HPV Awareness Day: The Need for Improved Screening

March 4th marks HPV Awareness Day. This event aims to educate on what HPV is and to be aware of the diseases and cancers it can cause, and to encourage people to get tested for HPV. Read on to find out more about the limitations with traditional HPV tests, and the new grant awarded to Prof. Sheila Graham here at the CVR which aims to improve the screening process.

Every year, cervical cancer affects over 600,000 people. Cases of this cancer are almost always related to high-risk human papillomavirus (HPV) infection. Cancers of the cervix are generally preceded by pre-cancerous cervical disease which, if caught early, can be effectively treated before the disease progresses to cancer.

In Scotland, HPV nucleic acid (NA) testing is currently the first screening approach for cervical disease. It is sensitive but not specific, so that women without disease can still test positive. Moreover, it cannot distinguish between infections that will regress versus those that may persist and cause clinically significant cellular changes. The additional clinical investigations required to determine if a patient is at risk of significant disease can result in considerable anxiety, as well as time and money costs for both the patient and the NHS. For these reasons, new tests are required to identify those infections that require closer monitoring from those that do not.

As opposed to traditional smear tests (liquid based cytology) carried out by a medical professional, vaginal self-sampling is a promising new approach to cervical screening that may be more acceptable to those who find cervical screening painful or uncomfortable, or who do not have adequate access to health services. The Graham Lab at the MRC-University of Glasgow Centre for Virus Research, led by Prof. Sheila Graham, aim to test whether a novel biomarker panel can be applied to self-taken samples to identify significant disease. Such a panel could help support a molecular solution to cervical screening which starts with a standard HPV NA test and is followed by the biomarker test.

The Graham Lab has recently received a new grant with the Chief Scientist Office to conduct this work, together with co-applicant Dr Kate Cuschieri, Director of the Scottish HPV Reference Laboratory, NHS Lothian. Previous work undertaken in Dumfries and Galloway and performed in collaboration with other Scots researchers in NHS Lothian and NHS Lanarkshire has shown the feasibility of offering self-sampling to both the attender and non-attender population. The results are very promising and indicate that self-taken samples show similar performance to clinician-taken samples in terms of sensitivity. These previous studies and associated experience act as an important grounding for new developments that can evolve the technology around self-sampling even further.

While current HPV screening methods allow for sensitive detection of HPV infection, they offer no indication on the likelihood of a transient infection progressing to cervical disease. For this, it is necessary to use biomarkers as an indicator of potential cervical disease progression or regression. The new grant awarded to the Graham Lab is a follow-on from previous Wellcome Trust-funded work that used RNA sequencing to identify changes in the transcriptome of HPV16-infected relative to uninfected cells, and showed that there was alteration in the expression of approximately 3,000 genes in HPV-infected epithelial cells. Quantification of the upregulation or downregulation of certain carefully selected genes in infected cells by RT-qPCR in liquid-based cytology samples provided promising evidence for their use as biomarkers of cervical disease. Samples of both low-grade and high-grade cervical lesions were analysed and changes in gene expression dependent on disease stage were recorded, showing the potential of these RNA biomarkers as sensitive and specific indicators of cervical disease progression. This work led to a translational MRC Confidence in Concept (CiC) award. The CiC project has resulted in selection of a set of RNA biomarkers for use in RT-qPCR, which have potential to be used to risk-stratify cervical disease in liquid-based cytology samples. One reviewer of the Graham Group’s new grant stated “the impact of the research is important since an “all-in-one” molecular test offering screening and triaging will increase the efficiency of cervical screening”.

The new Chief Scientist Office grant aims to evaluate the effectiveness of self-taken vaginal samples for risk-stratifying cervical disease using molecular tests, with the work placing a particular focus on the use RNA biomarkers to identify the risk of disease progression in patients. This work has the potential to be hugely impactful, with another reviewer of the grant proposal saying “if the present proposal is carried out, it may speed up cervical cancer elimination”.