Study finds genetic variation may protect against certain HPV-linked oral cancers

Andrew Olshan, PhD, and colleagues reported in Nature Genetics that immune system-related genetic variation may provide new insight into the mechanisms of protection against human papillomavirus-associated head and neck cancer.

Study finds genetic variation may protect against certain HPV-linked oral cancers click to enlarge Andrew Olshan, PhD, and colleagues report in Nature Genetics that immune system-related genetic variation may provide new insight into the mechanisms of protection against human papillomavirus-associated head and neck cancer.

A key variation in the genetic region important for regulation of the immune system provides heightened protection against the development of head and neck cancers in people infected with human papillomavirus (HPV).

This is the finding of a new large-scale genetic study of head and neck cancers co-authored by Andrew Olshan, PhD, associate director of population sciences at UNC’s Lineberger Comprehensive Cancer Center, the Barbara Sorenson Hulka Distinguished Professor in cancer epidemiology and chair of the Department of Epidemiology at the University of North Carolina’s Gillings School of Global Public Health. The study's findings were published in the Oct. 17 issue of Nature Genetics.

The study involved nearly 12,000 people – half with cancer of the oral cavity or pharynx, and half without any such cancer – and showed why some individuals infected with HPV may go on to develop oropharyngeal cancer while others do not. The researchers conducted extensive DNA analysis of more than seven million variants for each individual. The UNC site contributed samples from the Carolina Head and Neck Cancer (CHANCE) study, led by Olshan.

“These new findings on the association of immune system-related genetic variation may provide new insight into the mechanisms of protection against HPV-associated head and neck cancer,” said Olshan. “We hope these findings will inform tailored prevention measures and future immunotherapy.”

The study was led by researchers from the International Agency for Research on Cancer in partnership with 40 other research groups.

Head and neck cancers are a related group of cancers that involve the oral cavity, pharynx (oropharynx, nasopharynx and hypopharynx), and larynx. The study identified seven new genetic loci (locations of a gene on a chromosome): one that is linked to oropharyngeal cancer and six that are associated with oral cavity cancer, thus providing new insights into the development of these diseases.

The most prominent finding was an association between oropharyngeal cancer and genetic variation in the human leukocyte antigen (HLA) region, which is a genetic region important for regulation of the immune system.

One particular set of variants in the HLA region was associated with a more than four-fold protective effect against developing oropharyngeal cancer associated with HPV infection. The same genetic variants previously have been shown to protect against cervical cancer, which is known to be associated with HPV infection.

The most significant causes of all head and neck cancers are tobacco use and alcohol consumption. These exposures account for the development of approximately 80 percent of such cancers globally, with some variation for different sub-sites (65 percent for the oral cavity vs 86 percent for the larynx).

Oral infection with HPV, however, which is linked to sexual practices (particularly with HPV type 16), is an increasingly important cause of oropharyngeal cancer, especially in the United States and northern Europe. The proportion of HPV-related cases of oropharyngeal cancer varies widely and is estimated to be approximately 60 percent in the U.S., 30 percent in Europe and lower in South America. A recent analysis of tumor samples from the CHANCE study also found that as many of 60 percent of oropharyngeal cancers were positive for HPV.

HPV also is well known for causing cervical cancer, which is the fourth most common cancer in women worldwide. In 2012, there were an estimated 528,000 new cases and 266,000 deaths from cervical cancer. HPV type 16 also is associated with cancers at a variety of other sites, including the vulva, vagina, penis, anus and oropharynx.

“These findings provide important clues for new research and also will help inform ongoing work on HPV and smoking interactions, as well as the risk of head and neck impact on treatment and survival,” said Olshan. “Of course, additional replication of these findings in other diverse population is warranted, as is more research on the functional implications of this genetic variant.”

The CHANCE interdisciplinary research team will continue to explore the role of HPV and other factors in the etiology and outcomes of head and neck cancer. The team includes Olshan, UNC Linberger members Jose Zevallos, MD, associate professor of otolaryngology and adjunct assistant professor of epidemiology, and Neil Hayes, MD, associate professor of oncology, and postdoctoral fellow Angela Mazul, PhD.