Whole-Exome Sequencing of HPV Positive Tonsillar and Base of Tongue Squamous Cell Carcinomas Reveals a Global Mutational Pattern along with Relapse-Specific Somatic Variants

Abstract

To identify predictive/targetable markers in human papillomavirus positive (HPV+) tonsillar and base of tongue cancer (TSCC/BOTSCC), whole-exome sequencing (WES) of tumours of patients with/without recurrence was performed. Forty primary tumours and adjacent normal tissue were separated by micro-dissection from formalin-fixed paraffin-embedded tissue from patients treated with curative intent 2000–2014 at Karolinska University Hospital. Successful sequencing was obtained in primary tumours of 18 patients without and primaries of 17 with local or distant recurrence, as well as in 10 corresponding recurrences (i.e., five local relapses and five distant metastases) from these 17 patients. One variant—a high-impact deletion in the CDC27 gene—was observed only in primaries of 5/17 patients that had a recurrence after full treatment but in none of those without recurrence. In addition, 3 variants and 26 mutated genes, including CDC27, BCLAF1 and AQP7, were present in at least 30% of all primary tumours independent of prognosis. To conclude, a CDC27 deletion was specific and found in ~30% of samples from patients with a local relapse/distant metastasis and could, therefore, potentially be a prospective marker to predict prognosis. Commonly mutated genes, such as BCLAF1, should be further studied in the context of targeted therapy.

A novel HPV16 splicing enhancer critical for viral oncogene expression and cell immortalization

“…We showed that the effect of TRAP150 was enhanced by BCLAF1 (Figure 7D ). In this regard, it is of interest to note that BCLAF1 is mutationally inactivated in ∼40% of HPV-positive tonsillar and base of tongue cancer ( 54 ), suggesting that the absence of BCLAF1 may alter HPV16 E6/E7 mRNA splicing in these cancers.…”

Sequencing Analysis of MUC6 and MUC16 Gene Fragments in Patients with Oropharyngeal Squamous Cell Carcinoma Reveals Novel Mutations: A Preliminary Study

“…Kannan et al [34] detected numerous missense mutations in mucin genes, including MUC6 and MUC16, in tonsil samples obtained from HPV-16 positive patients with OPSCC. In addition, Ährlund-Richter et al [35] showed that MUC6 and MUC16 were mutated in over 30% of primary HPV-positive tonsillar squamous cell carcinoma (TSCC) and base of tongue squamous cell carcinoma (BOTSCC) with and without recurrence. In addition, Haft et al [36] found mutations in other mucin genes (MUC4 and MUC5B) in HPV-positive OPSCC patients from The Cancer Genome Atlas database (TCGA).…”

“…In addition, Haft et al [36] found mutations in other mucin genes (MUC4 and MUC5B) in HPV-positive OPSCC patients from The Cancer Genome Atlas database (TCGA). It has been found that mutated MUC6 and MUC16 were involved in pathways associated with the extracellular matrix and carbohydrates in patients with TSCC and BOTSCC [35]. It was shown that nine out of nineteen mucin genes (including MUC6 and MUC16) were frequently mutated in various cancer types, including HNSCC [37].…”

Targeted Therapy of HPV Positive and Negative Tonsillar Squamous Cell Carcinoma Cell Lines Reveals Synergy between CDK4/6, PI3K and Sometimes FGFR Inhibitors, but Rarely between PARP and WEE1 Inhibitors

“…To develop personalized medicine for these patients, in order to de-escalate or target treatment, attempts have been made to find prognostic biomarkers, of which many earlier on were defined by immunohistochemistry, and more recently by molecular methodology [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. Recently, phosphatidyl-inositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha ( PIK3CA ) and fibroblast growth factor receptor 3 ( FGFR3 ) mutations have frequently been revealed in HPV + TSCC/BOTSCC [ 26 , 27 ].…”