Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk.
Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk.
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DOI：
10.18632/oncotarget.6468
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发表时间：
2015-12-15
期刊：
影响因子：
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通讯作者：
Wrensch MR
中科院分区：
文献类型：
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作者：
Walsh KM;Codd V;Rice T;Nelson CP;Smirnov IV;McCoy LS;Hansen HM;Elhauge E;Ojha J;Francis SS;Madsen NR;Bracci PM;Pico AR;Molinaro AM;Tihan T;Berger MS;Chang SM;Prados MD;Jenkins RB;Wiemels JL;ENGAGE Consortium Telomere Group;Samani NJ;Wiencke JK;Wrensch MR
端粒维持已成为影响成人脑胶质瘤易感性和预后的重要分子特征。白细胞端粒长度(LTL)是否较长或较短与神经胶质瘤的风险有关仍不清楚，而且常常被年龄和患者治疗的影响所混淆。我们试图确定基因类型估计的LTL是否与胶质瘤风险相关，以及与LTL相关的遗传单核苷酸多态(SNPs)是否是胶质瘤风险因素。使用孟德尔随机化方法，我们评估了来自加州大学旧金山分校成人胶质瘤研究(652名患者和3735名对照)和癌症基因组图谱(478名非重叠患者和2559名对照)的两个独立的胶质瘤病例对照数据集中基因估计的相对LTL的差异。LTL估计是基于8个SNP的受试者基因型的加权线性组合，以前在Engage Consortium端粒项目中与LTL相关。在发现分析中，胶质瘤患者的平均估计LTL比对照组长31bp(5.7%)(P=7.82×10-8)，在复制分析中，胶质瘤患者比对照组(1.48×10-3)长27bp(5.0%)。随着LTL间隔的增加，胶质瘤风险单调增加(OR值=1.12；P=3.83×10-12)。在合并分析中，4个LTL相关SNP与胶质瘤的风险显著相关，包括端粒酶成分基因TERC(O.R.=1.14；95%C.I.=1.03-1.28)和TERT(O.R.=1.39；95%C.I.=1.27-1.52)，以及CST复合基因OBFC1(O.R.=1.18；95%C.I.=1.05-1.33)和CTC1(O.R.=1.14；95%C.I.=1.02-1.28)。未来还需要进一步研究CST复合体在胶质瘤发生中的作用，并进一步阐明衰老、端粒长度和分子致癌之间的复杂平衡。
Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82×10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48×10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83×10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis.