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Pre-diagnostic serum levels of EGFR and ErbB2 and genetic glioma risk variants: a nested case-control study
Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Computational Life Science Cluster (CLiC), Umeå University, 901 87 Umeå, Sweden.
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2016 (Engelska)Ingår i: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, nr 8, s. 11065-11072Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Genetic variants have been associated with the risk of developing glioma, but functional mechanisms on disease phenotypic traits remain to be investigated. One phenotypic trait of glioblastoma is the mutation and amplification of the epidermal growth factor receptor (EGFR) gene. We investigated associations between pre-diagnostic serum protein concentrations of EGFR and ErbB2, both members of the EGFR family, and future risk of glioma. Further, we studied if EGFR glioma risk variants were associated with EGFR and ErbB2 serum levels. We assessed the associations between genetic glioma risk variants and serum concentrations of EGFR and ErbB2, as measured in pre-diagnostic cohort serum samples of 593 glioma patients and 590 matched cancer-free controls. High serum EGFR and ErbB2 levels were associated with risk of developing glioblastoma (P = 0.008; OR = 1.58, 95 % CI = 1.13-2.22 and P = 0.017, OR = 1.63, 95 % CI = 1.09-2.44, respectively). High serum ErbB2 concentration was also associated with glioma risk overall (P = 0.049; OR = 1.39, 95 % CI = 1.00-1.93). Glioma risk variants were not associated with high serum protein abundance. In contrast, the EGFR risk variant rs4947986 (T) was correlated with decreased EGFR serum levels (study cohort P = 0.024 and controls P = 0.009). To our knowledge, this is the first study showing an association of EGFR and ErbB2 serum levels with glioma more than a decade before diagnosis, indicating that EGFR and ErbB2 serum proteins are important in early gliomagenesis. However, we did not find evidence that glioma risk variants were associated with high pre-diagnostic serum concentrations of EGFR and ErbB2.

Ort, förlag, år, upplaga, sidor
2016. Vol. 37, nr 8, s. 11065-11072
Nyckelord [en]
Glioma, SNP, Serum EGFR, Serum ErbB2, Pre-diagnostic
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
URN: urn:nbn:se:umu:diva-126327DOI: 10.1007/s13277-015-4742-yISI: 000382672900107PubMedID: 26906551OAI: oai:DiVA.org:umu-126327DiVA, id: diva2:1043882
Tillgänglig från: 2016-11-01 Skapad: 2016-10-03 Senast uppdaterad: 2019-02-14Bibliografiskt granskad
Ingår i avhandling
1. Molecular epidemiology approach: nested case-control studies in glioma and lymphoid malignancies
Öppna denna publikation i ny flik eller fönster >>Molecular epidemiology approach: nested case-control studies in glioma and lymphoid malignancies
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

BACKGROUND: Nested case-control studies aim to link molecular markers with a certain outcome. Repeated prediagnostic samples may improve the evaluation of marker-disease associations. However, data regarding the benefit of repeated samples in such studies are sparse. We aimed to assess the relationship between blood levels of various proteins and risk of glioma, B cell lymphoma, and multiple myeloma to gain further understanding of disease etiology and to evaluate the clinical relevance of the studied markers. To this end, marker-disease associations were evaluated considering the natural history of the studied disease and the time between blood sample collection and diagnosis using both single (I-II) and repeated prediagnostic blood samples (III-IV).

PATIENTS AND METHODS: We conducted four nested case-control studies and one meta-analysis using samples from three prospective cohorts: the Janus Serum Bank, the Northern Sweden Health and Disease study, and the European Prospective Investigation into Cancer and Nutrition study. The following studied endpoints and relationships were included: I) glioma risk and the association with the receptor tyrosine kinases (soluble) sEGFR and sERBB2; II) B cell lymphoma risk and the association with the immune markers sCD27 and sCD30; III) B cell lymphoma risk and the association with immune markers (CXCL13, sTNF-R1, sCD23, sCD27, and sCD30) and their trends over time; and IV) multiple myeloma risk and the association  with ten immune markers and growth factors (MCP-3, MIP-1α, MIP-1β, VEGF, FGF-2, fractalkine, TGF-α, IL-13, TNF-α, and IL-10) and their trends over time.

RESULTS: Risk of developing I) glioma was weakly associated with high blood levels of sERBB2. In addition, high levels of both sEGFR and sERBB2 assessed 15 years before diagnosis were associated with glioblastoma risk.

Risk of II) B cell lymphoma was associated with high levels of sCD30, whereas high levels of sCD27 were particularly associated with risk of chronic lymphocytic leukemia. Meta-analyses showed consistent results for sCD30 across cohorts and lymphoma subtypes, whereas results for sCD27 were less consistent across cohorts and subtypes.

In addition, III) B cell lymphoma risk was associated with levels of CXCL13, sCD23, sCD27, and sCD30 assessed in samples collected 17 years before diagnosis. Marker levels increased in cases closer to diagnosis, particularly for indolent lymphoma with a marked association for chronic lymphocytic leukemia and sCD23. Increasing marker levels closer to diagnosis were also observed for CXCL13 in future diffuse large B cell lymphoma patients.

Risk of IV) multiple myeloma was associated with low levels of MCP-3, VEGF, FGF-2, fractalkine, and TGF-α. Levels of these markers decreased in myeloma cases over time, especially for TGF-α. TGF-α assessed at time of the prediagnostic repeated sample seemed to help predict progression to multiple myeloma.

CONCLUSIONS: Both the natural history of the studied disease and the time between sample collection and diagnosis are crucial for the evaluation of marker-disease associations. Using repeated blood samples improves the understanding of marker-disease associations and might help to identify useful biomarker candidates.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, 2019. s. 53
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2016
Nyckelord
Glioma, B cell lymphoma, multiple myeloma, risk, repeated samples, prospective longitudinal study, nested case-control study, circulating sEGFR and sERBB2, circulating immune markers and growth factors, marker disease association, disease progression, NSHDS, Janus, linear mixed modeling
Nationell ämneskategori
Cancer och onkologi
Forskningsämne
epidemiologi; onkologi
Identifikatorer
urn:nbn:se:umu:diva-156421 (URN)978-91-7855-025-8 (ISBN)
Disputation
2019-03-22, Bergasalen, byggnad 27, Norrlands universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-02-22 Skapad: 2019-02-14 Senast uppdaterad: 2019-02-21Bibliografiskt granskad

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