Genetic Variant Reduces Risk for HPV-Related Oropharyngeal Cancer

Liam Davenport

October 28, 2016

The development of head and neck cancers may be influenced by an individual's human papillomavirus (HPV) infection status, reveals a large-scale study that found several novel genetic loci associated with oral cavity and pharyngeal cancers.

Using data from a dozen studies, Paul Brennan, PhD, section and group head, Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France, and colleagues identified seven novel genetic regions linked to developing the two cancers.

The team also showed that one variant in a gene linked to immune system regulation was associated with substantial reduction in the risk of developing oropharyngeal cancer associated with HPV infection.

The new findings were published online on October 17 as a letter to Nature Genetics.

"These results indicate that genes that control the immune system play a fundamental role in influencing whether an HPV infection goes on to develop into an HPV-related cancer," Dr Brennan commented in a statement.

Christopher Wild, PhD, director of the IARC, added: "There are many aspects of the development of head and neck cancers that we still don't understand, but these exciting results shed new light on genetic factors specifically linked to HPV-related cancers, which could play an important role in developing preventive strategies."

Increase in HPV-Postive Head and Neck Cancers

While tobacco use and alcohol consumption are the most significant causes of head and neck cancers, oral HPV infection, particularly with HPV type 16, is an increasingly important cause of oropharyngeal cancer, particularly in the United States and northern Europe.

Dr Brennan told Medscape Medical News: "There is reasonably consistent epidemiological data to suggest [the increase] is linked to changes in sexual practices. One would imagine this is linked to an increase in oral sex."

To determine genetic susceptibilities to developing oral cavity and pharyngeal cancers, the researchers examined data on 13,107 individuals from 12 epidemiologic studies from Europe, North America, and South America who had undergone genotyping. After stringent quality control, 6034 cases and 6585 cancer-free controls were analyzed.

Using the Haplotype Reference Consortium panel to perform genome-wide imputation, the team conducted extensive DNA analysis of approximately 7 million potentially cancer-related variants for each individual.

This revealed eight loci that were significantly associated with oral cavity and pharyngeal cancers (P 5 × 10–8), of which seven were novel. Loci associated with both oral and pharyngeal cancers were rs3828805 in HLA-DQB1 at 6p21.32, rs201982221 in LHPP at 10q26.13, and rs1453414 in OR52N2-TRIM5 at 11p15.4.

Oral cancer specifically was found to be associated with two novel loci, comprising rs6547741 in GPN1 at 2p23.3 and rs928674 in LAMC3 at 9q34.12, and two loci previously identified as cancer-related: rs8181047 in CDKN2B-AS1 at 9p21.3 and rs10462706 in CLPTM1L at 5p15.33.

Loci linked to oropharyngeal cancer were limited to the human leukocyte antigen (HLA) region, which is associated with immune system regulation. HLA allele imputation indicated that the class II haplotype HLA-DRB1*1301–HLA-DQA1*0103–HLA-DQB1*0603 was associated with a protective effect against oropharyngeal cancer, at an odds ratio of 0.59 (P = 2.7 × 10–9).

The researchers next conducted a post hoc analysis to determine the effect of the haplotype in 576 cases with information available on HPV status and 3662 controls.

This showed that HLA-DRB1*1301–HLA-DQA1*0103–HLA-DQB1*0603 was associated with significantly reduced risk for HPV-positive oropharyngeal cancer, at an odds ratio of 0.23 (P = 1 × 10–6), while there was no association in HPV-negative cases (odds ratio, 0.75; P = .16).

Discussing the findings in an interview, Dr Brennan told Medscape Medical News that he believes that the protective effect is due to the major histocompatibility complex (MHC) haplotype binding key peptides from early HPV early proteins, adding: "The resulting peptide MHC complex binds with high affinity to the TCR [T cell receptor] of the CD4+ T cell, generating a strong CD4 response."

"This then orchestrates the immune targeting of HPV-infected cells, which would reduce the risk of persistent infection and progression to high-grade disease. Clearly, if one could stimulate such a reaction, that could help to prevent HPV infections progressing."

In terms of ongoing research, Dr Brennan and his colleagues are "keen to identify to what extent this haplotype is relevant for other HPV-related cancers, whether it is restricted to HPV16 only (I suspect it is), and whether the haplotype is different across different populations."

Genotyping performed at the Center for Inherited Disease Research was funded through US National Institute of Dental and Craniofacial Research (NIDCR) grant 1X01HG007780-0. Genotyping for shared controls with the Lung OncoArray initiative was funded through grant X01HG007492-0. C.L. undertook this work during the tenure of a postdoctoral fellowship awarded by the International Agency for Research on Cancer. Participating institutions also list several funding sources for their work. The authors have disclosed no relevant financial relationships.

Nature Genet. Published online October 17, 2016. Abstract

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