To address the great need for improved therapies for adult glioma, this project will evaluate molecular features of tumor tissue, serologic immune factors and genetic polymorphisms as biomarkers of patient surival. The proposed studies are additions to ongoing recruitment of patients in a 16 year R01 funded population-based case control study and 5 years of SPORE funded clinic-based research in the UCSF Neuro-oncology Clinic (NOC). Together these sources provide among the country s largest datasets of well-characterized adult glioma patients with polymorphism, serologic, tumor marker, demographic and other epidemiologic, treatment, and survival data. We will continue to determine vital status and relevant treatment information for population based adult onset glioma cases diagnosed 1997-99 and 2001-04 and patients accrued through the UCSF NOC 2002-2006 (total number ~1500) and (b) accrue ~720 patients (questionnaire, blood, buccal, and tumor specimens) in the UCSF NOC 2007-2011. (Another population based series to begin May 2006 will bring the total number of patients diagnosed from 2006-2011 to ~960). Several biomarkers identified in our ongoing and other studies warrant further research.
In Aims 1, 2 of this proposal we will obtain a greater understanding of the mechanisms of improved survival among glioblastoma cases with elevated versus normal or borderline serum IgE levels observed in our current series and validate and expand findings to other potentially related serum markers (sCD23 and sCD14), tumor markers (CD23 protein and IL13RA2 mRNA expression), and constitutive SNPs in IL4, IL13, IL4R, IL13RA1, and IL13RA2. These markers will also be assessed in relation to tumor TP53 mutation and expression and EGFR amplification and expression (markers measured in the parent R01 study).
In Aim 3 we will determine whether polymorphisms in MGMT or tumor TP53 mutation or expression influence survival in the presence or absence of tumor MGMT methylation in patients treated or not treated with temozolomide.
In Aim 4 we will validate promising markers obtained from Aims 2 and 3 in newly diagnosed patients seen at the UCSF NOC from July 1, 2007-June 30, 2011 in ~120 of these GM cases on clinical trial protocols. Identification of predictive biomarkers related glioma survival is likely to aid in choosing the best treatments for each glioma patient, in enhancing definition of homogeneous subgroups for clinical trials based on uniform prognosis for rapid treatment evaluation, and in providing better prognostic information to patients.
The proposed study will help identify markers that may be useful in the treatment of adult glioma brain tumors. Specific therapies may be more effective in some patient groups that display specific genetic, immulogical, and tumor characteristics. The relevance of individualizing brain tumor treatment to public health and cancer medicine lies in sparing patients ineffective and potentially toxic therapies while guideing newer experimental treatments to those patients who may benefit the most from such interventions.
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|Andersson, Ulrika; Wibom, Carl; Cederquist, Kristina et al. (2014) Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer. Neuro Oncol 16:1333-40|
|Walsh, Kyle M; Codd, Veryan; Smirnov, Ivan V et al. (2014) Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk. Nat Genet 46:731-5|
|Walsh, K M; Chokkalingam, A P; Hsu, L-I et al. (2013) Associations between genome-wide Native American ancestry, known risk alleles and B-cell ALL risk in Hispanic children. Leukemia 27:2416-9|
|Koestler, Devin C; Christensen, Brock; Karagas, Margaret R et al. (2013) Blood-based profiles of DNA methylation predict the underlying distribution of cell types: a validation analysis. Epigenetics 8:816-26|
|Zheng, Shichun; Houseman, E Andres; Morrison, Zachary et al. (2011) DNA hypermethylation profiles associated with glioma subtypes and EZH2 and IGFBP2 mRNA expression. Neuro Oncol 13:280-9|
|Christensen, Brock C; Smith, Ashley A; Zheng, Shichun et al. (2011) DNA methylation, isocitrate dehydrogenase mutation, and survival in glioma. J Natl Cancer Inst 103:143-53|
|Shete, Sanjay; Lau, Ching C; Houlston, Richard S et al. (2011) Genome-wide high-density SNP linkage search for glioma susceptibility loci: results from the Gliogene Consortium. Cancer Res 71:7568-75|
|Christensen, Brock C; Kelsey, Karl T; Zheng, Shichun et al. (2010) Breast cancer DNA methylation profiles are associated with tumor size and alcohol and folate intake. PLoS Genet 6:e1001043|
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