Dora Il'yasova

Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium.

Epidemiologists in the Brain Tumor Epidemiology Consortium (BTEC) have prioritized areas for further research. Although many risk factors have been examined over the past several decades, there are few consistent findings, possibly because of small sample sizes in individual studies and differences between studies in patients, tumor types, and methods of classification. Individual studies generally have lacked samples of sufficient size to examine interactions. A major priority based on available evidence and technologies includes expanding research in genetics and molecular epidemiology of brain tumors. BTEC has taken an active role in promoting understudied groups, such as pediatric brain tumors; the etiology of rare glioma subtypes, such as oligodendroglioma; and meningioma, which, although it is not uncommon, has only recently been registered systematically in the United States. There also is a pressing need for more researchers, especially junior investigators, to study brain tumor epidemiology. However, relatively poor funding for brain tumor research has made it difficult to encourage careers in this area. In this report, BTEC epidemiologists reviewed the groups consensus on the current state of scientific findings, and they present a consensus on research priorities to identify which important areas the science should move to address. Cancer 2008;113(7 suppl):1953–68.

Circulating Levels of Inflammatory Markers and Cancer Risk in the Health Aging and Body Composition Cohort

Background: Chronic inflammation is associated with processes that contribute to the onset or progression of cancer. This study examined the relationships between circulating levels of the inflammatory markers interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) and total as well as site-specific cancer incidence. Methods: Study subjects (n = 2,438) were older adults (ages 70-79 years) participating in the Health Aging and Body Composition study, who did not report a previous cancer diagnosis (except for nonmelanoma skin cancer) at baseline. Incident cancer events (n = 296) were ascertained during an average follow-up of 5.5 years. Inflammatory markers were measured in stored baseline fasting blood samples. Results: The adjusted hazard ratios (95% confidence intervals) for incident cancer associated with a 1-unit increase on the natural log-scale were 1.13 (0.94-1.37), 1.25 (1.09-1.43), and 1.28 (0.96-1.70) for IL-6, CRP, and TNF-α, respectively. Markers were more strongly associated with cancer death: hazard ratios were 1.63 (1.19-2.23) for IL-6, 1.64 (1.20-2.24) for CRP, and 1.82 (1.14-2.92) for TNF-α. Although precision was low for site-specific analyses, our results suggest that all three markers were associated with lung cancer, that IL-6 and CRP were associated with colorectal cancer, and that CRP was associated with breast cancer. Prostate cancer was not associated with any of these markers. Conclusions: These findings suggest that (a) the associations between IL-6, CRP, and TNF-α and the risk of cancer may be site specific and (b) increased levels of inflammatory markers are more strongly associated with the risk of cancer death than cancer incidence.

Urinary Biomarkers of Oxidative Status

Oxidative damage produced by reactive oxygen species (ROS) has been implicated in the etiology and pathology of many health conditions, including a large number of chronic diseases. Urinary biomarkers of oxidative status present a great opportunity to study redox balance in human populations. With urinary biomarkers, specimen collection is non-invasive and the organic/metal content is low, which minimizes the artifactual formation of oxidative damage to molecules in specimens. Also, urinary levels of the biomarkers present intergraded indices of redox balance over a longer period of time compared to blood levels. This review summarizes the criteria for evaluation of biomarkers applicable to epidemiological studies and evaluation of several classes of biomarkers that are formed non-enzymatically: oxidative damage to lipids, proteins, DNA, and allantoin, an oxidative product of uric acid. The review considers formation, metabolism, and exertion of each biomarker, available data on validation in animal and clinical models of oxidative stress, analytical approaches, and their intra- and inter-individual variation. The recommended biomarkers for monitoring oxidative status over time are F₂-isoprostanes and 8-oxodG. For inter-individual comparisons, F₂-isoprostanes are recommended, whereas urinary 8-oxodG levels may be confounded by differences in the DNA repair capacity. Promising urinary biomarkers include allantoin, acrolein-lysine, and dityrosine.

Germline mutations in shelterin complex genes are associated with familial glioma

Gliomas are the most common brain tumor, with several histological subtypes of various malignancy grade. The genetic contribution to familial glioma is not well understood. Using whole exome sequencing of 90 individuals from 55 families, we identified two families with mutations in POT1 (p.G95C, p.E450X), a member of the telomere shelterin complex, shared by both affected individuals in each family and predicted to impact DNA binding and TPP1 binding, respectively. Validation in a separate cohort of 264 individuals from 246 families identified an additional mutation in POT1 (p.D617Efs), also predicted to disrupt TPP1 binding. All families with POT1 mutations had affected members with oligodendroglioma, a specific subtype of glioma more sensitive to irradiation. These findings are important for understanding the origin of glioma and could have importance for the future diagnostics and treatment of glioma.

GLIOGENE—an International Consortium to Understand Familial Glioma

Evidence for familial aggregation of glioma has been documented in both case-control and cohort studies and occurs apart from the well-described rare inherited genetic syndromes involving glioma: neurofibromatosis type 1 and 2, tuberous sclerosis, Turcots syndrome, and Li-Fraumeni syndrome. Nonsyndromic glioma families have been studied but no genes have been identified in the two published linkage studies of familial glioma probably due to the small number of families. Because glioma is a rare but devastating cancer, and a family history of glioma has been observed in ∼5% of the cases, we initiated an international consortium to identify glioma families not affected by syndromes to better understand the inherited factors related to this disease. The international consortium GLIOGENE is an acronym for “glioma gene” and includes 15 research groups in North America, Europe, and Israel to study familial glioma. The overarching goal is to characterize genes in glioma families using a genome-wide single-nucleotide polymorphism approach and conducting linkage analysis to identify new genomic regions or loci that could harbor genes important for gliomagenesis. Here, we review the rationale for studying familial glioma and our proposed strategy for the GLIOGENE study. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1730–4)

Medical Diagnostic Radiation Exposures and Risk of Gliomas

Abstract High-dose ionizing radiation is an established risk factor for glioma, but it remains unknown whether moderate- and low-dose radiation increase glioma risk. In this analysis, we assessed the evidence that self-reported exposures to diagnostic ionizing radiation, including computerized tomography (CT) scans, is associated with increased risk of adult glioma. While no independent association was observed for CT scans alone (3+ scans compared to none P u200a=u200a 0.08 and 1–2 scans compared to none P u200a=u200a 0.68), our findings suggest an increased risk of adult gliomas with cumulative exposure to three or more CT scans to the head and neck region (OR u200a=u200a 1.97, 95% CI: 0.92–4.23) limited to those who reported a family history of cancer: the P value for the interaction between having three or more CT scans and family history of cancer was 0.08. The stratum-specific adjusted OR for those with family history of cancer was more than three times that for the sub-group without family history of cancer. While there is some potential for symptom-related bias, one might expect this to be present for all diagnostic procedures rather than specific to one procedure. The interaction between CT scans and glioma with family history of cancer supports the biological plausibility of our findings, because similar results have been found for breast cancer and radiation. This observational data will increase awareness about potential risks associated with CT scans and the need to minimize the use of unnecessary examinations.

Comparing the reliability of responses to telephone-administered versus self-administered Web-based surveys in a case-control study of adult malignant brain cancer.

Introduction: To determine whether a Web-based survey was an acceptable method of data collection for a clinic-based case-control study of adult brain cancer, the authors compared the reliability of paired responses to a main and resurvey for participants completing surveys by telephone (n = 74) or self-administered on the Web (n = 465) between 2003 and 2006. Methods: Recruitment of cases was done at the Evanston Northwestern Healthcare Kellogg Cancer Care Center and the Duke University Medical Center Cancer Control division, and controls were friends and siblings of cases. Twenty-five variables were examined, including smoking, oral contraceptive and residential histories, water sources, meat preparation, fruit and vegetable consumption, and pesticide use. Weighted and simple κs were estimated for categorical and binary variables, respectively. Results: The number of concordant paired responses was summed for use in linear regression. Respondents were 97% White and 85% had postsecondary education. Kappas for individual questions ranged from 0.31 (duration of residence in a single family house) to 0.96 (ever smoked), with a median of 0.57 (95% confidence interval, 0.47-0.64). The median number of concordant responses was 16.2 (range, 5-22). Reliability was greater for controls than cases, Web-based versus telephone responders, females, and higher-income responders. Frequency of e-mail and Internet use was not associated with reliability. Conclusions: A self-administered, Web-based survey was a feasible and appropriate mode of interview in this study. The comparable reliability of Web compared with telephone responses suggest that Web-based self-interviews could be a cost-effective alternative to traditional modes of interview. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2639–46)

Urinary Biomarkers of Oxidative Status in a Clinical Model of Oxidative Assault

Background: We used doxorubicin-based chemotherapy as a clinical model of oxidative assault in humans. Methods: The study recruited newly diagnosed breast cancer patients (n = 23). Urine samples were collected immediately before (T0) and at 1 hour (T1) and 24 hours (T24) after i.v. administration of treatment. Measurements included allantoin and the isoprostanes iPF(2α)-III, iPF(2α)-VI, and 8,12-iso-iPF(2α)-VI along with the prostaglandin 2,3-dinor-iPF(2α)-III, a metabolite of iPF(2α)-III. All biomarkers were quantified using liquid chromatography–tandem mass spectrometry. Results: In all subjects, the levels of the biomarkers increased at T1: allantoin by 22% (P = 0.06), iPF(2α)-III by 62% (P < 0.05), iPF(2α)-VI by 41% (P < 0.05), 8,12-iso-iPF(2α)-VI by 58% (P < 0.05), and 2,3-dinor-iPF(2α)-III by 52% (P < 0.05). At T24, the F2-isoprostanes returned to their baseline levels; the levels of allantoin continued to increase, although the T24-T0 difference was not statistically significant. Conclusions: These results indicate that urinary F2-isoprostanes are valid biomarkers and allantoin is a promising biomarker of oxidative status in humans. Impact: The levels of biomarkers change quickly in response to oxidative assault and can be used to monitor oxidative status in humans in response to treatments related either to generation of free radicals (chemotherapy and radiation therapy) or to antioxidants (inborn metabolic diseases and Down syndrome). Cancer Epidemiol Biomarkers Prev; 19(6); 1506–10. ©2010 AACR.

Branched-chain amino acids and insulin metabolism: The Insulin Resistance Atherosclerosis Study (IRAS)

OBJECTIVE Recent studies using untargeted metabolomics approaches have suggested that plasma branched-chain amino acids (BCAAs) are associated with incident diabetes. However, little is known about the role of plasma BCAAs in metabolic abnormalities underlying diabetes and whether these relationships are consistent across ethnic populations at high risk for diabetes. We investigated the associations of BCAAs with insulin sensitivity (SI), acute insulin response (AIR), and metabolic clearance of insulin (MCRI) in a multiethnic cohort. RESEARCH DESIGN AND METHODS In 685 participants without diabetes of the Insulin Resistance Atherosclerosis Study (IRAS) (290 Caucasians, 165 African Americans, and 230 Hispanics), we measured plasma BCAAs (sum of valine, leucine, and isoleucine) by mass spectrometry and SI, AIR, and MCRI by frequently sampled intravenous glucose tolerance tests. RESULTS Elevated plasma BCAAs were inversely associated with SI and MCRI and positively associated with fasting insulin in regression models adjusted for potential confounders (β = −0.0012 [95% CI −0.0018, −0.00059], P < 0.001 for SI; β = −0.0013 [95% CI −0.0018, −0.00082], P < 0.001 for MCRI; and β = 0.0015 [95% CI 0.0008, 0.0023], P < 0.001 for fasting insulin). The association of BCAA with SI was significantly modified by ethnicity, with the association only being significant in Caucasians and Hispanics. Elevated plasma BCAAs were associated with incident diabetes in Caucasians and Hispanics (multivariable-adjusted odds ratio per 1-SD increase in plasma BCAAs: 1.67 [95% CI 1.21, 2.29], P = 0.002) but not in African Americans. Plasma BCAAs were not associated with SI-adjusted AIR. CONCLUSIONS Plasma BCAAs are associated with incident diabetes and underlying metabolic abnormalities, although the associations were generally stronger in Caucasians and Hispanics.

Correlation between two markers of inflammation, serum C-reactive protein and interleukin 6, and indices of oxidative stress in patients with high risk of cardiovascular disease.

Abstract As evidence of the involvement of inflammation and oxidative damage in pathogenesis of age-related chronic diseases is growing, epidemiologists need to develop measures of both conditions to study their relationships in human populations. One way of searching for appropriate biomarkers is to examine correlations between different inflammatory markers and oxidative indices. We examined cross-sectional correlations between two inflammatory markers, serum C-reactive protein (CRP) and interleukin (IL)-6, and three oxidative indices, plasma levels of α-tocopherol and β-carotene, and urinary levels of 2,3-dinor-5,6-dihydro-15-F2t-isoprostane (F2-IsoP), in 60 individuals at high risk of cardiovascular disease. Correlations between the biomarkers were examined graphically and using the Pearson correlation coefficient. No correlation was found between plasma levels of α-tocopherol and either of the inflammatory markers. Plasma β-carotene inversely correlated with IL-6 (r=−0.46, p=0.0002) and CRP (r=−0.41, p=0.001). Although urinary F2-IsoP did not correlate with IL-6, this biomarker positively correlated with CRP (r=0.31, p=0.002). As only urinary F2-IsoP levels have been validated against known oxidative assaults, their positive association with CRP levels is interpreted as evidence of an interconnection between low-level inflammation and oxidative status. Urinary levels of F2-IsoP and serum levels of CRP represent appropriate biomarkers for future studies of inflammation and oxidative status in humans.