Neuroepidemiology Program

Epidemiology–the study of the incidence, distribution, causes, and control of disease in a population–is a valuable counterpart to the clinical and basic science research being performed in the Department of Neurological Surgery. Despite decades of research into the potential causes of brain tumors, there are few known factors predictive of developing this terrible disease. Prior to the advent of new molecular techniques for characterizing tumors, researchers were unable to classify tumors into homogenous groups according to the genetic and epigenetic modifications in the cells that are responsible for tumor formation.

Epidemiological research can also provide insight in the area of brain tumor treatment. As brain tumors are relatively rare, and tumors that seem histologically identical can exhibit substantial variation in terms of progression, recurrence, and response to therapy, it is often difficult to predict the effectiveness of a specific treatment without large, well-characterized population samples. Specialists in neuroepidemiology provide the expertise needed to examine patterns of disease in the overall population.

Current Research Projects

Biomarker Development & Application in Brain Tumor Etiology
Principal Investigator: John Wiencke PhD

Genetic, molecular, and immunologic markers appiled in populations of brain tumor patients and controls provide insight into the causes of these neoplasms and new approaches to treatment. The laboratory of John Wiencke PhD collaborates on studies aimed at understanding the causes of adult and pediatric glioma and meningioma. Common genetic variants identified through the Humman Genome Project are being examined in large case-control studies to discover potential genetic factors in brain tumorigenesis.

Molecular alterations in tumor cells that are acquired during cancer formation are being studied to form more homogeneous subgroups of patients for both etiologic and clinical investigations. The laboratory tests for TP53 mutations, EGFR overexpression and amplification, and aberrant DNA methylation of a variety of genes, including the MGMT gene important in patients' response to alkylation therapy. Immune parameters and novel immune-related biomarkers that target the atopic division of the immune response are under development.

Sereological markers under developmnet include serum IgE, cytokines, serum CD23, CD14, and IL13RA2. Tumor-associated CD23 and IL13RA2 are being measured by immunohistochemistry and quantatative RT-PCR. Immune parameters may help identify patient groups who will respond differently to standard treatments and provide new avenues for developing immune-related treatments in the future.

Genetic & Molecular Epidemiology of Adult Glioma
Principal Investigator: Margaret Wrensch MPH, PhD

Since 1991, Margaret Wrensch, MPH, PhD, has been principal investigator for the ongoing San Francisco Bay Area Adult Glioma Study. Current studies in her laboratory focus on (1) the role of inherited genetic variation in glioma etiology and prognosis using large-scale genotyping platforms and incorporating information on tumor markers, questionnaire, diagnostic, and treatment data; and (2) extending and understanding our and others observations of the inverse associations of glioma with allergies, IgE, and immune function genes. These studies also contribute data to large collaborative studies organized through the Brain Tumor Epidemiology Consortium and the Wrensch laboratory participates in the newly funded international brain tumor family linkage study, Gliogene.

Published findings from ongoing studies include statistically significant or marginally significant associations of adult-onset glioma with family history of brain cancer, lower prevalence of IgG antibodies to varicella-zoster virus (replicated in an independent series of cases and controls), decreased history of allergies and decreased prevalence of IgE antibodies, increased consumption of cured meats in conjunction with decreased consumption of fruits and vegetables rich in vitamin C, decreased consumption of dietary calcium among female cases, increased years of smoking unfiltered cigarettes, and decreased consumption of non-steroidal anti-inflammatory drugs.

Dr. Wrensch and her colleagues have investigated inherited variation in a variety of candidate genes involved in DNA repair, carcinogen metabolism and immune function. They have shown that glioma survival is associated with several tumor and patient characteristics. As observed in some clinical series, tumor marker studies have confirmed the substantial molecular heterogeneity of tumor types even among those of similar histology. The Wrensch laboratory has demonstrated that tumor molecular characteristics within histological types are related to patient characteristics such as ethnicity and age, as well as to constitutive polymorphisms in methyl guanine methyl transferase. They continue to categorize the molecular pathology of tumors according to the presence or absence of p53 modifications and other genetic and protein alterations in efforts to define more etiologically homogeneous subgroups. They have also shown that residential exposures seven years prior to diagnosis to electromagnetic fields as measured by wire-codes and spot measurements did not differ among adult glioma cases and controls. They have not found important differences among cases and controls with respect to prior head injury or exposure to diagnostic x-rays. In addition to her work on glioma, Dr. Wrensch is co-investigator for a meningioma study focusing on risk factors and quality of life.

Molecular Neuroepidemiology
Principal Investigator: Shichun Zheng MD

The laboratory of Shichun Zheng MD investigates molecular cancer epidemiology, including genetic and epigenetic mechanisms in human cancers, as well as development of new research approaches for molecular epidemiological studies of cancer in different populations. In cancer cells, DNA methylation patterns are severely dysregulated and characterized by overall hypomethylation and paradoxical CpG island hypermethylation, which is associated with transcriptional inactivation of tumor suppressor genes. Dr. Zheng has been applying not only commonly used techniques, such as methylation-specific PCR and quantitative methylation-specific PCR, but also a large-scale integrated approach, involving chromatin immunoprecipitation microarray (ChIP-chip), to gain insight into the relative contribution of this epigenetic mechanism in the formation of human brain tumors. In addition to epigenetic mechanisms, Dr. Zheng has been utilizing expression microarray (gene chip) to study gene expression profile and its relationship with histological classes, age, survival, and other factors.