Gene Mutations Reflect Smoking History in Patients With HPV-Positive Oropharyngeal Cancer

Tobacco smoking worsens the prognosis for patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC), and this is likely due at least in part to differences in the somatic gene mutation signatures of patients with more pronounced smoking histories, suggests research reported at the 2016 Multidisciplinary Head and Neck Cancer Symposium in Scottsdale, Ariz.

If validated, the findings might lead to better prognostic risk stratification of patients and improved decision-making about OPSCC treatment intensity, the coauthors suggested.

“Throat cancer patients who smoked and had a history of fewer than 10 pack years had significantly better disease free and overall survival rates than the heavier smoking group,” noted lead author Jose P Zevallos, MD, MPH, FACS, assistant professor and director of oncologic research in the division of head and neck surgical oncology at the University of North Carolina, Chapel Hill, in an American Society for Radiation Oncology (ASTRO) news release. “Our analyses identified several key differences in molecular mutational profiles of the two groups that may shape these outcomes.”

Most patients diagnosed with HPV-associated OPSCC have a good prognosis, but that is less true for those who smoke. To discover whether differences in gene mutation signatures might explain survival differences, the researchers employed targeted next-generation sequencing and copy-number analysis of more than 800 genes, for 66 patients diagnosed in North Carolina with HPV-positive OPSCC between 2001 and 2006.

A pack-year is calculated by multiplying the patient’s self-reported number of packs of cigarettes smoked each day by the number of years the patient has smoked. The researchers identified heavy smokers as those self-reporting a smoking history of greater than 10 pack years, and “light” smokers as those reporting less than 10 pack years.

Lower pack-year smoking history (n = 26) was associated with better disease-free survival (DFS) and overall survival (OS) compared to heavy smokers (n = 40), the coauthors confirmed.

The most common gene mutations in both groups of smokers were HLA-A, PIK3CA, and MLL-3. However, TP53, CDKN2A, KRAS, and NOTCH1 mutations were “found almost exclusively” among heavy smokers, and were associated with poorer survival, the coauthors noted.

HLA-A mutations were significantly more frequent among lower pack-year smokers (73.1% vs 47.5%; P = .047), they reported.

“In addition to expected tobacco-associated mutations in the >10 pack-year group, we demonstrated a novel immune signature in the <10 pack-year group,” the coauthors reported.  Mutation frequencies were compared to data in the Catalogue of Somatic Mutations in Cancer (COSMIC) database.

Dr. Zevallos said that “what is most striking is that these genes are mutated almost exclusively in smokers. This molecular profile suggests that while HPV-positive OPSCC carcinogenesis initiates similarly, tumors in patients who smoke acquire novel mutations not traditionally associated with HPV-associated cancers.”

If their findings are validated, they could “further stratify risk in HPV-positive OPSCC and provide novel mutational parameters for treatment de-intensification,” the coauthors noted.