Nonsynonymous Coding Single-Nucleotide Polymorphisms Spanning the Genome in Relation to Glioblastoma Survival and Age at Diagnosis

Abstract

Purpose: Our aim was to discover possible inherited factors associated with glioblastoma age at diagnosis and survival. Although new genotyping technologies allow greatly expanded exploration of such factors, they pose many challenges. Experimental Design: In this pilot study, we (a) genotyped 112 newly diagnosed glioblastoma patients ascertained through a population-based study (group 1) with the ParAllele assay panel of f10,000 nonsynonymous coding single-nucleotide polymorphisms (SNP), (b) used several statistical and bioinformatic techniques to identify 17 SNPs potentially related to either glioblastoma age at diagnosis or survival, and (c) genotyped 16 of these SNPs using conventional PCR methods in an independent group of 195 glioblastoma patients (group 2). Results: In group 2, only one of the 16 SNPs, rs8057643 (located on 16p13.2), was significantly associated with glioblastoma age at diagnosis (nominal P = 0.0017; Bonferroni corrected P = 0.054). Median ages at diagnosis for those with 0, 1, or 2 Talleles were 66, 57, and 59 years in group 1and 64, 57, and 55 years in group 2 (combined P = 0.001). Furthermore, Cox regression analyses of time to death with number of Talleles adjusted for gender and patient group yielded a hazard ratio of 0.82 (95% confidence interval, 0.68-0.98; P = 0.03). Conclusions: Although limited by a relatively small sample size, this pilot study, using wellcharacterized, unambiguous disease characteristics, illustrates the necessity of independent replication owing to the likelihood of false positives. Several other challenges are discussed, including attempts to incorporate information on the potential functional importance of SNPs in genome-disease association studies.

New pattern of EGFR amplification in glioblastoma and the relationship of gene copy number with gene expression profile

“…Recent studies have been carried out on glioblastomas and different percentages of EGFR amplification have been detected. 7,17,18,38 Our results confirm an excess of EGFR copies in cases with a high-level of amplification. The SNP loci with copy-number changes were validated by qPCR.…”

“…15,16 Recent introduction of oligonucleotide microarrays designed for whole-genome genotyping of single nucleotide polymorphisms (SNPs) has facilitated the measurement of copy number changes at thousands of SNP loci. 17,18 We performed FISH analysis using an EGFR probe during metaphases of primary cultured cells and in paraffin sections from 40 cases of primary glioblastomas. The aim of this study was to investigate differences in the pattern of EGFR amplification in this tumor.…”

Epigenetic biomarkers of T-cells in human glioma

“…Details of subject ascertainment through the San Francisco regional populationbased registry's rapid case ascertainment program or the UCSF Neuro-oncology Clinic have been previously described. [50][51][52][53] Pertinent data for this analysis included age at histological diagnosis, gender, vital status, and survival time between diagnosis date and date of death for those deceased or between diagnosis date and date of last contact for those alive as well as cigarette smoking history and exposure to steroids, chemotherapy and/ or radiation therapy.…”

Pathway Analysis of Single-Nucleotide Polymorphisms Potentially Associated with Glioblastoma Multiforme Susceptibility Using Random Forests

“…Subject recruitment has been detailed previously (6,7). Briefly, eligible case subjects included incident adult (age >20 y) glioma cases diagnosed between August 1991 and April 1994 (series 1) and between May 1997 and August 1999 (series 2), who resided in six San Francisco Bay Area counties at the time of diagnosis.…”