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Meta-Analysis
. 2016 Dec 15;139(12):2655-2670.
doi: 10.1002/ijc.30288. Epub 2016 Sep 8.

Telomere structure and maintenance gene variants and risk of five cancer types

Sara Karami  1 , Younghun Han  2 , Mala Pande  3 , Iona Cheng  4 , James Rudd  1 , Brandon L Pierce  5 , Ellen L Nutter  1 , Fredrick R Schumacher  6 , Zsofia Kote-Jarai  7 , Sara Lindstrom  8 , John S Witte  9 , Shenying Fang  10 , Jiali Han  11 , Peter Kraft  12 , David J Hunter  12 , Fengju Song  13 , Rayjean J Hung  14 , James McKay  15 , Stephen B Gruber  6 , Stephen J Chanock  16 , Angela Risch  17 , Hongbing Shen  18 , Christopher A Haiman  6 , Lisa Boardman  19 , Cornelia M Ulrich  20   21 , Graham Casey  6 , Ulrike Peters  21 , Ali Amin Al Olama  22 , Andrew Berchuck  23 , Sonja I Berndt  16 , Stephane Bezieau  24 , Paul Brennan  15 , Hermann Brenner  25 , Louise Brinton  16 , Neil Caporaso  16 , Andrew T Chan  26   27 , Jenny Chang-Claude  28 , David C Christiani  8 , Julie M Cunningham  19 , Douglas Easton  22   29 , Rosalind A Eeles  7 , Timothy Eisen  30 , Manish Gala  26 , Steven J Gallinger  14 , Simon A Gayther  6 , Ellen L Goode  19 , Henrik Grönberg  31 , Brian E Henderson  6 , Richard Houlston  32 , Amit D Joshi  12 , Sébastien Küry  24 , Mari T Landi  16 , Loic Le Marchand  33 , Kenneth Muir  34   35 , Polly A Newcomb  21 , Jenny Permuth-Wey  36 , Paul Pharoah  29 , Catherine Phelan  36 , John D Potter  21 , Susan J Ramus  6 , Harvey Risch  37 , Joellen Schildkraut  38 , Martha L Slattery  20 , Honglin Song  29 , Nicolas Wentzensen  16 , Emily White  21 , Fredrik Wiklund  31 , Brent W Zanke  39 , Thomas A Sellers  36 , Wei Zheng  40 , Nilanjan Chatterjee  16 , Christopher I Amos  2 , Jennifer A Doherty  41 ; GECCO and the GAME-ON Network: CORECT, DRIVE, ELLIPSE, FOCI, and TRICL
Affiliations
Meta-Analysis

Telomere structure and maintenance gene variants and risk of five cancer types

Sara Karami et al. Int J Cancer. .

Abstract

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 × 10-5 ). 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.

Keywords: GWAS; breast cancer; cancer risk; colorectal cancer; lung cancer; meta-analysis; ovarian cancer; prostate cancer; telomere maintenance; telomere structure.

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Conflict of interest statement

Author’s disclosures of potential conflicts of interest: non for all authors.

Figures

Figure 1
Figure 1. Unconditional ASSET forest plots by cancer type and subtype for TERC SNPs rs80304993, rs62293480, and rs75316749
(A) Forest plot associations for the A allele for rs80304993. (B) Forest plot associations for the T allele for rs62293480. (C) Forest plot associations for the G allele for rs75316749.
Figure 2
Figure 2. Unconditional ASSET forest plots by cancer type and subtype for TERT-CLPTM1L SNPs rs37004, rs7717443, rs10866498, rs12655062, rs115960372, and rs2736098
(A) Forest plot associations for the T allele for rs37004. (B) Forest plot associations for the T allele for rs7717443. (C) Forest plot associations for the T allele for rs10866498. (D) Forest plot associations for the A allele for rs12655062. (E) Forest plot associations for the T allele for rs115960372. (F) Forest plot associations for the T allele for rs2736098.
Figure 3
Figure 3. Unconditional ASSET forest plots by cancer type and subtype for DCLRE1B SNPs rs974404 and rs12144215
(A) Forest plot associations for the G allele for rs974404. (B) Forest plot associations for the T allele for rs12144215.
See this image and copyright information in PMC

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