Genetic risk variants in the CDKN2A/B, RTEL1 and EGFR genes are associated with somatic biomarkers in glioma.
Genetic risk variants in the CDKN2A/B, RTEL1 and EGFR genes are associated with somatic biomarkers in glioma.
复制标题
DOI：
10.1007/s11060-016-2066-4
复制
发表时间：
2016-05
影响因子：
3.9
通讯作者：
Melin B
中科院分区：
文献类型：
--
作者：
Ghasimi S;Wibom C;Dahlin AM;Brännström T;Golovleva I;Andersson U;Melin B
在过去的几年中，全基因组关联研究发现了与特定胶质瘤亚型相关的常见生殖系遗传变异。我们的目的是研究这些生殖系风险变异和肿瘤表型之间的关联，包括拷贝数畸变和蛋白质表达。共纳入91例胶质瘤患者。选择了13种已知的TERT、EGFR、CCDC 26、CDKN 2A、CDKN 2B、PHLDB 1、TP 53和RTEL 1基因的遗传风险变异，用于研究与胶质瘤体细胞标志物的可能相关性：EGFR扩增、1 p/19 q共缺失和p53、Ki-67和突变IDH 1的蛋白表达。CDKN 2 A/B风险变体rs 4977756和CDKN 2 B风险变体rs 1412829与突变IDH 1的缺乏呈负相关（分别为p = 0.049和p = 0.002），即，大多数危险等位基因纯合子患者显示突变IDH 1无表达或低表达。RTEL 1风险变体rs6010620与没有1 p/19 q共缺失相关（p = 0.013），即，大多数危险等位基因纯合子患者没有显示1 p/19 q共缺失。此外，EGFR风险变体rs 17172430和CDKN 2B风险变体rs 1412829均显示与EGFR拷贝数增加相关的趋势（分别为p = 0.055和p = 0.051），即，大多数危险等位基因纯合子患者显示EGFR的染色体获得或扩增。我们的研究结果表明，CDKN 2A/B风险基因型与无IDH突变的原发性胶质母细胞瘤相关，RTEL 1风险基因型与1 p/19 q共缺失之间存在负相关，表明这些遗传变异对高级别脑肿瘤的发生具有分子影响。基因型与体细胞遗传畸变之间的关系还需要进一步的实验研究来阐明。本文的在线版本（doi：10.1007/s11060-016-2066-4）包含补充材料，可供授权用户使用。
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, Ki-67, and mutated IDH1. The CDKN2A/B risk variant, rs4977756, and the CDKN2B risk variant, rs1412829 were inversely associated (p = 0.049 and p = 0.002, respectively) with absence of a mutated IDH1, i.e., 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 = 0.013) with not having 1p/19q codeletion, i.e., 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 = 0.055 and p = 0.051, respectively) with increased EGFR copy number, i.e., 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 aberrations. The online version of this article (doi:10.1007/s11060-016-2066-4) contains supplementary material, which is available to authorized users.