title: Genetic polymorphisms in telomere pathway genes, telomere length, and breast cancer survival.
abstract: The impact of genetic variants in telomere pathway genes on telomere length and breast cancer survival remains unclear. We hypothesized that telomere length and genetic variants of telomere pathway genes are associated with survival among breast cancer patients. A population-based cohort study of 1,026 women diagnosed with a first primary breast cancer was conducted to examine telomere length and 52 genetic variants of 9 telomere pathway genes. Adjusted Cox regression analysis was employed to examine associations between telomere length, genetic variants and all-cause and breast cancer-specific mortality. Longer telomere length was significantly correlated with all-cause mortality in the subgroup with HER-2/neu negative tumors (HR=1.90, 95% CI: 1.12-3.22). Carrying the PINX1-33 (rs2277130) G-allele was significantly associated with increased all-cause mortality (HR=1.45, 95% CI: 1.06-1.98). Three SNPs (TERF2-03 rs35439397, TERT-14 rs2853677, and TERT-67 rs2853669) were significantly associated with reduced all-cause mortality. A similar reduced trend for breast cancer-specific mortality was observed for carrying the TERT-14 (rs2853677) T-allele (HR=0.57, 95% CI: 0.39-0.84), while carrying the POT1-18 (rs1034794) T-allele significantly increased breast cancer-specific mortality (HR=1.48, 95% CI: 1.00-2.19). However, none of the associations remained significant after correction for multiple tests. A significant dose-response effect was observed with increased number of unfavorable alleles/genotypes (PINX1-33 G-allele, POT1-18 T-allele, TERF2-03 GG, TERT-14 CC, and TERT-67 TT genotypes) and decreased survival. These data suggest that unfavorable genetic variants in telomere pathway genes may help to predict breast cancer survival.
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 650 West 168th Street, Black Building 1608, New York, NY 10032, USA. js2182@columbia.edu
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.forename: Marilie D
authors.initials: MD
authors.lastname: Gammon
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Terry
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Bradshaw
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wang
authors.forename: Susan L
authors.initials: SL
authors.lastname: Teitelbaum
authors.forename: Alfred I
authors.initials: AI
authors.lastname: Neugut
authors.forename: Regina M
authors.initials: RM
authors.lastname: Santella
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018797:Cell Cycle Proteins; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D009361:Neoplasm Invasiveness; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D017422:Sequence Analysis, DNA; D000089804:Shelterin Complex; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000235:genetics*; D034501:Telomere-Binding Proteins / Q000235:genetics; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C440808:PINX1 protein, human; C440849:POT1 protein, human; D000089804:Shelterin Complex; C504753:TERF2 protein, human; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; D025521:Tumor Suppressor Proteins; C509186:TERT protein, human; D019098:Telomerase