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

SIMPLE SUMMARY: To better prevent/combat recurrence and identify predictive/targetable markers upon diagnosis, we performed whole-exome sequencing (WES) of primary tumours and relapses of human papillomavirus positive (HPV(+)) tonsillar and base of tongue cancer (TSCC/BOTSCC) on patients treated with curative intent, with and without relapse. A specific deletion in the CDC27 gene was observed only in the primaries of 5/17 patients that recurred but in none of the 18 patients without recurrence. Furthermore, three specific variants and 26 mutated genes enriched in mucins were identified in at least 30% of all primaries irrespective of recurrence. To conclude, a specific CDC27 deletion could be specific for recurrent HPV(+) TSCC/BOTSCC, while BCLAF1, AQP7 and other globally mutated genes could be of significance for further investigation. 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.