It has been widely accepted that all cervical cancers are positive for human papillomavirus (HPV), and that expression of the oncogene is necessary for the development of the disease.

However, a team of scientists at the University of South Carolina have identified a new subtype of cervical cancer that is triggered by HPV, but its growth is not directed by the virus.

The study, published in the journal Oncotarget, reported that while virtually all cervical cancers contained HPV DNA, 8% did not express HPV transcripts, a phenomena referred to as HPV-inactive. These findings could have significant treatment implications in cervical cancer, where few biomarkers of response to targeted therapies are available.

“Cervical cancer patients are currently treated as a uniform group based on chemotherapy and radiation regimens that help the largest percentage of people; however, one third of these patients are not helped by standard therapies,” said Carolyn Banister, Ph.D, the lead scientist on the study, in a statement. “We have discovered the existence of a subgroup of cervical cancers with very different genetic features. These women may benefit from alternative treatments that are not usually given to cervical cancer patients.”

After an analysis of 255 cervical cancer samples, researchers found that HPV oncogenes were expressed in two different ways; at high levels, referred to as HPV-active class, or at low or zero levels, referred to as HPV-inactive class.

Patients with HPV-active and inactive oncogenes were found to have distinct differences. Patients harboring HPV-active tumors were on average 9 years younger at diagnosis than those with HPV-inactive tumors, and their survival was significantly higher. HPV-active patients had a median survival of 715 days compared to 3,046 days for HPV inactive patients (p = 0.0003).

Mutations between the two groups differed as well. Nineteen cancer driver genes had significantly higher mutation rates in the HPV-inactive class than in the HPV-active class, indicating that these mutated genes replace functions normally provided by the HPV oncogenes in regulating tumor cell growth.

For example, HPV-inactive tumors were 17 times more likely to contain disrupting TP53 gene mutations than HPV-active cervical cancers, rendering unnecessary the expression of the HPV E6 oncogene.

Based on these findings, study authors suggested a more personalized medicine approach may be beneficial in cervical cancer.

“The differences between HPV-inactive and HPV-active tumors suggest the use of different targeted therapeutic approaches,” wrote study authors in the Oncotarget article. “For example, gefitinib, an EGF-receptor inhibitor, may be more effective in treating HPV-active cervical cancers, while dasatinib may be more effective in treating HPV-inactive tumors.”

“Overall, somatic mutations in the genes upstream of AKT are more common in HPV-inactive tumors, suggesting that dual PI3K/MTOR inhibitors may be more effective for these patients. Finally, inflammation-associated gene sets are increased in HPV-active tumors, as are the targets for checkpoint inhibitor based immunotherapy such as, TIGIT, CTLA4, PDL-1, indicating that immunotherapy, in combination with standard radiotherapy and DNA-damaging chemotherapy protocols may also be more effective in treating HPV-active tumors.”

This treatment approach would be similar to what is currently being implemented in head and neck cancer, where it was already known that HPV-positive and HPV-negative tumors existed. Gene expression differences in HPV-positive and HPV-negative cervical cancers mirror what has been reported for head and neck cancers.

Previous studies by the University of South Carolina’s Lucia Pirisi-Kim Creek research group had reported the existence of an HPV-inactive class in head and neck cancer and raised the possibility that HPV-inactive cervical cancers might originate as virally driven cancers and subsequently act independent of HPV. This work confirmed these suspicions and discovered novel molecular genetic mechanisms driving the evolution of HPV-inactive cancers.