Head and neck squamous cell carcinoma (HNSCC) includes diverse cancers arising in the oral cavity, oropharynx, and larynx, with the main risk factors being environmental exposures such as tobacco, alcohol, and human papillomavirus (HPV) infection. The genetic factors contributing to susceptibility across different populations and tumour subsites remain incompletely understood. Here we show, through a genome-wide association and fine mapping study of over 19,000 HNSCC cases and 38,000 controls from multiple ancestries, 18 genetic risk variants and 11 signals from fine mapping of the human leukocyte antigen (HLA) region, all previously unreported. rs78378222, a regulatory variant for TP53 is associated with a 40% reduction in overall HNSCC risk. We also identify gene-environment interactions, with BRCA2 and ADH1B variants showing effects modified by smoking and alcohol use. Subsite-specific analysis of the HLA region reveals distinct immune-related associations across HPV-positive and HPV-negative tumours. These findings refine the genetic architecture of HNSCC and highlight mechanisms linking inherited variation, immunity, and environmental exposures.

• MeSH
• Alcohol Dehydrogenase genetics   MeSH
• Genome-Wide Association Study MeSH
• Squamous Cell Carcinoma of Head and Neck * genetics   MeSH
• Genetic Predisposition to Disease MeSH
• HLA Antigens genetics   MeSH
• Papillomavirus Infections genetics   complications   MeSH
• Gene-Environment Interaction MeSH
• Polymorphism, Single Nucleotide MeSH
• Smoking adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Tumor Suppressor Protein p53 genetics   MeSH
• Head and Neck Neoplasms * genetics   MeSH
• Alcohol Drinking MeSH
• BRCA2 Protein genetics   MeSH
• Risk Factors MeSH
• Carcinoma, Squamous Cell * genetics   MeSH
• Case-Control Studies MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• ADH1B protein, human MeSH Browser
• Alcohol Dehydrogenase MeSH
• BRCA2 protein, human MeSH Browser
• HLA Antigens MeSH
• Tumor Suppressor Protein p53 MeSH
• BRCA2 Protein MeSH
• TP53 protein, human MeSH Browser

Head and neck cancer (HNC) is the sixth most common cancer globally. Incidence and survival rates vary significantly across geographic regions and tumor subsites. This is partly due to differences in risk factor exposure, which includes tobacco smoking, alcohol consumption and human papillomavirus (HPV) infection, alongside detection and treatment strategies. The VOYAGER (human papillomaVirus, Oral and oropharYngeal cAncer GEnomic Research) consortium is a collaboration between five large North American and European studies which generated data on 10,530 participants (7,233 cases and 3,297 controls). The primary goal of the collaboration was to improve understing of the role of HPV and genetic factors in oral cavity and oropharyngeal cancer risk and outcome. Demographic and clinical data collected by the five studies were harmonized, and HPV status was determined for the majority of cases. In addition, 999 tumors were sequenced to define somatic mutations. These activities generated a comprehensive biomedical resource that can be utilized to answer critical outsting research questions to help improve HNC prevention, early detection, treatment, and surveillance.

• Keywords
• Head and neck cancer, human papilloma virus, oral cancer, oropharyngeal cancer, risk factors, survival,
• Publication type
• Journal Article MeSH
• Preprint MeSH

HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls. Lifetime smoking exposure, as measured by the Comprehensive Smoking Index (CSI), is associated with increased risk of both HPV-negative HNSCC (OR = 3.03, 95%CI:1.75-5.24, P = 7.00E-05) and HPV-positive HNSCC (OR = 2.73, 95%CI:1.39-5.36, P = 0.003). Drinks Per Week is also linked with increased risk of both HPV-negative HNSCC (OR = 7.72, 95%CI:3.63-16.4, P = 1.00E-07) and HPV-positive HNSCC (OR = 2.66, 95%CI:1.06-6.68, P = 0.038). Smoking and alcohol independently increase the risk of both HPV-positive and HPV-negative HNSCC. These findings have important implications for understanding the modifying risk factors between HNSCC subtypes.

• MeSH
• Squamous Cell Carcinoma of Head and Neck * virology   genetics   epidemiology   MeSH
• Papillomavirus Infections * virology   epidemiology   MeSH
• Polymorphism, Single Nucleotide MeSH
• Smoking * adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mendelian Randomization Analysis * MeSH
• Head and Neck Neoplasms * virology   genetics   epidemiology   MeSH
• Papillomaviridae genetics   MeSH
• Alcohol Drinking * adverse effects   MeSH
• Risk Factors MeSH
• Case-Control Studies MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Head and neck cancer is often diagnosed late and prognosis for most head and neck cancer patients remains poor. To aid early detection, we developed a risk prediction model based on demographic and lifestyle risk factors, human papillomavirus (HPV) serological markers and genetic markers. A total of 10 126 head and neck cancer cases and 5254 controls from five North American and European studies were included. HPV serostatus was determined by antibodies for HPV16 early oncoproteins (E6, E7) and regulatory early proteins (E1, E2, E4). The data were split into a training set (70%) for model development and a hold-out testing set (30%) for model performance evaluation, including discriminative ability and calibration. The risk models including demographic, lifestyle risk factors and polygenic risk score showed a reasonable predictive accuracy for head and neck cancer overall. A risk model that also included HPV serology showed substantially improved predictive accuracy for oropharyngeal cancer (AUC = 0.94, 95% CI = 0.92-0.95 in men and AUC = 0.92, 95% CI = 0.88-0.95 in women). The 5-year absolute risk estimates showed distinct trajectories by risk factor profiles. Based on the UK Biobank cohort, the risks of developing oropharyngeal cancer among 60 years old and HPV16 seropositive in the next 5 years ranged from 5.8% to 14.9% with an average of 8.1% for men, 1.3% to 4.4% with an average of 2.2% for women. Absolute risk was generally higher among individuals with heavy smoking, heavy drinking, HPV seropositivity and those with higher polygenic risk score. These risk models may be helpful for identifying people at high risk of developing head and neck cancer.

• Keywords
• HPV serostatus, head and neck cancer risk, polygenic risk score, risk prediction models,
• MeSH
• Genetic Markers MeSH
• Papillomavirus Infections * MeSH
• Middle Aged MeSH
• Humans MeSH
• Human Papillomavirus Viruses MeSH
• Human papillomavirus 16 genetics   MeSH
• Head and Neck Neoplasms * MeSH
• Oropharyngeal Neoplasms * MeSH
• Oncogene Proteins, Viral * genetics   MeSH
• Antibodies, Viral MeSH
• Risk Factors MeSH
• Transcription Factors genetics   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Genetic Markers MeSH
• Oncogene Proteins, Viral * MeSH
• Antibodies, Viral MeSH
• Transcription Factors MeSH

Although several oropharyngeal cancer (OPC) susceptibility loci have been identified, most previous studies lacked detailed information on human papillomavirus (HPV) status. We conduct a genome-wide analysis by HPV16 serology status in 4,002 oral cancer cases (OPC and oral cavity cancer (OCC)) and 5,256 controls. We detect four susceptibility loci pointing to a distinct genetic predisposition by HPV status. Our most notable finding in the HLA region, that is now confirmed to be specific of HPV(+)OPC risk, reveal two independent loci with strong protective effects, one refining the previously reported HLA class II haplotype association. Antibody levels against HPV16 viral proteins strongly implicate the protective HLA variants as major determinants of humoral response against L1 capsid protein or E6 oncoprotein suggesting a natural immune response against HPV(+)OPC promoted by HLA variants. This indicates that therapeutic vaccines that target E6 and attenuate viral response after established HPV infections might protect against HPV(+)OPC.

• MeSH
• Genome-Wide Association Study MeSH
• Gene Expression MeSH
• Genetic Predisposition to Disease MeSH
• Haplotypes MeSH
• HLA Antigens classification   genetics   immunology   MeSH
• Immunity, Humoral * MeSH
• Papillomavirus Infections genetics   immunology   pathology   virology   MeSH
• Smoking physiopathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Human papillomavirus 16 immunology   pathogenicity   MeSH
• Quantitative Trait Loci MeSH
• Meta-Analysis as Topic MeSH
• Oropharyngeal Neoplasms genetics   immunology   pathology   virology   MeSH
• Mouth Neoplasms genetics   immunology   pathology   virology   MeSH
• Oncogene Proteins, Viral genetics   immunology   MeSH
• Antibodies, Viral biosynthesis   MeSH
• Repressor Proteins genetics   immunology   MeSH
• Risk Factors MeSH
• Aged MeSH
• Case-Control Studies MeSH
• Capsid Proteins genetics   immunology   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• E6 protein, Human papillomavirus type 16 MeSH Browser
• HLA Antigens MeSH
• Oncogene Proteins, Viral MeSH
• Antibodies, Viral MeSH
• Repressor Proteins MeSH
• Capsid Proteins MeSH

BACKGROUND: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses. METHODS: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects. RESULTS: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk. CONCLUSIONS: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

• Keywords
• Mendelian Randomization, TERT, chromosome 5p15.33, lung cancer, mediation analysis, telomere length,
• MeSH
• Adenocarcinoma of Lung epidemiology   MeSH
• Squamous Cell Carcinoma of Head and Neck epidemiology   MeSH
• Telomere Homeostasis genetics   MeSH
• Leukocytes metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Chromosomes, Human, Pair 5 genetics   MeSH
• Mendelian Randomization Analysis MeSH
• Head and Neck Neoplasms epidemiology   MeSH
• Lung Neoplasms epidemiology   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Carcinoma, Squamous Cell epidemiology   MeSH
• Telomere metabolism   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

• MeSH
• Asian People genetics   MeSH
• White People genetics   MeSH
• Gene Frequency MeSH
• Genetic Predisposition to Disease ethnology   genetics   MeSH
• Genotype MeSH
• HLA Antigens genetics   MeSH
• Major Histocompatibility Complex genetics   MeSH
• Polymorphism, Single Nucleotide MeSH
• Middle Aged MeSH
• Humans MeSH
• Chromosome Mapping * MeSH
• Lung Neoplasms ethnology   genetics   MeSH
• Peptides genetics   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• HLA Antigens MeSH
• Peptides MeSH