VIENNA – A prospective sequencing-based gene expression study has uncovered a link between a parasitic infection that disproportionately affects resource-poor areas of the world and cancer-related gene activity in the cervix.
The results, presented Sunday at the European Society of Clinical Microbiology and Infectious Diseases global congress, point to a potential role for the parasites — and, surprisingly, for their only effective treatment — in cervical cancer.
Infection with the parasite Schistosoma haematobium causes the disease schistosomiasis and is particularly prevalent in regions with poor access to clean water and sanitation, infecting more than 110 million people worldwide by depositing eggs that infiltrate the urinary and reproductive tracts.
Infection with the parasite is known to be a cause of bladder cancer, but its role in cervical cancer remains unclear.
To investigate this connection, a team led by Anna Maria Mertelsmann, a researcher at University Hospital Zurich and Weill Cornell Medicine specializing in infectious diseases and molecular oncology, analyzed gene expression in cervical tissue samples collected from 39 Tanzanian women — 20 of whom had S. haematobium infections and 19 of whom did not.
Mertelsmann told GenomeWeb that the research built on a prior study published in 2018 by researchers including some of her colleagues from the Center for Global Health at Weill Cornell Medicine. That study demonstrated altered cervical mucosal gene expression and lower interleukin-15 levels in women infected with S. haematobium as compared to those with a related parasite, Schistosoma mansoni, factors that may influence HIV acquisition and cancer risk.
"There were some signals there that showed there might be different expression in oncogenic pathways in infected women, as well as an impairment of epithelial integrity," Mertelsmann said.
That created the impetus to look further into these findings but also to investigate what happens to gene expression after women are treated with praziquantel, the only current treatment for schistosomiasis.
"We know that praziquantel only eradicates the adult worms, not the eggs that actually cause symptoms and problems of schistosomiasis," Mertelsmann said. "There is a lot of evidence showing that symptoms … and clinical findings persist despite treatment. It makes sense because the eggs that cause the problems probably still remain; we just don't know for how long or if they will ever be cleared."
In the new study, the researchers collected cervical samples from the 39 subjects at baseline and four to 12 months after praziquantel treatment for those infected. They conducted Illumina RNA sequencing on the samples and analyzed differential gene expression with various open-source informatics packages. Qiagen's Ingenuity Pathway Analysis also helped them identify gene networks related to infection and posttreatment changes.
The researchers found that nine genes were expressed differently between infected and uninfected women, including four linked to cancer — BLK proto-oncogene, long intergenic non-protein coding RNA 2084, trichohyalin, and TCL1 family AKT coactivator A.
In addition, 23 genes were expressed differentially in women who cleared the infection after treatment, and 29 genes differed between women posttreatment and those who were not infected.
Posttreatment, certain cancer-related biological pathways were more active, particularly those involved in inflammation, tissue remodeling, and the breakdown of protective barriers in the cervix. These changes were linked to increased blood vessel formation, activation of tumor-related processes, and reduced apoptosis, a process involved in eliminating abnormal cells.
"I think, in general, it shows there is a clear signal," Mertelsmann said. "There is a difference between infected and uninfected women … and there seems to be a sign that there are more pro-oncogenic genes expressed or protective genes less expressed."
Mertelsmann was quick to point out that the gene expression changes were in genes related to cancer activity in general, not necessarily cervical cancer specifically. And, she noted, the small sample size of the study means that larger longitudinal studies are needed to validate the findings and "really see what the implications are of this."
She and her colleagues have already embarked on a larger study of 180 women over 12 months using the same gene expression analysis methods. Samples for this study have already been collected but analysis has not yet begun, she said.
One major implication that the researchers are keen to explore is what this means for treatment with praziquantel, as the genes that were differentially expressed in treated women and uninfected women were different from the differentially expressed genes in infected versus uninfected women, suggesting that the drug could be involved in oncogenic pathways, at least shortly after treatment.
"We only followed women for up to 12 months, and we had more samples from women at four and six months because … you tend to lose women to follow-up, unfortunately, particularly in these rural areas," Mertelsmann said. "We don't know what would happen further along after treatment. Do these changes revert?"
These results also mirror what some other studies have shown — that adjunctive therapies might be needed in schistosomiasis patients to help with the cervical mucosal wound healing that seems to persist despite eradication of the adult worms from the patient's system.
Longer term, she said, the researchers can envision a scenario where monitoring gene expression in schistosomiasis patients may help inform treatment.
"We're unfortunately far away from that," she said. "But that's ideally the long-term goal."