Significant Association of oncogene YAP1 with Poor Prognosis and Cetuximab Resistance in Colorectal Cancer Patients
Menée sur plusieurs cohortes de patients atteints d'un cancer colorectal (1 028 patients au total), cette étude évalue l'association entre une signature indicatrice de l'activation de l'oncogène YAP1 et la survie sans progression après un traitement à l'aide de cetuximab
Purpose: 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
Experimental Design: 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.
Results: 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).
Conclusions: Activation of YAP1 is highly associated with poor prognosis for CRC and may be useful in identifying patients with metastatic CRC resistant to cetuximab.
Clinical Cancer Research , résumé, 2014