Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers.
Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers.
复制标题
与端粒长度相关的常见遗传变异会增加患神经母细胞瘤和其他儿童癌症的风险。
DOI：
10.1093/carcin/bgw037
复制
发表时间：
2016
期刊：
影响因子：
4.7
通讯作者：
Wiemels,JosephL
中科院分区：
文献类型：
--
作者：
Walsh,KyleM;Whitehead,ToddP;deSmith,AdamJ;Smirnov,IvanV;Park,Minsun;Endicott,AlysonA;Francis,StephenS;Codd,Veryan;ENGAGEConsortiumTelomereGroup;Samani,NileshJ;Metayer,Catherine;Wiemels,JosephL
异常端粒延长是成人和儿童癌细胞的一个重要特征。除了体细胞突变外，端粒维持基因的种系多态性也会影响端粒长度。这些端粒相关的多态性是否影响儿童恶性肿瘤的风险仍未得到充分研究。我们收集了三组儿童恶性肿瘤的全基因组数据[神经母细胞瘤（N= 1516），急性淋巴细胞白血病（N= 958）和骨肉瘤（N= 660）]和三个对照人群（N= 6892）。通过病例对照比较，我们分析了在之前的全基因组关联研究中与白细胞端粒长度（LTL）个体间变异明确相关的基因中的8个单核苷酸多态性（snp）：ACYP2、TERC、NAF1、TERT、OBFC1、CTC1、znf208和rtel1。其中6个snp与神经母细胞瘤风险相关（P< 0.05）， 1个与白血病风险相关，1个与骨肉瘤风险相关。与较长的LTL相关的等位基因增加了所有这些显著相关snp的癌症风险。使用8个LTL相关snp的加权线性组合，我们观察到神经母细胞瘤患者的LTL比对照组更倾向于更长，基因典型估计LTL的每个标准差增加与神经母细胞瘤的几率增加1.15倍相关（95%CI = 1.09-1.22；P= 7.9×10−7）。这种效应在青少年发病的神经母细胞瘤患者中更为明显（OR = 1.46; 95%CI = 1.03-2.08）。基因典型估计LTL增加一个标准差与骨肉瘤风险（OR = 1.10; 95%CI = 1.01-1.19；P= 0.017）和白血病风险（OR = 1.07; 95%CI = 1.00-1.14；P= 0.044）的相关性更弱，特别是对于复发的白血病患者（OR = 1.19; 95%CI = 1.01-1.40；P= 0.043）。这些结果表明，延长LTL的遗传倾向是神经母细胞瘤和其他儿童癌症的一个新发现的危险因素。
Aberrant telomere lengthening is an important feature of cancer cells in adults and children. In addition to somatic mutations, germline polymorphisms in telomere maintenance genes impact telomere length. Whether these telomere-associated polymorphisms affect risk of childhood malignancies remains largely unexplored. We collected genome-wide data from three groups with pediatric malignancies [neuroblastoma (N= 1516), acute lymphoblastic leukemia (ALL) (N= 958) and osteosarcoma (N= 660)] and three control populations (N= 6892). Using case–control comparisons, we analyzed eight single nucleotide polymorphisms (SNPs) in genes definitively associated with interindividual variation in leukocyte telomere length (LTL) in prior genome-wide association studies:ACYP2,TERC,NAF1,TERT,OBFC1,CTC1,ZNF208andRTEL1. Six of these SNPs were associated (P< 0.05) with neuroblastoma risk, one with leukemia risk and one with osteosarcoma risk. The allele associated with longer LTL increased cancer risk for all these significantly associated SNPs. Using a weighted linear combination of the eight LTL-associated SNPs, we observed that neuroblastoma patients were predisposed to longer LTL than controls, with each standard deviation increase in genotypically estimated LTL associated with a 1.15-fold increased odds of neuroblastoma (95%CI = 1.09–1.22;P= 7.9×10−7). This effect was more pronounced in adolescent-onset neuroblastoma patients (OR = 1.46; 95%CI = 1.03–2.08). A one standard deviation increase in genotypically estimated LTL was more weakly associated with osteosarcoma risk (OR = 1.10; 95%CI = 1.01–1.19;P= 0.017) and leukemia risk (OR = 1.07; 95%CI = 1.00–1.14;P= 0.044), specifically for leukemia patients who relapsed (OR = 1.19; 95%CI = 1.01–1.40;P= 0.043). These results indicate that genetic predisposition to longer LTL is a newly identified risk factor for neuroblastoma and potentially for other cancers of childhood.
登录
查看更多内容
DOI：
10.1056/nejmoa1407279
发表时间：
2015-06-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Eckel-Passow JE;Lachance DH;Molinaro AM;Walsh KM;Decker PA;Sicotte H;Pekmezci M;Rice T;Kosel ML;Smirnov IV;Sarkar G;Caron AA;Kollmeyer TM;Praska CE;Chada AR;Halder C;Hansen HM;McCoy LS;Bracci PM;Marshall R;Zheng S;Reis GF;Pico AR;O'Neill BP;Buckner JC;Giannini C;Huse JT;Perry A;Tihan T;Berger MS;Chang SM;Prados MD;Wiemels J;Wiencke JK;Wrensch MR;Jenkins RB
通讯作者：
Jenkins RB
影响因子：
8.8
作者：
Chen X;Bahrami A;Pappo A;Easton J;Dalton J;Hedlund E;Ellison D;Shurtleff S;Wu G;Wei L;Parker M;Rusch M;Nagahawatte P;Wu J;Mao S;Boggs K;Mulder H;Yergeau D;Lu C;Ding L;Edmonson M;Qu C;Wang J;Li Y;Navid F;Daw NC;Mardis ER;Wilson RK;Downing JR;Zhang J;Dyer MA;St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project
通讯作者：
St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project
DOI：
10.1056/nejmoa1508054
发表时间：
2015-12-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Zhang J;Walsh MF;Wu G;Edmonson MN;Gruber TA;Easton J;Hedges D;Ma X;Zhou X;Yergeau DA;Wilkinson MR;Vadodaria B;Chen X;McGee RB;Hines-Dowell S;Nuccio R;Quinn E;Shurtleff SA;Rusch M;Patel A;Becksfort JB;Wang S;Weaver MS;Ding L;Mardis ER;Wilson RK;Gajjar A;Ellison DW;Pappo AS;Pui CH;Nichols KE;Downing JR
通讯作者：
Downing JR
影响因子：
3.8
作者：
Spinella JF;Cassart P;Garnier N;Rousseau P;Drullion C;Richer C;Ouimet M;Saillour V;Healy J;Autexier C;Sinnett D
通讯作者：
Sinnett D
影响因子：
--
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
通讯作者：
Wrensch MR