New cervical cancer test detects precancerous lesions years in advance

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Martin Widschwendter and Chiara Herzog from the EUTOPS Institute at the Universi
Martin Widschwendter and Chiara Herzog from the EUTOPS Institute at the University of Innsbruck © Patrick Saringer
A newly developed test detects early precancerous changes in the cervix. This procedure works better than currently available methods and detects the changes years before cancer develops. The test was developed under the direction of Martin Widschwendter, Professor of Cancer Prevention and Screening at the University of Innsbruck. The new test is part of a research program that aims to predict the risk of four types of cancer (breast, ovarian, uterine body and cervical cancer) from a single cervical smear.

The study published today in the journal Genome Medicine reports on a new, more sensitive and informative method of cervical cancer screening - the WID-CIN test - that can reliably identify or predict precancerous lesions of the cervix. Currently, cervical cancer screening in Austria consists of examining microscopic changes in the cells of the cervix. However, the new test detects precancerous lesions even when no changes are yet visible microscopically and could thus enable more targeted screening. The method was developed by Martin Widschwendter, Professor of Cancer Prevention and Screening at the University of Innsbruck and University College London, his team and colleagues at the Karolinska Institute in Stockholm.

Test examines DNA methylation

The study is part of a comprehensive research program to develop a screening test for all cancers specific to women using a single sample. This test will thus predict future risk for four cancers, breast, ovarian, uterine and cervical, based on different molecular signatures.

The new WID-CIN test is part of the spanning test and examines DNA methylation of cervical cells. DNA methylation is a change in the genetic code that can be influenced by environmental factors. It tells the cells which parts of the genetic code to read. These so-called epigenetic changes can increase the risk of certain diseases such as cancer. The researchers hope that this will not only detect the precursors of cancer, but also predict future cancer risk.

How screening works in Austria

In Austria, women can currently undergo an annual cervical screening. During this screening, a cell smear is taken from the cervix using a soft brush. The cells contained in the sample are examined under a microscope for changes that can lead to cancer if left untreated. With this test ("cytology", for cell examination), abnormal cells on the cervix are detected. Women with cell changes are invited for follow-up examinations and closely examined by a specialist using a colposcope, an instrument that magnifies the view of the cervix. Unlike in Austria, in other Western countries a test for the virus that causes cervical cancer - the human papilloma virus (HPV) - is often performed first. If the result is positive, cytology then follows.

If cell changes (cervical intraepithelial neoplasia - CIN) are found, the degree of change is determined (1-3). Early cell changes (CIN1 and 2) often regress spontaneously. Therefore, only closer-meshed examinations are performed for the time being until the cells have returned to normal or treatment is required. For high-grade cell changes (CIN3), affected women have the changed cells removed with a procedure called LLETZ ("large loop excision of the transformation zone"), which removes the abnormal cells before they can develop into an invasive cancer.


Conventional methods are outperformed

The newly developed WID-CIN test outperformed cytology and results suggest that it also outperforms other new molecular tests already available for detecting women with CIN3 and cancer in terms of accuracy. The WID-CIN test thus represents a significant advance in the early detection of cervical cancer. Specifically, the test detected more than half of HPV-infected women (55%) who currently had no visible cell changes at all but who developed a distinct precancerous lesion (CIN3) within the following four years. As part of the study, the researchers examined 1,254 cervical screening samples. These came from the cervical screening program in the Stockholm region of Sweden and were stored at the Karolinksa Center for Cervical Cancer Elimination (Stockholm, Sweden). The samples were from women with cell changes ranging from CIN1 to CIN3, women with HPV but without cell changes in the cervix, and samples from women without cell changes in the cervix who developed CIN3 within four years.

The research team is now moving to the next phase of the study, in which they will test the new technology on screening samples from women who have been vaccinated against HPV. HPV vaccination against cancer-causing subtypes does dramatically reduce the incidence of cervical cancer. However, other subtypes can cause cancer that are not detected by current tests. The new WID-CIN test detects precancerous subtypes based on cancer-associated epigenetic changes and thus could detect all precancerous subtypes across HPV types.

Quotes:

Prof. Martin Widschwendter, European Translational Oncology Prevention and Screening Institute (EUTOPS), University of Innsbruck, and UCL’s Department of Women’s Cancer, Institute for Women’s Health, UK, says: "Vaccination against cervical cancer-causing human papilloma virus (HPV) is now widespread, leading to changes in the amount and types of virus circulating in the population. In turn, approaches to cervical cancer screening need to be adjusted to ensure that programs continue to provide benefit.

Our work has shown how, in addition to detecting cervical precancers, testing a cervical specimen can also provide information about a woman’s risk for three other cancers - breast, ovarian and uterine. Building new, holistic, risk-predictive screening programs on top of existing, effective cervical sampling offers real potential for cancer prevention in the future."

Chiara Herzog, molecular physician at the EUTOPS Institute : "Cervical cancer prevention is a historical success story in preventive medicine: the Pap test showed as early as 1941 that early intervention can prevent cancer. Our screening and risk prediction tools have been improving ever since. The new WID test is more accurate and detects precancerous lesions before microscopic changes occur. As a result, screening can be more targeted. This is good news for cervical cancer prevention and anyone who wants to get screened."

Promotion and participation:

This research project was funded by the Horizon 2020 FORECEE project, the gynecological cancer charity The Eve Appeal, and the Swedish Foundation for Strategic Research. Professor Martin Widschwendter was also supported by an Advanced Grant from the European Research Council (BRCA-ERC). Key collaborators on the research program included Dr Chiara Herzog, Molecular Physician at the EUTOPS Institute at the University of Innsbruck, Professor Joakim Dillner and Principal Investigator Dr Karin Sundström and the team from the Karolinska Center for Cervical Cancer Control (Sweden).

Publication:

The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer. James E. Barrett, Karin Sundström, Allison Jones, Iona Evans, Jiangrong Wang, Chiara Herzog, Joakim Dillner, and Martin Widschwendter.Genome Medicine (2022). https://doi.org/10.1­186/s13073­’022 -01116-9




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