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

Abstract

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. Genotypephenotype 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

Patient-Derived Xenograft and Organoid Models for Precision Medicine Targeting of the Tumour Microenvironment in Head and Neck Cancer

“…Multiple studies have genetically characterised HNSCC PDX tumours and compared gene expression, gene mutation status, and DNA copy number to the donor clinical specimen or HNSCC population data from The Cancer Genome Atlas [ 9 ]. All studies report a high concordance in expression levels, mutation frequency, and copy number profiles between PDX models and HNSCC tumours across the whole genome or for particular oncogenic variants [ 75 , 76 , 78 , 79 , 82 , 83 , 84 , 85 , 88 , 92 , 93 , 95 ]. Although discordances in some genes were observed, gene expression patterns were more similar to patient tumours for PDX tumours than for HNSCC cell lines [ 75 ].…”

“…We have reported that our own HNSCC PDX models have hypoxic fractions that are within the range of published clinical data based on immunostaining with the hypoxia-marker pimonidazole and that a correlation was observed for the expression of the Toustrup 15-gene hypoxia signature between the PDX tumours and donor clinical specimens [ 62 , 63 ]. However, two other studies have reported higher hypoxic fractions in PDX tumours compared to primary tumours based on pimonidazole immunostaining and a hypoxia score derived from ranking the median expression of genes in the Toustrup hypoxia gene signature [ 84 , 90 ]. These differences may be explained by the high inter-tumour variability in pimonidazole immunostaining [ 97 , 98 , 99 ] and different analysis methods for the Toustrup gene signature.…”

“…While these HPV-positive HNSCC cell lines mostly recapitulate the genomic landscape of HNSCC tumours, they do lack some of the common genetic abnormalities present in clinical HNSCC tumours, particularly PIK3CA activating mutations [ 69 , 103 ]. A number of groups have developed HPV-positive HNSCC PDX models, which, with the exception of the 80% engraftment rate at the University of Wisconsin [ 81 , 85 ], generally have a lower engraftment rate than HPV-negative tumour models [ 80 , 82 , 83 , 84 ] ( Table 1 ). Recent studies have revealed that these PDX models retain molecular markers and genomic features representative of HPV-positive clinical disease, including p16 staining, HPV-16 E6 and E7 RNA and DNA, and PIK3CA and NOTCH1 mutations [ 80 , 81 , 82 , 83 , 84 , 86 ]…”

Human Papillomavirus 16 (HPV16) E2 Repression of TWIST1 Transcription Is a Potential Mediator of HPV16 Cancer Outcomes

“…Head and neck squamous cell carcinoma (HNSCC) TWIST1 mRNA expression data were obtained from The Cancer Genome Atlas using cBio Cancer Genomics Portal ( 49 , 50 ). HNSCC tumor samples (Firehose Legacy) were analyzed for HPV status and viral genome integration as previously described utilizing the HPV16 E2:E7 ratio of mRNA sequencing reads ( 46 , 71 ). Samples without available TWIST1 mRNA expression data were omitted.…”

Human papillomavirus 16 E2 repression of TWIST1 transcription is a potential mediator of HPV16 cancer outcomes

“…mRNA expression data were obtained from The Cancer Genome Atlas using cBio Cancer Genomics Portal (49,50). HNSCC tumor samples (Firehose Legacy) were analyzed for HPV status and viral genome integration as previously described utilizing HPV16 E2:E7 ratio of mRNA sequencing reads (46,71). Samples without available TWIST1 mRNA expression data were omitted.…”