路中的新癌基因YAP 1在包括结直肠癌（CRC）在内的许多癌症中被观察到激活。我们研究了YAP 1的激活是否与CRC的预后或治疗结果显著相关。在CRC细胞中鉴定了反映YAP 1激活的基因表达特征，并根据该特征将CRC患者分为两组：激活的YAP 1 CRC（AYCC）或失活的YAP 1 CRC（IYCC）。对5个试验队列中的分层患者进行评价，以确定签名对CRC预后和对西妥昔单抗治疗反应的影响。在四个独立的I-III期疾病患者队列中，激活的YAP 1特征与CRC的不良预后相关（总n = 1，028）。在多变量分析中，YAP 1标签对无病生存期的影响与其他临床变量无关[风险比（HR），1.63; 95%置信区间（CI），1.25-2.13; P < 0.001]。在IV期CRC和野生型KRAS患者中，IYCC患者在西妥昔单抗单药治疗后的疾病控制率和无进展生存期（PFS）优于AYCC患者;然而，在KRAS突变患者中，IYCC和AYCC患者在西妥昔单抗单药治疗后的PFS持续时间没有差异。在多变量分析中，YAP 1激活对PFS的影响与KRAS突变状态和其他临床变量无关（HR，1.82; 95% CI，1.05-3.16; P = 0.03）。YAP 1的激活与CRC的不良预后高度相关，可能有助于识别西妥昔单抗耐药的转移性CRC患者。
Activation of YAP1, novel oncogene in Hippo pathway, has been observed in many cancers including colorectal cancer (CRC). We investigated if activation of YAP1 is significantly associated with prognosis or treatment outcomes in CRC A gene expression signature reflecting YAP1 activation was identified in CRC cells, and CRC patients were stratified into two groups according to this signature: activated YAP1 CRC (AYCC) or inactivated YAP1 CRC (IYCC). Stratified patients in five test cohorts were evaluated to determine the effect of the signature on CRC prognosis and response to cetuximab treatment. The activated YAP1 signature was associated with poor prognosis for CRC in four independent patient cohorts with stage I–III disease (total n = 1,028). In a multivariate analysis, the impact of the YAP1 signature on the disease-free survival was independent of other clinical variables [hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.25–2.13; P < 0.001]. In patients with stage IV CRC and wild-type KRAS, IYCC patients had a better disease control rate and progression-free survival (PFS) after cetuximab monotherapy than did AYCC patients; however, in patients with KRAS mutations, PFS duration after cetuximab monotherapy was not different between IYCC and AYCC patients. In multivariate analysis, the effect of YAP1 activation on PFS was independent of KRAS mutation status and other clinical variables (HR, 1.82; 95% CI, 1.05–3.16; P = 0.03). Activation of YAP1 is highly associated with poor prognosis for CRC and may be useful in identifying patients with metastatic CRC resistant to cetuximab.