A nested case-control study of 277 prediagnostic serum cytokines and glioma

Abstract

Recent research shows bidirectional communication between the normal brain and the peripheral immune system. Glioma is a primary brain tumor characterized by systemic immunosuppression. To better understand gliomagenesis, we evaluated associations between 277 prediagnostic serum cytokines and glioma. We used glioma (n = 487) and matched control (n = 487) specimens from the Janus Serum Bank Cohort in Oslo, Norway. Conditional logistic regression allowed us to identify those cytokines that were individually associated with glioma. Next, we used heat maps to compare case to control Pearson correlation matrices of 12 cytokines modeled in an in silico study of the interaction between the microenvironment and the tumor. We did the same for case-control correlation matrices of lasso-selected cytokines and all 277 cytokines in the data set. Cytokines related to glioma risk (P ≤ .05) more than 10 years before diagnosis are sIL10RB, VEGF, beta-Catenin and CCL22. LIF was associated with decreased glioma risk within five years before glioma diagnosis (odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.23, 0.94). After adjustment for cytokines above, the previously observed interaction between IL4 and sIL4RA persisted (> 20 years before diagnosis, OR = 1.72, 95% CI = 1.20, 2.47). In addition, during this period, case correlations among 12 cytokines were weaker than were those among controls. This pattern was also observed among 30 lasso- selected cytokines and all 277 cytokines. We identified four cytokines and one interaction term that were independently related to glioma risk. We have documented prediagnostic changes in serum cytokine levels that may reflect the presence of a preclinical tumor.

Serially measured pre-diagnostic levels of serum cytokines and risk of brain cancer in active component military personnel

“…Only one other study of glioma, conducted in Norway (JSBC study), assessed pre-diagnostic cytokine levels. 23,24 While the current and JSBC study are similar in size (457 and 487 case/control sets, respectively), the JSBC investigators used a single pre-diagnostic serum sample to measure 277 cytokines. 23,24 They found five cytokines (VEGF, beta-Catenin, CCL22, LIF, and sIL10RB) to be significantly associated with risk of glioma at different time periods prior to glioma diagnosis, i.e., discovery rate within the false positive range; the associations with IL-15 and IL-16 in that study were null.…”

“…20–22 Also, a recent case-control study nested in the Janus Serum Bank Cohort (JSBC) in Norway assessed 277 cytokines and identified five (sIL10RB, VEGF, beta-Catenin, CCL22, and LIF) independently related to glioma risk in one of five periods prior to glioma diagnosis based on a single pre-diagnostic sample. 23,24 These findings remain unconfirmed.…”

Establishing a many-cytokine signature via multivariate anomaly detection

“…follow the same multivariate distribution). This can already be a problem if the number of variables (cytokines) is only ~10 13 , and is greatly exacerbated if the number of variables grows large, which is the case for current research where even hundreds 14 of cytokines are analysed simultaneously. The problem of anomaly detection for many-variable data sets is even worse in the case of ratios: For d variables, there are ratios which grows large very quickly, even for modest d .…”

Searching for the roots of brain cancer

“…In an attempt to better understand the link between immunity and brain cancer, Schwartzbaum went back to the archived Norway blood samples and measured the levels of various immune-system proteins called cytokines in people with glioma, years before their diagnosis 6 . She expected to find that people who went on to develop glioma had lower levels of cytokine than did those who did not develop the cancer.…”