Study on Cervical Cancer Screening in Canada

Collaboration with UK Scientists

A collaborative study between Canadian researchers and scientists from the United Kingdom focused on evaluating the accuracy of a cervical cancer test based on epigenetics. It is well established that infection with the HPV virus is linked to the onset of cervical cancer, with research indicating that nearly all patients diagnosed with cervical cancer test positive for the HPV virus. However, not every individual who is HPV positive will develop cervical cancer. Some women may develop a precancerous condition known as cervical intraepithelial neoplasia (CIN).

Understanding Cervical Intraepithelial Neoplasia

Cervical intraepithelial neoplasia (CIN) is characterized by abnormal cell growth on the cervix’s surface. In the United States, nearly one million women are diagnosed with CIN, and it is particularly prevalent among women aged 25 to 35 years. CIN is classified into three grades based on the severity of cell abnormality.

– **CIN1**: The least severe form, affecting less than one-third of cervical tissue.
– **CIN2**: Indicates moderate severity.
– **CIN3**: The most severe form, where over two-thirds of the surface tissue is affected, potentially leading to cancer if untreated.

While CIN1 often resolves without intervention, persistent HPV infections increase the risk of disease progression over time. Due to the asymptomatic nature of CIN, effective screening methods are essential for early detection, particularly for CIN2 and CIN3.

Current Screening Methods

Two primary methods for screening CIN include liquid-based cytology (LBC) and HPV testing.

– **Liquid-Based Cytology (LBC)**: This method involves collecting cervical cells and storing them in a liquid medium before microscopic examination. While widely used, LBC exhibits low sensitivity for detecting CIN2+ cases, necessitating follow-up screenings to confirm the persistence of HPV infection.

– **HPV Testing**: This approach detects the presence of the HPV virus and is highly sensitive for identifying CIN2 or CIN3 cases. However, it has lower specificity, meaning not all women who test positive for HPV will have abnormal cervical cell growth. A screening method that combines high sensitivity and specificity is needed.

Research on Epigenetic Biomarkers

Study Background and Goals

The study, led by researchers at Queen Mary University of London, utilized samples collected from a large clinical trial in Canada to investigate whether an epigenetic biomarker could serve as an effective cervical screening method. The findings were published in the November 2018 issue of the International Journal of Cancer.

Significance of Epigenetic Biomarkers

Epigenetic biomarkers are emerging as promising tools for screening cervical diseases. The term “epigenetic” refers to changes on top of genes that regulate gene expression. A common epigenetic modification is the addition of methyl groups to DNA.

Predictive Capability of Methylation Levels

Lead researcher Dr. Attila Lorincz previously demonstrated that methylation levels on HPV genes could predict the diagnosis of CIN2/3 in HPV-positive women. To further validate these findings, Dr. Lorincz and his team measured methylation levels in samples from a subset of women in the HPV FOCAL (For CerviCAL Cancer Screening) trial.

The subset included 257 women aged 25 to 65 who initially tested HPV positive and had positive LBC results with confirmed pathology outcomes.

Comparative Analysis of Screening Methods

The researchers assessed methylation levels on HPV 16 and HPV 18 DNA, as well as a human tumor suppressor gene, EPB41L3, to calculate an S5 risk score. They then compared the S5 risk score’s predictive power and diagnostic capabilities to those of other common screening methods, including HPV genotyping and LBC.

Out of 107 cases diagnosed with CIN2/3, the S5 risk score identified 81 at the beginning of the trial, whereas the combination of LBC and HPV testing detected 73 cases initially, with 34 diagnosed only at the 12-month follow-up.

Effectiveness of the S5 Risk Score

Results indicated that the S5 risk score accurately detected 93% of CIN grade 3 cases, compared to 86.4% for the combined LBC and HPV genotyping methods. However, the specificity of the S5 risk score was 41.8%, while the combined method had a specificity of 49.8%.

Link Between Epigenetic Changes and Disease Progression

Notably, all samples from eight women diagnosed with cervical cancer after enrollment tested positive on the S5 screen. For four of these women, a second sample collected after enrollment showed increased methylation levels, indicating a potential link between disease progression and methylation changes. However, the methylation levels in cancer samples were still lower than those found in Grade 3 CIN samples, and the retrospective nature of the study may introduce certain biases.

Conclusion: Implications of the S5 Risk Score

The S5 risk score represents a significant advancement in cervical cancer screening methods. It is particularly adept at early detection of CIN3 and high-grade disease, potentially reducing the need for follow-up screenings required by LBC or HPV genotyping tests. Early treatment can consequently lower the risk of progressing to cervical cancer.

Additionally, the S5 risk score offers a cost-effective solution in public health, as a negative result suggests a low likelihood of developing cervical disease, thereby minimizing the need for follow-up tests. Dr. Lorincz emphasized, “All cancers were predicted by the epigenetic signature up to 5 years before diagnosis. In addition, 93% of precancers [CIN3 samples] were detected in the study.”

References

– Walboomers JM et al., Human papillomavirus is a necessary cause of invasive cervical cancer worldwide, J Pathol, 1999, 189 (1):12-9
– Data on prevalence of CIN diagnoses retrieved from https://my.clevelandclinic.org/health/diseases/15678-cervical-intraepithelial-neoplasia-cin
– Klaer SK et al., Long-term absolute risk of cervical intraepithelial neoplasia in women with mildly abnormal cervical cytology, Int J Cancer, 2013, 133(3):637-44
– Discussion of the study in HemOnc Today retrieved from https://www.healio.com/hematology-oncology/gynecologic-cancer/news/in-the-journals/%7B626d94d8-42f4-4bef-887e-ffc254628e32%7D/epigenetic-cervical-cancer-test-may-represent-enormous-development