Karami Sara, Han Younghun, Pande Mala, Cheng Iona, Rudd James, Pierce Brandon L, Nutter Ellen L, Schumacher Fredrick R, Kote-Jarai Zsofia, Lindstrom Sara, Witte John S, Fang Shenying, Han Jiali, Kraft Peter, Hunter David J, Song Fengju, Hung Rayjean J, McKay James, Gruber Stephen B, Chanock Stephen J, Risch Angela, Shen Hongbing, Haiman Christopher A, Boardman Lisa, Ulrich Cornelia M, Casey Graham, Peters Ulrike, Amin Al Olama Ali, Berchuck Andrew, Berndt Sonja I, Bezieau Stephane, Brennan Paul, Brenner Hermann, Brinton Louise, Caporaso Neil, Chan Andrew T, Chang-Claude Jenny, Christiani David C, Cunningham Julie M, Easton Douglas, Eeles Rosalind A, Eisen Timothy, Gala Manish, Gallinger Steven J, Gayther Simon A, Goode Ellen L, Grönberg Henrik, Henderson Brian E, Houlston Richard, Joshi Amit D, Küry Sébastien, Landi Mari T, Le Marchand Loic, Muir Kenneth, Newcomb Polly A, Permuth-Wey Jenny, Pharoah Paul, Phelan Catherine, Potter John D, Ramus Susan J, Risch Harvey, Schildkraut Joellen, Slattery Martha L, Song Honglin, Wentzensen Nicolas, White Emily, Wiklund Fredrik, Zanke Brent W, Sellers Thomas A, Zheng Wei, Chatterjee Nilanjan, Amos Christopher I, Doherty Jennifer A
Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH.
The Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH.
Int J Cancer. 2016 Dec 15;139(12):2655-2670. doi: 10.1002/ijc.30288. Epub 2016 Sep 8.
Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level p value cutoffs ≤3.08 × 10 ). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk.
端粒覆盖染色体末端，保护它们免受降解、双链断裂和端对端融合的影响。端粒由端粒酶维持，端粒酶是一种由TERT编码的逆转录酶，以及一种由TERC编码的RNA模板。TERT和相邻的CLPTM1L区域中的基因座与多种癌症的风险相关。因此，我们研究了22个端粒结构和维持基因区域中的变异与结直肠癌、乳腺癌、前列腺癌、卵巢癌和肺癌风险之间的关联。我们对61851例癌症病例和74457例欧洲血统对照中的204993个直接测量和推断的单核苷酸多态性（SNP）进行了基于子集的荟萃分析。使用顺序条件分析（基因水平p值截止≤3.08×10）确定SNP次要等位基因的独立关联。在观察到的与癌症风险相关的13个独立SNP中，有7个基因座有新发现。在DCLRE1B区域，rs974494和rs12144215分别与前列腺癌和肺癌以及结直肠癌、乳腺癌和前列腺癌呈负相关。在TERC区域，rs75316749与结直肠癌、乳腺癌、卵巢癌和肺癌呈正相关。在DCLRE1B区域，rs974404和rs12144215分别与前列腺癌和肺癌以及结直肠癌、乳腺癌和前列腺癌呈负相关。在POT1附近，rs116895242与结直肠癌、卵巢癌和肺癌呈负相关，而RTEL1 rs34978822与前列腺癌和肺癌呈负相关。跨癌症类型的端粒相关基因中的复杂关联模式可能为不同组织中端粒功能障碍影响癌症风险的机制提供见解。
