We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America; we detected 8 loci (P<5x10–8), 7 of which are novel for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2/TRIM5). Oral cancer was associated with two new regions 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer loci: 9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region and classical HLA allele imputation revealed a protective association with the class II haplotype DRB1*1301-DQA1*0103-DQB1*0603 (odds ratio (OR)=0.59, P=2.7x10–9). Stratified analyses on a subgroup of oropharyngeal cases with human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR=0.23, P=1.6x10–6) compared to HPV-negative cancers (OR=0.75, P=0.16).

Differences in HNC aetiology according to age group may exist. The lower AF of cigarette smoking and alcohol drinking in young adults may be due to the reduced length of exposure due to the lower age. Other characteristics, such as those that are inherited, may play a more important role in HNC in young adults compared with older adults.