In the largest omics study of its kind, a team of researchers have identified two distinct molecular subgroups of cervical cancer – one of which is far more aggressive. The findings, published in Nature Communications, could improve the clinical management of cervical cancer patients.
Cervical screening and the introduction of the national HPV vaccination programme has drastically reduced the rate of cervical cancer in the UK. However, around 850 women still die every year from the disease. Worldwide, cervical cancer remains a major cause of cancer-related deaths in women, accounting for 528,000 new cases and 266,000 deaths each year.
For their study, the team used multi-omics analysis to investigate DNA, RNA and metabolite markers in 236 cervical squamous cell carcinoma cases (CSCC) – the most common form of cervical cancer – from a US public database. This initial analysis revealed two distinct subgroups, which the team termed C1 and C2.
On closer inspection, they discovered the C1 tumours had a much higher number of cytotoxic T cells. This would suggest that patients with C1 tumours would exhibit a stronger immune response within the tumour microenvironment. Based on this, the team decided to explore whether there was an observable difference in how the two types of cancer impacted patient prognosis.
They gathered patient follow up data from a further 313 CSCC cases in Norway and Austria and found a similar trend – nearly a quarter of patients fell into the C2 subtype and C1 tumours contained far more killer T cells. They also found that those with C2 tumours were more than twice as likely to die from their cancer in the follow-up period (20 years). This difference in outcomes was similar across the US patient cohort as well.
“Despite major steps forward in preventing cervical cancer, many women still die from the disease,” said co-corresponding author, Tim Fenton, Associate Professor in Cancer Biology, School of Cancer Sciences Centre for Cancer Immunology, University of Southampton. “Our findings suggest that determining whether a patient has a C1 or a C2 cervical cancer could help in planning their treatment, since it appears to provide additional prognostic information beyond that gained from clinical staging (examining the size and degree to which the tumour has spread beyond the cervix at the time of diagnosis).”
Taking it global
To get a better perspective on the global scale, they added 94 Ugandan CSCC cases into the mix. In this group, C2 tumours were much more common in HIV-positive patients, suggesting a link to their weaker anti-tumour immune response. Across the 3 cohorts from different geographical regions, the C2 tumours had distinct genomic alterations leading to loss of the STK11 tumour suppressor gene, increased expression of immune checkpoint genes, and distinct differences in the TME.
“Given the differences in the anti-tumour immune response observed in C1 and C2 tumours, this classification might also be useful in predicting which patients are likely to benefit from emerging immunotherapy drugs such as pembrolizumab (Keytruda®, an immunotherapy drug recently approved for use in cervical cancer), but C1/C2 typing will need to be incorporated into clinical trials to test this,” said Fenton.
The final key finding from the paper is that the C1/C2 grouping seemed to provide more useful information about the potential prognosis of a patient compared to the type of HPV virus present. It seems that the two most common HPV strains are found at high levels in these two cancer subtypes, but HPV type does not seem to influence prognosis. More data is needed from cohorts in Africa, Asia, and South America to confirm these findings, but they could enable improved clinical management of cervical cancer patients in the future.