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. 2015 Jan 15;21(2):357-64.
doi: 10.1158/1078-0432.CCR-14-1374. Epub 2014 Nov 11.

Significant association of oncogene YAP1 with poor prognosis and cetuximab resistance in colorectal cancer patients

Keun-Wook Lee  1 , Sung Sook Lee  2 , Sang-Bae Kim  3 , Bo Hwa Sohn  3 , Hyun-Sung Lee  4 , Hee-Jin Jang  4 , Yun-Yong Park  5 , Scott Kopetz  6 , Sung Soo Kim  7 , Sang Cheul Oh  8 , Ju-Seog Lee  9
Affiliations

Significant association of oncogene YAP1 with poor prognosis and cetuximab resistance in colorectal cancer patients

Keun-Wook Lee et al. Clin Cancer Res. .

Abstract

Purpose: Activation of YAP1, a novel oncogene in the Hippo pathway, has been observed in many cancers, including colorectal cancer. We investigated whether activation of YAP1 is significantly associated with prognosis or treatment outcomes in colorectal cancer.

Experimental design: A gene expression signature reflecting YAP1 activation was identified in colorectal cancer cells, and patients with colorectal cancer were stratified into two groups according to this signature: activated YAP1 colorectal cancer (AYCC) or inactivated YAP1 colorectal cancer (IYCC). Stratified patients in five test cohorts were evaluated to determine the effect of the signature on colorectal cancer prognosis and response to cetuximab treatment.

Results: The activated YAP1 signature was associated with poor prognosis for colorectal cancer 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 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 colorectal cancer 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 colorectal cancer and may be useful in identifying patients with metastatic colorectal cancer resistant to cetuximab.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Figures

Figure 1
Figure 1
Construction of a prediction model using gene expression profiles for NCI-H716 cells and analyses of survival in patient cohorts 1–4. (A) Schematic of the strategy used to construct the prediction model and evaluate predicted CRC outcomes according to gene expression signature. CON, control. (B-E) Kaplan-Meier plots of the AYCC and IYCC patients in cohorts 1–4. P values were calculated using log-rank tests. +, censored data.
Figure 2
Figure 2
PFS according to YAP1 signature in (A) all patients (n = 80), (B) patients with WT KRAS (n = 43), and (C) patients with mutant KRAS (n = 27) in cohort 5. KRAS mutation data were not available for 10 patients.
Figure 3
Figure 3
Genetic changes in CRC cells according to YAP1 signature in cohort 6. Genetic data were retrieved from the TCGA database and analyzed.
See this image and copyright information in PMC

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