Details

Autor(en) / Beteiligte

• Facompre, Nicole D.
• Rajagopalan, Pavithra
• Sahu, Varun
• Pearson, Alexander T.
• Montone, Kathleen T.
• James, Claire D.
• Gleber‐Netto, Frederico O.
• Weinstein, Gregory S.
• Jalaly, Jalal
• Lin, Alexander
• Rustgi, Anil K.
• Nakagawa, Hiroshi
• Califano, Joseph A.
• Pickering, Curtis R.
• White, Elizabeth A.
• Windle, Bradford E.
• Morgan, Iain M.
• Cohen, Roger B.
• Gimotty, Phyllis A.
• Basu, Devraj

Titel

Identifying predictors of HPV‐related head and neck squamous cell carcinoma progression and survival through patient‐derived models

Ist Teil von

• International journal of cancer, 2020-12, Vol.147 (11), p.3236-3249

Ort / Verlag

Hoboken, USA: John Wiley & Sons, Inc

Erscheinungsjahr

2020

Link zum Volltext

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• Therapeutic innovation for human papilloma virus‐related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is impaired by inadequate preclinical models and the absence of accurate biomarkers. Our study establishes the first well‐characterized panel of patient‐derived xenografts (PDXs) and organoids from HPV+ HNSCCs while determining fidelity of the models to the distinguishing genetic features of this cancer type. Despite low engraftment rates, whole exome sequencing showed that PDXs retain multiple distinguishing features of HPV+ HNSCC lost in existing cell lines, including PIK3CA mutations, TRAF3 deletion and the absence of EGFR amplifications. Engrafted HPV+ tumors frequently contained NOTCH1 mutations, thus providing new models for a negatively prognostic alteration in this disease. Genotype‐phenotype associations in the models were then tested for prediction of tumor progression and survival in published clinical cohorts. Observation of high tumor mutational burdens (TMBs) in the faster‐growing models facilitated identification of a novel association between TMB and local progression in both HPV+ and HPV− patients that was prognostic in HPV− cases. In addition, reduced E7 and p16INK4A levels found in a PDX from an outlier case with lethal outcome led to detection of similar profiles among recurrent HPV+ HNSCCs. Transcriptional data from the Cancer Genome Atlas was used to demonstrate that the lower E2F target gene expression predicted by reduced E7 levels has potential as a biomarker of disease recurrence risk. Our findings bridge a critical gap in preclinical models for HPV+ HNSCCs and simultaneously reveal novel potential applications of quantifying mutational burden and viral oncogene functions for biomarker development. What's new? While the incidence of human papillomavirus (HPV)‐related head and neck squamous cell carcinoma (HNSCC) is increasing, therapeutic development has been slow to progress, due in part to insufficient biomarkers and lack of experimental models. Here, the authors present detailed characterization of HPV‐positive patient‐derived xenograft (PDX) and organoid models generated from HPV‐positive HNSCCs, which typically grow poorly outside the human body. The models retained genetic hallmarks frequently lost in HPV‐positive HNSCC cell lines. In addition, fast growing PDX and organoid models were found to harbor a high tumor mutational burden, which predicted tumor progression and survival when tested in patient cohorts.