title: A comprehensive study of the association between the EGFR and ERBB2 genes and glioma risk.
abstract: Glioma is the most common type of adult brain tumor and glioblastoma, its most aggressive form, has a dismal prognosis. Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR, ERBB2, ERBB3, ERBB4) family, and the vascular endothelial growth factor receptor (VEGFR), play a central role in tumor progression. We investigated the genetic variants of EGFR, ERBB2, VEGFR and their ligands, EGF and VEGF on glioma and glioblastoma risk. In addition, we evaluated the association of genetic variants of a newly discovered family of genes known to interact with EGFR: LRIG2 and LRIG3 with glioma and glioblastoma risk. Methods. We analyzed 191 tag single nucleotide polymorphisms (SNPs) capturing all common genetic variation of EGF, EGFR, ERBB2, LRIG2, LRIG3, VEGF and VEGFR2 genes. Material from four case-control studies with 725 glioma patients (329 of who were glioblastoma patients) and their 1 610 controls was used. Haplotype analyses were conducted using SAS/Genetics software. Results. Fourteen of the SNPs were significantly associated with glioma risk at p< 0.05, and 17 of the SNPs were significantly associated with glioblastoma risk at p< 0.05. In addition, we found that one EGFR haplotype was related to increased glioblastoma risk at p=0.009, Odds Ratio [OR] = 1.67 (95% confidence interval (CI): 1.14, 2.45). The Bonferroni correction made all p-values non-significant. One SNP, rs4947986 next to the intron/exon boundary of exon 7 in EGFR, was validated in an independent data set of 713 glioblastoma and 2 236 controls, [OR] = 1.42 (95% CI: 1.06,1.91). Discussion. Previous studies show that regulation of the EGFR pathway plays a role in glioma progression but the present study is the first to find that certain genotypes of the EGFR gene may be related to glioblastoma risk. Further studies are required to reinvestigate these findings and evaluate the functional significance.
authors.affiliation: Department of Radiation Sciences, Oncology, Umeå University Hospital, Umeå, Sweden. Ulrika.andersson@onkologi.umu.se
authors.forename: Ulrika
authors.initials: U
authors.lastname: Andersson
authors.forename: Judith
authors.initials: J
authors.lastname: Schwartzbaum
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wiklund
authors.forename: Sara
authors.initials: S
authors.lastname: Sjöström
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Spyros
authors.initials: S
authors.lastname: Tsavachidis
authors.forename: Anders
authors.initials: A
authors.lastname: Ahlbom
authors.forename: Anssi
authors.initials: A
authors.lastname: Auvinen
authors.forename: Helle
authors.initials: H
authors.lastname: Collatz-Laier
authors.forename: Maria
authors.initials: M
authors.lastname: Feychting
authors.forename: Christoffer
authors.initials: C
authors.lastname: Johansen
authors.forename: Anne
authors.initials: A
authors.lastname: Kiuru
authors.forename: Stefan
authors.initials: S
authors.lastname: Lönn
authors.forename: Minouk J
authors.initials: MJ
authors.lastname: Schoemaker
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Swerdlow
authors.forename: Roger
authors.initials: R
authors.lastname: Henriksson
authors.forename: Melissa
authors.initials: M
authors.lastname: Bondy
authors.forename: Beatrice
authors.initials: B
authors.lastname: Melin
mesh_terms: D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D003718:Denmark; D004739:England; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005387:Finland; D005838:Genotype; D005910:Glioma / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D013548:Sweden
chemical_list: D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human