Researchers have identified two subtypes of human papillomavirus-positive head and neck cancers, giving them a better idea of why some patients respond better to treatment than others.
Non-canonical HPV carcinogenesis drives radiosensitization of head and neck tumors Meaning Human papillomavirus (HPV+)-associated head and neck squamous cell carcinoma (HNSCC) is now the most common HPV-associated cancer with increasing incidence. HPV-mediated oncogenesis is generally believed to be based on the integration of viral DNA into the host genome, loss of expression of the HPV early gene 2 (HPV E2), activation of the catalytic alpha subunit of phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), and apolipoprotein B mRNA editing catalytic polypeptide-mediated mutagenesis (APOBEC). We report the identification of a subclass of HPV+ carcinomas comprising ~45% of HPV+ HNSCC that is not associated with any of these classic features. Patients in this subgroup have significantly improved clinical outcomes, and cellular models with genomic and transcriptomic features of this class have increased radiation sensitivity. |
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University of North Carolina Health Care
Cases of head and neck cancers associated with the human papillomavirus (HPV), known as head and neck squamous cell carcinoma (HNSCC), are increasing rapidly across the United States. Unfortunately, relatively little is known about the factors that contribute to these tumors and what makes some tumors more aggressive and resistant to treatment than others.
To determine why some patients respond better to radiation therapy than others, researchers from the UNC School of Medicine’s Department of Otolaryngology/Head and Neck Surgery and the Lineberger Comprehensive Cancer Center formed a strong collaboration with researchers from the Yale Cancer Center. , the Yale Head and Neck Cancer Specialized Program of Research Excellence (SPORE), and the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN).
Together, they published a new study in the Proceedings of the National Academy of Sciences , revealing that HPV+ head and neck cancers can be divided into two distinct subtypes that determine how well patients will respond to therapy, with one subtype responding better to radiotherapy. The researchers also discovered a new mechanism of HPV carcinogenesis through the study that enhances growing efforts to personalize treatment for patients with HPV+ head and neck squamous cell carcinoma (HNSCC).
"We are the first to describe these two subtypes," said Wendell Yarbrough, MD, MMHC, FACS, Thomas J. Dark Distinguished Professor of Otolaryngology/Head and Neck Surgery, "Using this research, we can firmly identify two groups of patients and may associate their tumor subtype with treatment outcomes."
Currently, many patients with HPV+ HNSCC are treated with high-dose radiation combined with chemotherapy. But side effects, including muscle fibrosis, difficulty swallowing and hardening of the arteries, can last a lifetime. Personalized therapy may allow oncologists to make better treatment decisions for their patients; However, it can be difficult for doctors to determine the type and intensity of treatment without knowing how the patient’s tumor will respond to the therapy.
To address this need, members of Yarbrough’s team, including Travis Schrank, MD, PhD, Natalia Isaeva, PhD, and Wesley Stepp, MD, PhD, who also co-authored the paper, began coordinating a research cohort at UNC, taking publicly available data from the University of Chicago and some validation data from E1308, a large clinical trial from a national cooperative group that was conducted through ECOG-ACRIN.
They then analyzed the tumor samples and identified several clusters of co-expressed genes. Only one of these sets of coexpressed genes separated the high- and low-expressing tumors, and analysis of the genes in this set found that they represented targets of a master transcription factor called NF-kB. NF-κB plays an important role in inflammation and cell death and has been associated with HNSCC carcinogenesis.
To their surprise, the researchers found that the two distinct subtypes directly correlated with patient outcomes. Tumors with low NF-kB activity were associated with a worse prognosis, while tumors with high NF-kB activity were associated with a better prognosis.
The subtypes identified by high or low NF-kB activity were strikingly different from each other, from the genes that were mutated in the cancers, the factors driving the mutations, the number of mutations per cancer, HPV gene expression, integration of HPV, gene methylation, and infiltration of certain immune cells into the tumor.
"One of our very tenacious and intelligent residents, Wesley Stepp, co-author of the paper, was really instrumental in organizing that group of patients into the UNC cohort," Schrank said. "All the organizations that collaborated on this research project were very willing to work with us."
Patient survival was the most obvious and important distinction between the two tumor types. To better understand why one subtype may have better outcomes, researchers built cell models of each subtype in the lab.
"Tumors with high NF-kB activity responded better to radiation therapy and potentially contributed to improved patient survival," Yarbrough said. "We know that there is something about the activation of the NF-kB pathway that makes tumors more sensitive to radiation therapy, which could explain how and why these patients survive better."
Ultimately, these data could be used to identify patients whose therapy can be safely reduced to treat the tumor, decrease side effects, and improve quality of life. Now that researchers have a better understanding of the new mechanism of HPV carcinogenesis, the findings may lead to the development of new personalized treatments that are more efficient and have fewer side effects.
