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Polymorphisms in Apoptosis and Cell Cycle Control Genes and Risk of Brain Tumors in Adults

¹ Division of Cancer Epidemiology and Genetics, ² Core Genotyping Facility, ³ Neuro-oncology Branch, and ⁴ Pediatric Oncology Branch, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland; ⁵ Department of Neurosurgery, Brigham and Women's Hospital and ⁶ Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts; ⁷ Division of Neurosurgery, Western Pennsylvania Hospital, Pittsburgh, Pennsylvania; and ⁸ Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona

Requests for reprints: Preetha Rajaraman, REB, National Cancer Institute, NIH, Department of Health and Human Services, EPS Room 7085, 6120 Executive Boulevard, Bethesda, MD 20892-7238. Phone: 301-496-8847; Fax: 301-402-0207. E-mail: rajarama{at}mail.nih.gov

Despite the potential importance of the cell cycle and apoptosis pathways in brain tumor etiology, little has been published regarding brain tumor risk associated with common gene variants in these pathways. Using data from a hospital-based case-control study conducted by the National Cancer Institute between 1994 and 1998, we evaluated risk of glioma (n = 388), meningioma (n = 162), and acoustic neuroma (n = 73) with respect to 12 single nucleotide polymorphisms from 10 genes involved in apoptosis and cell cycle control: CASP8, CCND1, CCNH, CDKN1A, CDKN2A, CHEK1, CHEK2, MDM2, PTEN, and TP53. We observed significantly decreased risk of meningioma with the CASP8 Ex14-271A>T variant [odds ratio (OR)_AT, 0.8; 95% confidence interval (95% CI), 0.5-1.2; OR_AA, 0.5; 95% CI, 0.3-0.9; P_trend = 0.03] and increased risk of meningioma with the CASP8 Ex13+51G>C variant (OR_GC, 1.4; 95% CI, 0.9-2.1; OR_CC, 3.6; 95% CI, 1.0-13.1; P_trend = 0.04). The CT haplotype of the two CASP8 polymorphisms was associated with significantly increased risk of meningioma (OR, 1.7; 95% CI, 1.1-2.6), but was not associated with risk of glioma or acoustic neuroma. The CCND1 Ex4-1G>A variant was associated with increased risk for glioma, and the Ex8+49T>C variant of CCNH was associated with increased risk of glioma and acoustic neuroma. The MDM2 Ex12+162A>G variant was associated with significantly reduced risk of glioma. Our results suggest that common variants in the CASP8, CCND1, CCNH, and MDM2 genes may influence brain tumor risk. Future research in this area should include more detailed coverage of genes in the apoptosis/cell cycle control pathways. (Cancer Epidemiol Biomarkers Prev 2007;16(8):1655–61)

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