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


METHODS
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.
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Gyeonggi-do, Korea.
Keun-Wook
KW
Lee
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Hematology-Oncology, Inje University Haeundae Paik Hospital, Busan, Korea.
Sung Sook
SS
Lee
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Sang-Bae
SB
Kim
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Bo Hwa
BH
Sohn
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Thoracic Surgery, Center for Lung Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi-do, Korea.
Hyun-Sung
HS
Lee
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Thoracic Surgery, Center for Lung Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi-do, Korea.
Hee-Jin
HJ
Jang
ASAN Institute for Life Sciences, ASAN Medical Center, Department of Medicine, University of Ulsan College of Medicine, Seoul, Korea.
Yun-Yong
YY
Park
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Scott
S
Kopetz
Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea.
Sung Soo
SS
Kim
Division of Hemato-Oncology, Department of Internal Medicine, Korea University Medical Center, Korea University College of Medicine, Seoul, Korea.
Sang Cheul
SC
Oh
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea. jlee@mdanderson.org.
Ju-Seog
JS
Lee
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D006801:Humans; D010750:Phosphoproteins / Q000235:genetics*; D011379:Prognosis; D014157:Transcription Factors; D059467:Transcriptome; D016896:Treatment Outcome; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000068818:Cetuximab