Human papillomaviruses are associated with benign and malignant epithelial lesions. Subsets of HPV are high-risk and are causative agents of the majority of head and neck squamous cell carcinomas (HNSCC) in the oropharynx. The incidence of HPV-related HNSCC has dramatically increased over the last 2 decades, outnumbering the incidence of uterine cervical cancer in the United States and emphasizing the importance of unraveling HPV-driven head and neck cancer biology with a goal of providing patients with efficient treatment while minimizing therapy-related side effects.
Treatment for advanced HNSCC, irrespective of HPV status, includes chemotherapy and radiation, which causes long-term side effects, such as difficulty swallowing and speech dysfunction, neck muscle fibrosis, xerostomia, accelerated dental decay, and lymphedema. To decrease the morbidity associated with therapy, a major goal of the head and neck oncology community is to de-escalate therapy for HPV-associated tumors. Unfortunately, there does not currently exist appropriate biomarkers that can risk-stratify HPV+ HNSCC patients to identify those patients that will benefit from reduced doses of radiation treatment. Presently, selection of appropriate patients for de-escalation clinical trials depends only on the absence of aggressive histologic tumor characteristics and history of minimal tobacco use. The issue with current de-escalation is that despite the relatively good prognosis associated with HPV-associated HNSCC, up to 25% of patients with HPV-positive tumors suffer recurrent or metastatic disease despite aggressive and morbid therapy.
A recent The Cancer Genome Atlas (TCGA) head and neck cancer study reported frequent homozygous deletions and truncating mutations in TNF receptor-associated factor 3 (TRAF3) in 36 HPV-associated head and neck tumors. Our analysis of the whole TCGA HNSCC cohort, presented here, revealed TRAF3 genetic alterations in 14% of HPV+ head and neck cancers (n=65). TRAF3 is known negative regulator of NF-kB; about 10% of multiple myeloma contain deletions and similar truncating mutations in TRAF3 leading to constitutive activation of the NF-kB pathway. We found that one more NF-kB inhibitor, the tumor suppressor cylindromatosis (CYLD) was mutated in another 14% of HPV+ HNSCC (n=65). Mutations in TRAF3 and CYLD were nearly mutually exclusive, together totaling 28% of HPV+ head and neck tumors that are dependent on overactive NF-kB. No other type of solid cancer, including HPV-driven cervical cancer, had a significant number of TRAF3 or CYLD mutations. Targeted sequencing of 27 HPV-associated HNSCC from Yale head and neck cancer biorepository revealed mutations in other NF-kB regulators in addition to TRAF3 and CYLD.
Importantly, Kaplan–Meier survival analysis revealed that these HPV+ patients, whose tumors contained TRAF3 / CYLD mutations, fared significantly better, as compared to HPV+ patients with wild-type TRAF3 and CYLD. In fact, survival of patients with HPV+ tumors lacking TRAF3/CYLD mutations was similar to patients with HPV-negative head and neck cancer.