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Molecular epidemiology approach: nested case-control studies in glioma and lymphoid malignancies
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.ORCID iD: 0000-0002-0711-0830
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2019. , p. 53
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2016
Keywords [en]
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
National Category
Cancer and Oncology
Research subject
Epidemiology; Oncology
Identifiers
URN: urn:nbn:se:umu:diva-156421ISBN: 978-91-7855-025-8 (print)OAI: oai:DiVA.org:umu-156421DiVA, id: diva2:1288945
Public defence
2019-03-22, Bergasalen, byggnad 27, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2019-02-22 Created: 2019-02-14 Last updated: 2019-02-21Bibliographically approved
List of papers
1. Pre-diagnostic serum levels of EGFR and ErbB2 and genetic glioma risk variants: a nested case-control study
Open this publication in new window or tab >>Pre-diagnostic serum levels of EGFR and ErbB2 and genetic glioma risk variants: a nested case-control study
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2016 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, no 8, p. 11065-11072Article in journal (Refereed) 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.

Keywords
Glioma, SNP, Serum EGFR, Serum ErbB2, Pre-diagnostic
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-126327 (URN)10.1007/s13277-015-4742-y (DOI)000382672900107 ()26906551 (PubMedID)
Available from: 2016-11-01 Created: 2016-10-03 Last updated: 2019-02-14Bibliographically approved
2. Soluble B-cell activation marker of sCD27 and sCD30 and future risk of B-cell lymphomas: a nested case-control study and meta-analyses
Open this publication in new window or tab >>Soluble B-cell activation marker of sCD27 and sCD30 and future risk of B-cell lymphomas: a nested case-control study and meta-analyses
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2016 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 138, no 10, p. 2357-2367Article in journal (Refereed) Published
Abstract [en]

Pre-diagnostic serum/plasma concentrations of B-cell activation markers have been associated with future risk of B-cell lymphomas (BCL) in HIV-infected patients and in the general population. Current evidence for the general population is however limited and relies on relatively small numbers of observations, especially for specific histologies. We carried out a nested case-control study, including 218 BCL and 218 matched controls, within two prospective cohorts, to investigate the association between plasma levels of soluble (s)CD27 and sCD30 and future risk of BCL, and main histologic subtypes separately. To expand the evidence further, we performed meta-analyses of the published data on these associations from prospective studies among the general population. Our study revealed a significant relationship between sCD30 concentration and BCL risk (OR=0.86, 1.53, 1.76, for the 2(nd) -4(th) quartiles respectively, P-trend=0.01). Similar increased risks were observed for diffuse large B-cell lymphoma and follicular lymphoma. Analyses of sCD27 blood concentrations did not show significant associations with BCL, (OR=0.90, 1.26, 1.65 for the 2(nd) -4(th) quartiles, respectively, P-trend=0.17), but significant associations were observed for chronic lymphocytic leukaemia and for the group of 'other BCL' subtypes. Our findings involving sCD30 were confirmed within our meta-analyses of five prospective cohorts, while results were more heterogeneous for sCD27 with the exception of CLL which was found consistently in all studies. Data to date suggest that chronic B-cell stimulation might be an important mechanism involved in B-cell lymphomagenesis both in HIV-infected and in the general population.

Place, publisher, year, edition, pages
John Wiley & Sons, 2016
Keywords
lymphoma, sCD30, sCD27, meta-analyses, prospective study
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-116971 (URN)10.1002/ijc.29969 (DOI)000372257300006 ()26684261 (PubMedID)
Available from: 2016-02-16 Created: 2016-02-16 Last updated: 2019-02-14Bibliographically approved
3. Biomarker Dynamics in B-cell Lymphoma: A Longitudinal Prospective Study of Plasma Samples Up to 25 Years before Diagnosis
Open this publication in new window or tab >>Biomarker Dynamics in B-cell Lymphoma: A Longitudinal Prospective Study of Plasma Samples Up to 25 Years before Diagnosis
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2017 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 6, p. 1408-1415Article in journal (Refereed) Published
Abstract [en]

The B-cell activation markers CXCL13, sCD23, (S)CD27, and sCD30 are associated with future lymphoma risk. However, a lack of information about the individual dynamics of markerdisease association hampers interpretation. In this study, we identified 170 individuals who had donated two prediagnostic blood samples before B-cell lymphoma diagnosis, along with 170 matched cancer-free controls from the Northern Sweden Health and Disease Study. Lymphoma risk associations were investigated by subtype and marker levels measured at baseline, at the time of the repeated sample, and with the rate of change in the marker level. Notably, we observed strong associations between CXCL13, sCD23, sCD27, and sCD30 and lymphoma risk in blood samples collected 15 to 25 years before diagnosis. B-cell activation marker levels increased among future lympho-ma cases over time, while remaining stable among controls. Associations between slope and risk were strongest for indolent lymphoma subtypes. We noted a marked association of sCD23 with chronic lymphocytic leukemia (ORSlope - 28, Ptrend(-)7.279 x 10 (-10)). Among aggressive lymphomas, the association between diffuse large B-cell lymphoma risk and slope was restricted to CXCL13. B-cell activation seemed to play a role in B-cell lymphoma development at early stages across different subtypes. Furthermore, B-cell activation presented differential trajectories in future lymphoma patients, mainly driven by indolent subtypes. Our results suggest a utility of these markers in predicting the presence of early occult disease and/or the screening and monitoring of indolent lymphoma in individual patients. 

Place, publisher, year, edition, pages
American Association for Cancer Research, 2017
National Category
Cancer and Oncology Hematology
Identifiers
urn:nbn:se:umu:diva-140249 (URN)10.1158/0008-5472.CAN-16-2345 (DOI)000396845600015 ()28108506 (PubMedID)
Available from: 2017-10-17 Created: 2017-10-17 Last updated: 2019-02-20Bibliographically approved
4. Immune marker changes and risk of multiple myeloma: a nested case-control study using repeated prediagnostic blood samples
Open this publication in new window or tab >>Immune marker changes and risk of multiple myeloma: a nested case-control study using repeated prediagnostic blood samples
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Biomarkers reliably predicting progression to multiple myeloma (MM) are lacking. Myeloma risk has been associated with low blood levels of monocyte chemotactic protein-3 (MCP-3), macrophage inflammatory protein-1 alpha (MIP-1α), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), fractalkine, and transforming growth factor alpha (TGF-α). In this study, we aimed to replicate these findings and also study the individual dynamics of each marker in a prospective longitudinal cohort, thereby examining their potential as markers of myeloma progression. For this purpose, we identified 65 myeloma cases within the Northern Sweden Health and Disease Study as well as 65 individually matched controls, each with two donated blood samples. Samples from myeloma cases were donated in median 13 and 4 years prior to myeloma diagnosis. Known risk factors of progression were determined by protein-, and immunofixation electrophoresis, and free light chain assays. We observed lower levels of MCP-3, VEGF, FGF-2, fractalkine, and TGF-α in myeloma patients than in controls, consistent with previous data. We also observed that these markers decreased among future myeloma patients while remaining stable in controls. Decreasing trajectories were marked for TGF-α (P = 2.5 x 10-4) indicating progression to MM. Investigating this, we found that low levels of TGF-α assessed at time of the repeated sample were independently associated with risk of progression in a multivariable model (hazard ratio = 3.5; P = 0.003). TGF-α can potentially improve early detection of MM.

Keywords
prospective longitudinal study, multiple myeloma risk, progression, marker trajectories
National Category
Clinical Medicine
Research subject
Oncology; Cancer Epidemiology
Identifiers
urn:nbn:se:umu:diva-156420 (URN)
Funder
Swedish Research CouncilSwedish Cancer Society
Available from: 2019-02-14 Created: 2019-02-14 Last updated: 2019-05-10

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