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Glioma-related activity in peripheral immune system apparent 5 years before diagnosis
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Researchers have identified positive and negative associations between five prediagnostic serum cytokines and subsequent glioma diagnosis.
Judith Schwartzbaum, PhD, associate professor of epidemiology at The Ohio State University, and colleagues conducted a nested case-control study in which they assessed the associations between 277 prediagnostic serum cytokines and glioma diagnosis.
They performed their analysis on 487 glioma specimens and 487 matched control specimens included in the Janus Serum Bank Cohort in Oslo, Norway.
Results showed levels of vascular endothelial growth factor, CCL22 and beta-catenin cytokines appeared higher among cases than controls more than 10 years before diagnosis (P < .05).
Conversely, the leukemia inhibitory factor cytokine appeared associated with decreased glioma risk (OR = 0.47; 95% CI, 0.23-0.94).
“We have identified five serum cytokines and a cytokine-soluble receptor interaction, each associated with changes in the preclinical risk [for] glioma,” Schwartzbaum and colleagues wrote. “In addition, we also saw weakening of case cytokine correlations within 5 years before diagnosis, consistent with those in our previous study of allergy-related cytokines and glioma.
“Further studies are needed to attempt replication of our results in different populations,” the researchers added. “Preclinical studies of additional immune function biomarkers, including immune function cells, should be conducted with the ultimate goal of identifying gliomagenesis in its earliest stages.”
HemOnc Today spoke with Schwartzbaum about the study, the potential implications of the results, and the key questions she would like to see addressed in future research.
Question: How did the idea for this study come about?
Answer: Glioblastoma, which is the most common type of glioma, is associated with a 15- to 17-month average survival probability. People often are diagnosed after they have experienced symptoms for 3 to 6 months. By this time, the tumor is aggressive. Clinicians have thought that this tumor appears suddenly without pre-existing indicators, but the prediagnostic period is poorly understood because clinicians do not observe it and epidemiologists are interested in risk factors, not evidence of an existing tumor. The preclinical period has been studied in animals, but whether their prediagnostic response to glioma is the same as that in humans is not known. We also know that the immune system is important in the development of gliomas. A history of allergy or chicken pox decreases risk for this type of tumor, and people with glioma are severely immune suppressed, indicating that the immune system participates in tumor development or progression. With all of this in mind, we decided to look at prediagnostic circulating cytokines.
Q: How did you conduct the study?
A: The Scandinavians have wonderful population registries. Since 1972, the Janus Serum Bank has asked people who undergo routine physicals to donate serum for cancer research. The bank now has approximately 300,000 serum samples. The serum samples were linked with the Cancer Registry of Norway, which registers everyone with cancer in the country. There were 487 people who had donated serum who eventually received a glioma diagnosis. The average serum collection time was 15 years prior to glioma diagnosis, so we could see whether proximity to the time of tumor diagnosis affected circulating cytokine levels. We matched cases to controls of the same age, sex and date of blood draw. We then compared both individual cytokine levels and associations among cytokines in the serum of future cases and controls.
Q: What did you find?
A: We found that cases had higher levels of the cytokines VEGF, CCL22 and beta-catenin than controls more than 10 years before glioma diagnosis. This does not necessarily mean that glioma was present 10 years before diagnosis, but it may suggest that these cytokines increase glioma risk. Because cytokines interact, it is difficult to make inferences about individual cytokines. Therefore, we started looking at cytokine associations among future cases and controls. We first chose 12 cytokines identified by a previous research group, and we looked at associations more than15 years before glioma diagnosis. We found similar cytokine associations among cases and controls. However, when we got to 5 years before glioma diagnosis, the associations among the cytokines in cases weakened but those in controls did not. This suggests the presence of glioma-related activity in the peripheral immune system within 5 years of diagnosis. This finding is consistent with studies that showed more two-way communication between the peripheral immune system and the brain than previously thought.
Q: What are the clinical implications of the findings?
A: We need to replicate these results. Our findings eventually may be used in combination with imaging and genetic risk factors to identify cases in the earliest stages of glioma development. The problem with a rare disease — such as glioma — is that people cannot be screened unless there is a screening test with virtually no false positives. Clearly, we do not want to tell a woman she has a brain tumor when she does not. Thus, further research is required before our observations may be used in the clinic.
Q: Did your findings surprise you?
A: Yes. We were surprised by our case-control cytokine findings more than 10 years before glioma diagnosis. The VEGF result was unexpected because this cytokine is associated with glioma and helps the tumor establish a blood supply. However, it also is associated with inflammation, which may increase glioma risk. We did not expect overall weakening of correlations among case cytokines within 5 years before diagnosis. Further study will be required to interpret this finding.
Q: What will future research entail?
A: First, we have to replicate our cytokine findings. We also plan to look at other indicators of peripheral immune system activity, such as evidence of T-cell exhaustion. We will have to go back to Scandinavia to obtain blood samples because we do not have similar population-based resources in the United States.
Q: Is there anything else that you would like to mention?
A: There appears to be prediagnostic systemic immune activity that may, with further study, be used in combination with imaging and genetic risk variants to identify glioma in an earlier stage of development than is now possible. – by Jennifer Southall
Reference:
Schwartzbaum J, et al. PLoS One. 2015;doi:10.1371/journal.pone.0137503.
Schwartzbaum J, et al. PLoS One. 2017;doi:10.1371/journal.pone.0178705.
For more information:
Judith Schwartzbaum, PhD, can be reached at The Ohio State University, 1841 Neil Ave.,
308 Cunz Hall, Columbus, OH, 43210; email: schwartzbaum.1@osu.edu.
Disclosure: Schwartzbaum reports no relevant financial disclosures.