Two new studies by the Medical University of Graz have identified key precursors to both HPV- and non-HPV-associated cervical cancer.
Performed by researchers Olaf Reich, Sigrid Regauer and Karl Kashofer, the results of these studies significantly shift the understanding of this cancer, which is the fourth most common type in women globally.
Worldwide around 600,000 women develop cervical cancer annually, and roughly half of these women die — above all in countries with insufficient prevention.
The most common cause of cervical cancer is a persistent infection with human papillomavirus (HPV), a disease primarily spread via sexual contact.
Although the number of HPV-related cervical cancer cases are decreasing in developed countries due to the introduction of vaccinations and HPV testing, HPV still accounts for 70% of all cervical cancer cases.
HPV-associated cancer: new precursor identified
It used to be unclear whether thin high-grade squamous intraepithelial lesions (thin HSILs) could actually be considered true precursors of cancer.
The study published in the journal Laboratory Investigation has provided the first genetic evidence: Thin HSILs exhibit changes in their DNA and gene activity that are similar to those in malignant and advanced cancers.
This proves that thin HSILs are early forms of HPV-associated cervical cancer. These thin HSILs have been difficult to detect; rarely appearing conspicuous under the microscope or in clinical tests with a colposcope, they often require the use of biomarkers in diagnostics.
"We were also able to show that this common precursor of HPV-associated cancer does not develop in the flat squamous epithelium of the outer layer of the cervical mucosa as previously assumed but in the columnar epithelium (inner layer of the cervical mucosa) without any minor changes as precursors," explains Olaf Reich, head of the dysplasia and research unit of the Division of Gynaecology at the Medical University of Graz.
"These findings have important consequences for future prevention, diagnostics and therapy," says the researcher.
HPV-independent precursors described for the first time
In a second study published in the American Journal of Surgical Pathology, the researchers describe HPV-negative changes to the cervical mucosa that can develop into cancer without the presence of HPV.
These rare differentiated cervical intraepithelial neoplasia (d-CIN) resemble precursors of vulvar cancer.
"Instead of HPV-associated changes, HPV-independent precursors of cancer exhibit typical defects in genes such as TP53, PIK3CA or SMARCB1, which promote malignant tumour growth and reduce the effectiveness of chemotherapy to treat tumors," noted Karl Kashofer, head of the Diagnostic Genome Analysis lab at the Diagnostic and Research Institute of Pathology at Med Uni Graz.
These highly differentiated changes to the cervix can be easily overlooked because they first appear to be harmless and are also difficult to distinguish from benign changes in cervical smears.
"Our work shows that there are true HPV-negative precursors to cervical cancer. Thus we have refuted the so-called "hit-and-run" theory according to which HPV originally played a role in tumor development then disappears during tumour growth," explains WHO author Sigrid Regauer of the Diagnostic and Research Institute of Pathology at Med Uni Graz.
"For the first time, we have verified that there are actually HPV-independent types of cervical cancer."
Moving forward
Following these findings, Reich believes that there may be significant consequences for prophylaxis and treatment of cervical cancer and its precursors.
"We used to protect against HPV-associated cancer with the HPV vaccine by preventing HPV infection. In the future, the earliest precursors of cancer in the thin HSIL might be induced to regress by therapeutic HPV-specific cervical carcinoma vaccines," he stated.
"Because of their specific gene defects, HPV-independent carcinomas are candidates for the new molecular therapies, which are also referred to as targeted therapies. They are associated with the hope of being able to effectively stop HPV-independent cancer cells that have developed in the cervix and also of having fewer side effects," Reich concluded.
