A prospective study of inflammatory biomarkers and growth factors and risk of glioma in the UK Biobank

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Introduction

Gliomas are tumors arising from the glial cells of the brain and comprise 80% of all primary adult brain tumors. The etiology of gliomas is not well understood, and ionizing radiation remains the only well-validated environmental risk factor for glioma [12] . Men are at substantially higher risk of developing glioma than women, with a male:female ratio of approximately 1.58 for glioblastoma, the highest grade form [3] .

Chronic inflammation has been linked to a higher risk of some cancer sites; however, the causal mechanisms underlying these relationships are not fully understood [45] . The role of inflammation in the incidence of glioma remains poorly studied [1] . Blood levels of C-reactive protein (CRP) are a general marker of systemic inflammation, and CRP has been positively associated with increased risk of cancers of other sites, including prostate and colorectal, in some, though not all, studies [67] . Most studies of CRP and glioma were retrospective in design and subject to bias, or examined associations with prognosis after diagnosis rather than associations with risk 8910 .

Increases in white blood cell count (WBC) due to injury or stress represent an additional marker of inflammation; the neutrophil-to-lymphocyte ratio (NLR) may better reflect the balance of innate and adaptive immunity and may be more reproducible than WBC [11] . NLR has been positively associated with risk of other cancers, including lung [12] , breast [13] , and overall cancer risk [14] . Elevated NLR has been associated with poor overall survival in glioma patients [1516] , though no study has evaluated its relationship with glioma risk.

Insulin-like growth factor-1 (IGF-1) is part of a family of hormones that regulate normal cell growth and development. Some studies have suggested that IGF-1 also plays a role in suppressing inflammation [1718] . The role of IGF-1 in glioma development is unclear, with mixed results in previous case-control studies [1920] . In a prospective, nested case-control study of 280 patients with glioma in the European Prospective Investigation of Cancer and Nutrition (EPIC) cohort, higher levels of IGF-1 were positively associated with low-grade glioma (LGG) risk, but not with glioma overall [19] .

To shed further light on the role of IGF-1 and systemic inflammation in glioma risk, we examined the association of related circulating biomarkers, specifically CRP, WBC, NLR, and IGF-1, with glioma risk in the UK Biobank.