TY - JOUR
T1 - Epithelial-to-mesenchymal transition is a prognostic marker for patient outcome in advanced stage HNSCC patients treated with chemoradiotherapy
AU - van der Heijden, Martijn
AU - Essers, Paul B.M.
AU - Verhagen, Caroline V.M.
AU - Willems, Stefan M.
AU - Sanders, Joyce
AU - de Roest, Reinout H.
AU - Vossen, David M.
AU - Leemans, C. René
AU - Verheij, Marcel
AU - Brakenhoff, Ruud H.
AU - van den Brekel, Michiel W.M.
AU - Vens, Conchita
N1 - Funding Information: Authors acknowledge financial support from the Dutch Cancer Society-Alpe d'Huzes (Alp 7072, acronym DESIGN) and the EU 7th Framework Program (ARTFORCE - n? 257144). The authors are grateful for financial support from Brunel and Verwelius and would like to thank the NKI Genomics Core Facility for performing RNA sequencing, the NKI RHPC facility for providing computational resources and the Core Facility-Molecular Pathology and Biobanking (CFMPB) for supplying NKI/AVL biobank material and support. At the CFMPB, we thank Linde Braaf, Sten Cornelissen and Ingrid Hofland in particular for their immunohistochemistry and molecular labwork. The authors declare that they have no known competing interests. Funding Information: Authors acknowledge financial support from the Dutch Cancer Society -Alpe d’Huzes (Alp 7072, acronym DESIGN) and the EU 7th Framework Program (ARTFORCE - n° 257144). The authors are grateful for financial support from Brunel and Verwelius and would like to thank the NKI Genomics Core Facility for performing RNA sequencing, the NKI RHPC facility for providing computational resources and the Core Facility-Molecular Pathology and Biobanking (CFMPB) for supplying NKI/AVL biobank material and support. At the CFMPB, we thank Linde Braaf, Sten Cornelissen and Ingrid Hofland in particular for their immunohistochemistry and molecular labwork. Publisher Copyright: © 2020 The Authors
PY - 2020/6/1
Y1 - 2020/6/1
N2 - Background: The prognosis of patients with HPV-negative advanced stage head and neck squamous cell carcinoma (HNSCC) remains poor. No prognostic markers other than TNM staging are routinely used in clinic. Epithelial-to-mesenchymal transition (EMT) has been shown to be a strong prognostic factor in other cancer types. The purpose of this study was to determine the role of EMT in HPV-negative HNSCC outcomes. Methods: Pretreatment tumor material from patients of two cohorts, totalling 174 cisplatin-based chemoradiotherapy treated HPV-negative HNSCC patients, was RNA-sequenced. Seven different EMT gene expression signatures were used for EMT status classification and generation of HNSCC-specific EMT models using Random Forest machine learning. Results: Mesenchymal classification by all EMT signatures consistently enriched for poor prognosis patients in both cohorts of 98 and 76 patients. Uni- and multivariate analyses show important HR of 1.6–5.8, thereby revealing EMT's role in HNSCC outcome. Discordant classification by these signatures prompted the generation of an HNSCC-specific EMT profile based on the concordantly classified samples in the first cohort (cross-validation AUC > 0.98). The independent validation cohort confirmed the association of mesenchymal classification by the HNSCC-EMT model with poor overall survival (HR = 3.39, p < 0.005) and progression free survival (HR = 3.01, p < 0.005) in multivariate analysis with TNM. Analysis of an additional HNSCC cohort from PET-positive patients with metastatic disease prior to treatment further supports this relationship and reveals a strong link of EMT to the propensity to metastasize. Conclusions: EMT in HPV-negative HNSCC co-defines patient outcome after chemoradiotherapy. The generated HNSCC-EMT prediction models can function as strong prognostic biomarkers.
AB - Background: The prognosis of patients with HPV-negative advanced stage head and neck squamous cell carcinoma (HNSCC) remains poor. No prognostic markers other than TNM staging are routinely used in clinic. Epithelial-to-mesenchymal transition (EMT) has been shown to be a strong prognostic factor in other cancer types. The purpose of this study was to determine the role of EMT in HPV-negative HNSCC outcomes. Methods: Pretreatment tumor material from patients of two cohorts, totalling 174 cisplatin-based chemoradiotherapy treated HPV-negative HNSCC patients, was RNA-sequenced. Seven different EMT gene expression signatures were used for EMT status classification and generation of HNSCC-specific EMT models using Random Forest machine learning. Results: Mesenchymal classification by all EMT signatures consistently enriched for poor prognosis patients in both cohorts of 98 and 76 patients. Uni- and multivariate analyses show important HR of 1.6–5.8, thereby revealing EMT's role in HNSCC outcome. Discordant classification by these signatures prompted the generation of an HNSCC-specific EMT profile based on the concordantly classified samples in the first cohort (cross-validation AUC > 0.98). The independent validation cohort confirmed the association of mesenchymal classification by the HNSCC-EMT model with poor overall survival (HR = 3.39, p < 0.005) and progression free survival (HR = 3.01, p < 0.005) in multivariate analysis with TNM. Analysis of an additional HNSCC cohort from PET-positive patients with metastatic disease prior to treatment further supports this relationship and reveals a strong link of EMT to the propensity to metastasize. Conclusions: EMT in HPV-negative HNSCC co-defines patient outcome after chemoradiotherapy. The generated HNSCC-EMT prediction models can function as strong prognostic biomarkers.
KW - Chemoradiotherapy
KW - Epithelial to mesenchymal transition
KW - HNSCC
KW - Head and neck cancer
KW - Prognostic biomarkers
KW - RNA-Seq
UR - http://www.scopus.com/inward/record.url?scp=85085483159&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.radonc.2020.05.013
DO - https://doi.org/10.1016/j.radonc.2020.05.013
M3 - Article
C2 - 32413532
SN - 0167-8140
VL - 147
SP - 186
EP - 194
JO - Radiotherapy and oncology
JF - Radiotherapy and oncology
ER -
