Head and neck cancer is the sixth most common cancer type worldwide. In the USA in 2023, an estimated 54 540 new cases of cancer of the oral cavity and pharynx were diagnosed and 11 580 people died from the disease. Tobacco use and alcohol consumption are established risk factors for head and neck cancer. Oral infection with human papillomavirus (HPV), especially HPV type 16, is an important risk factor for, in particular, oropharyngeal cancer. VOYAGER used samples and data from five large studies on head and neck cancer (with a total of more than 10 000 patients) to learn more about the role of genetic factors in risk and prognosis of oral cavity cancer and oropharyngeal cancer.
Genotype information for more than half of the patients was available from earlier work (PMID:27749845). Demographic and clinical data collected by the five studies were harmonized. Blood samples collected at diagnosis were used to determine whether patients had HPV infection-associated oropharyngeal cancer, and tumours from more than 1800 patients were sequenced.
The studies conducted as part of this NIDCR-funded project (R01 DE025712) have led to increased knowledge about the inherited genetic variants that affect risk of oral cavity cancer and HPV infection-associated oropharyngeal cancer, the somatic alterations that are present in oral cavity and oropharyngeal tumours, and how inherited genetic variants and somatic alterations in the tumour affect disease outcome.
Aim 1: Evaluate the relationship between germline variants and risk of HPV-associated oropharyngeal cancer
The etiology of oropharyngeal cancer differs by tumour HPV status. Therefore, it was anticipated that genetic contributions to risk of HPV-positive oropharyngeal cancer versus risk of HPV-negative oropharyngeal cancer, and also oral cancer (which is primarily HPV-negative), would be different. The researchers determined the HPV status of the patients with oropharyngeal cancer from the five studies in North America and Europe that participated in VOYAGER, using HPV16 E6 serology. Subsequently, they evaluated the relationship between germline variants and risk of HPV-positive oropharyngeal cancer compared with risk of HPV-negative oropharyngeal cancer. Information on germline variants had been obtained in a previous study, the OncoArray project (PMID:27749845). Building on the strong genetic association observed between the HLA region and oropharyngeal cancer in a previous genome-wide association study (PMID:27749845), the primary focus was on variants in this region. A full genome-wide association analysis of oropharyngeal cancer stratified by HPV status was performed to also enable identification of additional loci differentially associated with risk of HPV-positive and HPV-negative oropharyngeal cancer. Modifying effects of age, sex, tobacco use, and alcohol consumption were explored.
Aim 2: Comprehensively assess somatic mutation patterns in oral cancer and oropharyngeal cancer
Using well-annotated tumour samples available from patients in the five studies in North America and Europe, the researchers aimed to further elucidate the somatic mutations present in the overall population of oral cancer and oropharyngeal cancer, and in clinically and biologically relevant subsets. A total of more than 1800 tumours were sequenced. Targeted sequencing (~800 genes) was performed. Mutation patterns were assessed and described by anatomical site, HPV status, demographic factors, tobacco use, and alcohol consumption. Associations between germline variants and somatic mutations were explored.
Aim 3: Examine molecular markers, HPV, and smoking history in oral cancer and oropharyngeal cancer outcome
Using the available outcome data for the patients with tumour sequencing information, the researchers systematically examined the relationship between the occurrence of specific somatic alterations and HPV-positive oropharyngeal cancer, HPV-negative oropharyngeal cancer, and oral cancer outcome. Models incorporating molecular markers and relevant demographic and clinical factors were developed to assess prognosis. The role of smoking in outcome was explored. In particular, the researchers evaluated whether the adverse impact of smoking on HPV-positive outcome is mediated through the presence of specific somatic alterations. Associations between germline variants and outcome were also explored, with a particular focus on the HLA region.