A groundbreaking discovery represents a major advance” in understanding cervical cancer

A groundbreaking discovery represents a major advance” in understanding cervical cancer

Scientists have found that cervical cancer can be divided into two distinct molecular subgroups - one far more aggressive than the other - in the largest 'omics' study of its kind, led by researchers at UCL and the University of Southampton.

The researchers, published in Nature Communications, say the groundbreaking findings represent a "major advance" in understanding disease and provide a tantalizing new clue for determining the best treatments for individual patients.

Cervical cancer is a leading cause of cancer-related deaths in women, causing 528,000 new cases and 266,000 deaths worldwide each year. It is almost always caused by the human papillomavirus (HPV), a common virus that can be passed from one person to another during sex.

Even in the UK, where NHS cervical cancer screening has dramatically reduced cancer incidence and the national HPV vaccination program aims to reduce rates even further, around 850 women die from the disease every year.

For the study, researchers first used a multi-omics approach, analyzing and comparing a combination of different markers, including DNA, RNA, proteins and metabolites, in 236 cases of cervical squamous cell carcinoma (CSCC), the most common form of cervical cancer, available in a publicly available US database.

That analysis found that cancers in the U.S. were divided into two distinct “omics” subgroups, which they called C1 and C2. Further investigation revealed that C1 tumors contained much higher numbers of specialized white blood cells known as cytotoxic T cells, which are known to be powerful serial killers of tumor cells. The results suggest that patients with C1 tumors would have a stronger immune response within the tumor microenvironment.

The scientists then asked the question: Do the two subtypes affect cervical cancer patients in different ways?

To answer this question, the team, which also included researchers from the University of Kent, the University of Cambridge, Oslo University Hospital, the University of Bergen and the University of Innsbruck, derived molecular profiles and examined the clinical outcomes of an additional 313 CSCC cases conducted in Norway and Austria, for which much more detailed patient follow-up data was available.

Through this integrated analysis, the researchers found that, as in the US cohort, almost a quarter of patients fell into the C2 subtype and that C1 tumors, in turn, contained far more killer T cells than C2 tumors. Importantly, the data also showed that C2 was far more clinically aggressive and resulted in worse outcomes for patients. This difference in outcomes between patients with C1 and C2 tumors was very similar in the US and European cohorts.

Next, by analyzing another cohort of 94 Ugandan CSCC cases, the team found that C2 tumors were much more common than C1 tumors in patients who were also HIV-positive, highlighting the association with a weaker antitumor immune response in this group.

Interestingly, the C1/C2 grouping appeared to be more informative than the HPV type present. Cervical cancer can be caused by at least 12 different “high-risk” HPV types, and there are conflicting reports as to whether the type of HPV present in cervical cancer affects the patient's prognosis. This new study suggests that although certain types of HPV are more common in C1 or C2 tumors, the prognosis is related to the group to which the tumor was assigned, rather than the type of HPV it contains.

Co-corresponding author Tim Fenton, Associate Professor of Cancer Biology at the University of Southampton's School of Cancer Sciences Center for Cancer Immunology, said: "Despite major advances in cervical cancer prevention, many women still die from the disease. Ours." The results suggest that determining whether a patient has C1 or C2 cervical cancer could be helpful in planning her treatment, as it appears to provide additional prognostic information beyond that obtained from clinical staging (examining the size and extent to which the tumor has spread beyond that). cervix at the time of diagnosis).

“Given the differences in the antitumor immune response observed in C1 and C2 tumors, this classification could also be useful in predicting which patients are likely to benefit from new immunotherapeutics such as pembrolizumab (Keytruda®, an immunotherapy drug recently approved for use in cervical cancer), but the C1/C2 typing needs to be included in clinical trials to test this.”

Co-corresponding author, Kerry Chester, Professor of Molecular Medicine at the UCL Cancer Institute, said: "This collaborative multidisciplinary research is a major advance in our understanding of cervical cancer. Through careful molecular profiling and genetic analysis of cervical cancer tumors we have gained valuable new insights into the tumor microenvironment and factors obtained that may make the cancer less aggressive in some patients.

“The inclusion of patient cohorts in Norway and Austria, for whom very detailed clinical information was available to complement the molecular data, was a key factor in the success of the study.”

The research was funded primarily by the Debbie Fund, established in memory of Deborah Phillips, who died of cervical cancer in 2010 at the age of 48.

We created the Debbie Fund to improve treatment options for women with cervical cancer, and this research aims to do just that. We are pleased to have made this highly collaborative project possible and are very impressed by the efforts of all scientists involved. As always, we are very grateful for the continued support of our donors, without whom this would not have been possible.”

Katy Moyle, Chair of the Debbie Fund

Source:

University College London

Reference:

Chakravarthy, A., et al. (2022) Integrated analysis of cervical squamous cell carcinoma cohorts from three continents reveals conserved subtypes of prognostic significance. Nature communication. doi.org/10.1038/s41467-022-33544-x.

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