Genetic risk variants in the Emphasis Type="Itali

Authors: Soma Ghasimi Carl Wibom Anna M Dahlin Thomas Brännström Irina Golovleva Ulrika Andersson Beatrice Melin

Publish Date: 2016/02/02

Volume: 127, Issue: 3, Pages: 483-492

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Abstract

During the last years genome wide association studies have discovered common germline genetic variants associated with specific glioma subtypes We aimed to study the association between these germline risk variants and tumor phenotypes including copy number aberrations and protein expression A total of 91 glioma patients were included Thirteen well known genetic risk variants in TERT EGFR CCDC26 CDKN2A CDKN2B PHLDB1 TP53 and RTEL1 were selected for investigation of possible correlations with the glioma somatic markers EGFR amplification 1p/19q codeletion and protein expression of p53 Ki67 and mutated IDH1 The CDKN2A/B risk variant rs4977756 and the CDKN2B risk variant rs1412829 were inversely associated p = 0049 and p = 0002 respectively with absence of a mutated IDH1 ie the majority of patients homozygous for the risk allele showed no or low expression of mutated IDH1 The RTEL1 risk variant rs6010620 was associated p = 0013 with not having 1p/19q codeletion ie the majority of patients homozygous for the risk allele did not show 1p/19q codeletion In addition the EGFR risk variant rs17172430 and the CDKN2B risk variant rs1412829 both showed a trend for association p = 0055 and p = 0051 respectively with increased EGFR copy number ie the majority of patients homozygote for the risk alleles showed chromosomal gain or amplification of EGFR Our findings indicate that CDKN2A/B risk genotypes are associated with primary glioblastoma without IDH mutation and that there is an inverse association between RTEL1 risk genotypes and 1p/19q codeletion suggesting that these genetic variants have a molecular impact on the genesis of high graded brain tumors Further experimental studies are needed to delineate the functional mechanism of the association between genotype and somatic genetic aberrationsGlioma includes several subtypes Traditionally they have been classified solely on histopathological features though classification is currently changing towards accounting for molecular markers as well 1 Previous studies have indicated that subtypes of glioma display separate molecular and genetic profiles resulting from their separate etiologic pathways The somatic mutations and aberrations are sometimes correlated 2 such as the link between IDH1 mutation and 1p/19q codeletion in low grade glioma 3 4 5 Some of these markers like IDH1 mutation and MGMT methylation have diagnostic value and are useful prognostic and predictive factors relating to patient survival and response to treatment 6 7 8 9 10 1p/19q codeletion is thought to be a distinguishing feature for oligodendroglioma and TP53 mutations for astrocytoma and even though they are not mutually exclusive they are a clear support in the diagnostic classification 11 IDH1 mutations are known as an important diagnostic marker especially for low graded tumors and secondary glioblastoma 12 13 In combination with loss of nuclear ATRX expression IDH1 1p/19q and TERT promoter mutations define the most frequent type of infiltrative astrocytoma 14 15 while mutations in the EGFR gene seen in 35  of all cases of glioblastoma are associated with primary glioblastoma 16 In several of these genes that typically harbor somatic mutations in glioma genome wide association studies GWAS have discovered common germline variants that are associated with risk of developing glioma including variants in EGFR CDKN2A TERT and TP53 17 18 19 20 21 22 Furthermore germline variants at 8q2421 are known to be associated with oligodendroglial tumors and astrocytoma with mutated IDH1 or IDH2 23 Several single nucleotide polymorphisms SNPs have also been shown to associate with tumor grade Variants in CDKN2B and RTEL1 are strongly associated with highgrade glioma while variants in CCDC26 and PHLDB1 are associated with lowgrade glioma 18 24To investigate whether germline genetic risk variants are linked to specific molecular characteristics of the tumor we selected 13 glioma risk variants established in the previous studies mainly GWAS Supplementary Table 1 and studied their correlation with the glioma somatic biomarkers EGFR alteration 1p/19q codeletion IDH1 mutation p53 and Ki67 protein expression We used immunohistochemistry IHC and fluorescence in situ hybridization FISH analyses to assess the biomarkers In addition FISH results were compared with the results from one of our previous studies where somatic copy number data were calculated from SNP array 25 profiles to explore if the different methods can detect similar genetic aberrations

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