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The value of subcutaneous xenografts for individualised radiotherapy in HNSCC: robust gene signature correlates with radiotherapy outcome in patients and xenografts.
Radiother. Oncol. 191:110055 (2023)
PURPOSE: To assess the robustness of prognostic biomarkers and molecular tumour subtypes developed for patients with head and neck squamous cell carcinoma (HNSCC) on cell-line derived HNSCC xenograft models, and to develop a novel biomarker signature by combining xenograft and patient datasets. MATERIALS AND METHODS: Mice bearing xenografts (n=59) of ten HNSCC cell lines and a retrospective, multicentre patient cohort (n=242) of the German Cancer Consortium-Radiation Oncology Group (DKTK-ROG) were included. All patients received postoperative radiochemotherapy (PORT-C). Gene expression analysis was conducted using GeneChip Human Transcriptome Arrays. Xenografts were stratified based on their molecular subtypes and previously established gene classifiers. The dose to control 50% of tumours (TCD50) was compared between these groups. Using differential gene expression analyses combining xenograft and patient data, a gene signature was developed to define risk groups for the primary endpoint loco-regional control (LRC). RESULTS: Tumours of mesenchymal subtype were characterized by a higher TCD50 (xenografts, p<0.001) and lower LRC (patients, p<0.001) compared to the other subtypes. Similar to previously published patient data, hypoxia- and radioresistance-related gene signatures were associated with high TCD50 values. A 2-gene signature (FN1, SERPINE1) was developed that was prognostic for TCD50 (xenografts, p<0.001) and for patient outcome in independent validation (LRC: p=0.007). CONCLUSION: Genetic prognosticators of outcome for patients after PORT-C and subcutaneous xenografts after primary clinically relevant irradiation show similarity. The identified robust 2-gene signature may help to guide patient stratification, after prospective validation. Thus, xenografts remain a valuable resource for translational research towards the development of individualized radiotherapy.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Gene Signature ; Head And Neck Squamous Cell Carcinoma ; Hypoxia ; Molecular Subtypes ; Postoperative Radiochemotherapy ; Radiosensitivity ; Xenograft; Squamous-cell Carcinoma; Good Prognosis Subgroups; Local Tumor-control; Postoperative Radiochemotherapy; Fractionated-irradiation; Expression Classifier; Hypoxic Modification; Marker Expression; Clonogenic Cells; Egfr-inhibition
Language
english
Publication Year
2023
HGF-reported in Year
2023
ISSN (print) / ISBN
0167-8140
e-ISSN
1879-0887
Journal
Radiotherapy and Oncology
Quellenangaben
Volume: 191,
Article Number: 110055
Publisher
Elsevier
Publishing Place
Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland
Reviewing status
Peer reviewed
POF-Topic(s)
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30203 - Molecular Targets and Therapies
30203 - Molecular Targets and Therapies
Research field(s)
Radiation Sciences
PSP Element(s)
G-521800-001
G-501300-001
G-501300-001
Grants
Research Center/German Cancer Consortium
WOS ID
001171270600001
Scopus ID
85184192147
PubMed ID
38109944
Erfassungsdatum
2024-01-10