Background: The magnitude of risk conferred by the interaction between tobacco and alcohol use on the risk of head and neck cancers is not clear because studies have used various methods to quantify the excess head and neck cancer burden. Methods: We analyzed individual-level pooled data from 17 European and American case-control studies (11,221 cases and 16,168 controls) participating in the International Head and Neck Cancer Epidemiology consortium. We estimated the multiplicative interaction parameter (ψ) and population attributable risks (PAR). Results: A greater than multiplicative joint effect between ever tobacco and alcohol use was observed for head and neck cancer risk (ψ = 2.15; 95% confidence interval, 1.53-3.04). The PAR for tobacco or alcohol was 72% (95% confidence interval, 61-79%) for head and neck cancer, of which 4% was due to alcohol alone, 33% was due to tobacco alone, and 35% was due to tobacco and alcohol combined. The total PAR differed by subsite (64% for oral cavity cancer, 72% for pharyngeal cancer, 89% for laryngeal cancer), by sex (74% for men, 57% for women), by age (33% for cases 60 years), and by region (84% in Europe, 51% in North America, 83% in Latin America). Conclusions: Our results confirm that the joint effect between tobacco and alcohol use is greater than multiplicative on head and neck cancer risk. However, a substantial proportion of head and neck cancers cannot be attributed to tobacco or alcohol use, particularly for oral cavity cancer and for head and neck cancer among women and among young-onset cases. (Cancer Epidemiol Biomarkers Prev 2009;18(2):541–50)

Background Sexual contact may be the means by which head and neck cancer patients are exposed to human papillomavirus (HPV). Methods We undertook a pooled analysis of four population-based and four hospital-based case–control studies from the International Head and Neck Cancer Epidemiology (INHANCE) consortium, with participants from Argentina, Australia, Brazil, Canada, Cuba, India, Italy, Spain, Poland, Puerto Rico, Russia and the USA. The study included 5642 head and neck cancer cases and 6069 controls. We calculated odds ratios (ORs) of associations between cancer and specific sexual behaviours, including practice of oral sex, number of lifetime sexual partners and oral sex partners, age at sexual debut, a history of same-sex contact and a history of oral–anal contact. Findings were stratified by sex and disease subsite. Results Cancer of the oropharynx was associated with having a history of six or more lifetime sexual partners [OR = 1.25, 95% confidence interval (CI) 1.01, 1.54] and four or more lifetime oral sex partners (OR = 2.25, 95% CI 1.42, 3.58). Cancer of the tonsil was associated with four or more lifetime oral sex partners (OR = 3.36, 95 % CI 1.32, 8.53), and, among men, with ever having oral sex (OR = 1.59, 95% CI 1.09, 2.33) and with an earlier age at sexual debut (OR = 2.36, 95% CI 1.37, 5.05). Cancer of the base of the tongue was associated with ever having oral sex among women (OR = 4.32, 95% CI 1.06, 17.6), having two sexual partners in comparison with only one (OR = 2.02, 95% CI 1.19, 3.46) and, among men, with a history of same-sex sexual contact (OR = 8.89, 95% CI 2.14, 36.8). Conclusions Sexual behaviours are associated with cancer risk at the head and neck cancer subsites that have previously been associated with HPV infection.

Background: Head and neck squamous cell carcinoma (HNSCC) is commonly associated with tobacco and alcohol exposures, although dietary factors, particularly folate, and human papillomavirus, are also risk factors. Epigenetic alterations are increasingly implicated in the initiation and progression of cancer. Genome-wide (global) hypomethylation seems to occur in early neoplasia and is a feature of genomic DNA derived from solid tumor tissues, including HNSCC. This study aimed to determine whether global methylation in DNA derived from whole blood, a proxy tissue, is associated with HNSCC and to assess potential modification of this property by environmental or behavioral risk factors. Methods: Global DNA methylation levels were assessed using a modified version of the combined bisulfite restriction analysis of the LRE1 sequence in a population-based case-control study of HNSCC from the Boston area. Results: Hypomethylation lead to a significant 1.6-fold increased risk for disease (95% confidence interval, 1.1-2.4), in models controlled for other HNSCC risk factors. Smoking showed a significant differential effect (P < 0.03) on blood relative methylation between cases and controls. Furthermore, in cases, variant genotype in the MTHFR gene and low folate intake showed relationships with decreased global methylation, whereas in controls, antibody response to human papillomavirus 16 was associated with an increased global methylation level. Discussion: DNA hypomethylation in nontarget tissue was independently associated with HNSCC and had a complex relationship with the known risk factors associated with the genesis of HNSCC. (Cancer Epidemiol Biomarkers Prev 2007;16(1):108–14)

Human papillomavirus type 16 (HPV16) seropositivity and alcohol and tobacco use have been associated with risk of head and neck squamous cell carcinoma (HNSCC). However, it is less clear whether HPV16 influences HNSCC risk associated with alcohol and tobacco use. Incident cases of HNSCC diagnosed between December 1999 and December 2003 were identified from nine medical facilities in Greater Boston, MA. Control subjects were frequency matched to case subjects on age, sex, and town of residence. A total of 485 case subjects and 549 control subjects reported information on lifetime smoking and alcohol consumption and provided sera, which was used to determine presence of HPV16 antibodies. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of HNSCC risk by alcohol consumption (drinks per week: <3, 3 to <8, 8 to 0 to <20, 20 to <45, ≥45), adjusting for age, sex, race, education, and HPV16 serology. Polytomous logistic regression was used to estimate odds ratios and 95% confidence intervals for the association of HPV16 serology, alcohol consumption, and tobacco use in site-specific analyses. All statistical tests were two-sided. The strongest risk factors by tumor site were smoking for laryngeal cancer, alcohol for cancer of the oral cavity, and HPV16 for pharyngeal cancer. For pharyngeal cancer, risk increased with increasing alcohol consumption (OR_{≥25 versus <3 drinks per week} = 5.1, 95% CI = 2.4 to 11.0) and smoking (OR_{≥45 pack-years versus never smoker} = 6.9, 95% CI = 3.1 to 15.1) among HPV16-seronegative subjects but not among HPV16-seropositive subjects (P_{interaction, HPV16 serology and alcohol} = .002; P_{interaction, HPV16 serology and smoking} = .007). Among light drinkers or never smokers, HPV16 seropositivity was associated with a 30-fold increased risk of pharyngeal cancer. Alcohol or tobacco use does not further increase risk of HPV16-associated pharyngeal cancer. HNSCC risk associated with smoking, alcohol, and HPV16 differs by tumor site.