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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2016, Vol. 10 Issue (2) : 191-203     DOI: 10.1007/s11684-016-0450-2
RESEARCH ARTICLE |
Association between telomere length and survival in cancer patients: a meta-analysis and review of literature
Xinsen Xu,Kai Qu,Qing Pang,Zhixin Wang,Yanyan Zhou,Chang Liu()
Department of Hepatobiliary Surgery, the First Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an 710061, China
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Abstract  

The relationship between telomere length and cancer survival has been widely studied. To gain a deeper insight, we reviewed the published studies. A total of 29 studies evaluated telomere length in the peripheral blood; 22 studies evaluated telomere length in the tumor tissue. First, in the peripheral blood studies, for solid tumor patients with shortened telomere length, the combined hazard ratios (HRs) for mortality and tumor progression were 1.21 (95%CI, 1.10–1.32) and 1.71 (95%CI, 1.37–2.13), respectively. Meanwhile, in hematology malignancy, the combined HRs for mortality and tumor progression were 2.83 (95%CI, 2.14–3.74) and 2.65 (95%CI, 2.18–3.22), respectively. Second, in the studies that use tumor tissue, for patients with shortened telomeres, the combined HRs for mortality and tumor progression were 1.26 (95%CI, 0.95–1.66) and 1.65 (95%CI, 1.26–2.15), respectively. In the studies that calculate the telomere length ratios of tumor tissue to adjacent normal mucosa, for patients with lower telomere length ratios, the combined HRs were 0.66 (95%CI, 0.53–0.83) and 0.74 (95%CI, 0.41–1.32) for mortality and tumor progression, respectively. In conclusion, shortened telomere in peripheral blood and tumor tissue might indicate poor survival for cancer patients. However, by calculating the telomere length ratios of tumor tissue to adjacent normal mucosa, the lower ratio might indicate better survival.

Keywords telomere      survival      cancer      meta-analysis     
Corresponding Authors: Chang Liu   
Just Accepted Date: 25 April 2016   Online First Date: 17 May 2016    Issue Date: 27 May 2016
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-016-0450-2     OR     http://academic.hep.com.cn/fmd/EN/Y2016/V10/I2/191
Fig.1  Flow diagram illustrating the screening and selection process.
Study Country/?region Cancer type Center Study ?type Treatment Age Cohort ?size Events ?No. DNA ?source Measurement ?methods Cutoff Survival ?analysis Score
PB study
Solid Cancer
Qu 2015 [41] China Gastric cancer Two Prospective Surgical resection 58 693 280 PB PCR(T/S) ROC curve Cox 17
Chen 2015 [40] China Glioma Single Prospective Surgical resection 44 301 194 PB PCR(T/S) Median Cox 16
Lin 2015 [39] US Bladder cancer Two Prospective Not specified 65 464 353 PB PCR(T/S) Median Cox 15
Russo 2014 [38] Italy Bladder cancer Single Prospective Not specified 64 463 113 PB PCR(T/S) Median Cox 16
Kotsopoulos 2014 [29] Canada Ovarian cancer Multicenter Prospective Not specified NA 1042 611 PB PCR(T/S) Quartilea Cox 14
Duggan 2014 [30] US Breast cancer Three Prospective Not specified NA 1183 135 PB PCR(T/S) Median Cox 17
Chen 2014 [31] China Colorectal cancer Two Prospective Surgical resection NA 571 150 PB PCR(T/S) ROC curves Cox 16
Weischer 2013 [32] Denmark Multiple cancer Multicenter Prospective Not specified 62 3142 1730 PB PCR(T/S) Quartilea Cox 14
Liu 2012 [33] China Liver cancer Two Prospective Transarterial ?chemoembolization 54 269 155 PB PCR(T/S) Median Cox 17
Shen 2012 [34] US Breast cancer Multicenter Prospective Not specified NA 1026 192 PB PCR(T/S) Median Cox 13
Willeit 2010 [35] Italy Multiple cancer Single Prospective Not specified NA 92 44 PB PCR(T/S) Tertileb Cox 17
Svenson 2009 [36] Sweden Renal cancer Single Prospective Surgical resection 65 105 32 PB PCR(T/S) Quartilec Cox 14
Svenson 2008 [37] Sweden Breast cancer Single Prospective Surgical resection 57 265 23 PB PCR(T/S) Quartilec Cox 16
hematonosis
Lin 2014 [42] UK Leukemia Two Prospective Not specified 65 200 NA PB STELA assay Median Cox 16
Mansouri 2013 [43] Sweden Leukemia Multicenter Prospective Not specified 64 265 NA PB PCR(T/S) ROC curves Cox 14
Rampazzo 2012 [44] Italy Leukemia Two Prospective Not specified 62 173 NA PB PCR(T/S) Median Cox 15
Spanoudakis 2011 [57] Greece Myeloproliferative ?neoplasms Single Prospective Chemotherapy NA 44 NA PB and ?bone ?marrow FISH ROC curves KM 12
Borssen 2011 [58] Sweden Leukemia Single Prospective Not specified 9 169 37 Bone ?marrow PCR(T/S) Mean Cox 13
Sellmann 2011 [45] Germany Leukemia Single Prospective Not specified NA 78 17 PB Flow-FISH ROC curves Cox 15
Rossi 2010 [46] Italy Leukemia Single Prospective Not specified NA 128 NA PB Southern Reported* Cox 14
Rossi 2009 [47] Italy Leukemia Single Prospective Not specified 61 191 20 PB Southern ROC curves Cox 15
Roos 2008 [48] Germany Leukemia Single Prospective Not specified 56 147 NA PB PCR(T/S) Median Cox 13
Ghaffari 2008 [49] Iran Leukemia Single Prospective Not specified 35 40 7 PB Telo assay CART technique KM 11
Ricca 2007 [50] Italy Leukemia Single Prospective Chemotherapy 62 201 NA PB Southern ROC curves KM 14
Avigad 2007 [51] Israel Ewing sarcoma Single Prospective Not specified 14 32 13 PB Telo assay ROC curves Cox 14
Grabowski 2005 [52] Sweden Leukemia Three Prospective Not specified 66 296 NA PB and ?bone ?marrow PCR(T/S) Median KM 11
Rigolin 2004 [53] Italy Myelodysplastic ?syndromes Single Prospective Not specified 72 55 8 PB Flow-FISH Median KM 13
Hultdin 2003 [54] Sweden Leukemia Two Prospective Not specified 65 61 33 PB and ?bone ?marrow Southern Median KM 12
Bechter 1998 [55] Austria Leukemia Single Prospective Chemotherapy 66 58 19 Bone ?marrow Southern Median KM 14
Iwama 1997 [56] Japan Leukemia Single Prospective Chemotherapy 45 44 18 Bone ?marrow Southern Mean−2×SD KM 14
Tissue study
Tumor tissue
Augustine 2015 [67] US Colorectal cancer Single Prospective Chemotherapy 60 75 NA Tumor PCR(T/S) Median Cox 16
Pezzolo 2014 [68] Italy Neuroblastoma Two Prospective None 2 102 26 Tumor FISH ROC curve Cox 12
Jeon 2014 [66] Korean Lung cancer Single Prospective Surgical resection 63 164 58 Tumor PCR(T/S) Quartiled Cox 17
Jebaraj 2013 [59] Germany Lymphoma Single Prospective Not specified 65 67 NA Tumor PCR(T/S) Median KM 13
Lu 2011 [60] Italy Breast cancer Single Prospective Surgical resection 57 348 60 Tumor PCR(T/S) Median Cox 16
Heaphy 2007 [61] US Breast cancer Multicenter Prospective Not specified 59 530 100 Tumor slot blot Twice of normal Cox 15
Ohali 2006 [62] Israel Neuroblastoma Single Prospective Chemotherapy 2 51 NA Tumor Telo assay ROC curves Cox 15
Fordyce 2006 [63] US Breast cancer Two Prospective Surgical resection 53 140 NA Tumor Slot blot ROC curves Cox 15
Aranda 2005 [64] Spain Colorectal cancer Single Prospective Surgical resection 69 91 NA Tumor Telo assay Median KM 14
Patel 2002 [65] India Head and neck ?cancer Single Prospective Not specified 50 110 NA Tumor Southern Median KM 12
T/N ratio
Zhang 2014 [69] China Esophageal cancer Single Prospective Surgical resection 56 70 41 T/N ratio PCR(T/S) 0.8 Cox 17
Lötsch 2013 [78] Austria Glioblastoma Single Prospective Surgical resection 60 100 NA T/N ratio PCR(T/S) 1 Cox 15
Kuhn 2011 [70] US Ovarian cancer Two Prospective Not specified 57 212 NA T/N ratio Flow-FISH 1 Cox 13
Valls 2011 [71] Spain Colorectal cancer Single Prospective Surgical resection NA 125 47 T/N ratio Southern 1 Cox 16
Baydar 2010 [72] Turkey Prostate cancer Single Prospective Surgical resection 62 57 NA T/N ratio Flow-FISH 1 Cox 17
Gertler 2008 [73] Germany Esophagus cancer Single Prospective Surgical resection 62 46 21 T/N ratio Telo assay 1.17 Cox 16
Frias 2008 [74] Spain lung cancer Single Prospective Surgical resection 64 83 NA T/N ratio Telo assay 1 Cox 14
Sainger 2007 [75] India Oral cancer Single Prospective Not specified 45 85 NA T/N ratio Southern Median KM 13
Hsu 2005 [76] Taiwan, ?China Esophagus cancer Single Prospective Surgical resection 60 74 49 T/N ratio Telo assay 0.85 Cox 15
Hsu 2004 [79] Taiwan, ?China Lung cancer Single Prospective Surgical resection 64 79 35 T/N ratio Telo assay 0.75 Cox 15
Gertler 2004 [4] Germany Colorectal cancer Single Prospective Surgical resection 65 57 28 T/N ratio Telo assay 0.9 Cox 16
Tab.1  Characteristics of studies included in the meta-analysis
Stratified study No. of studies No. of patients HR (95%CI) Heterogeneity Meta-regression
I2 P P
Study population 0.245
?General population 2 3234 1.34 (1.16–1.54) 88% 0.003
?Special cancer type 11 6382 1.12 (1.00–1.27) 87% <0.001
Sample size 0.721
?≥1000 4 6393 1.21 (1.08–1.35) 47% 0.125
?<1000 9 3223 1.21 (1.03–1.42) 90% <0.001
Cutoff value 0.968
?Median 6 3706 1.06 (0.91–1.23) 87% <0.001
?Other cutoff 7 5910 1.31 (1.17–1.48) 87% <0.001
Quality 0.246
?≥15 9 4301 1.29 (1.10–1.50) 89% <0.001
?<15 4 5315 1.16 (1.04–1.31) 79% 0.002
Area 0.808
?Asia 4 1834 1.20 (0.99–1.44) 93% <0.001
?America/Europe 9 7782 1.21 (1.09–1.35) 82% <0.001
Age 0.592
?≥60 4 4174 1.33 (1.16–1.52) 84% <0.001
?<60 4 1528 0.92 (0.76–1.13) 92% <0.001
Center 0.957
?Multi-center 8 8390 1.20 (1.09–1.33) 87% <0.001
?Single-center 5 1226 1.23 (0.96–1.57) 89% <0.001
Tab.2  Meta-regression analysis of studies that reported the association of peripheral blood telomere length and overall survival of solid cancer patient
Stratified study No. of studies No. of patients HR (95%CI) Heterogeneity Meta-regression
I2 P P
Sample size 0.368
?≥200 4 962 3.07 (2.18–4.32) 83% <0.001
?<200 8 765 2.40 (1.48–3.89) 70% 0.001
Cutoff value 0.982
?Median 6 817 2.65 (1.77–3.98) 62% 0.021
?Other cutoff 6 910 2.99 (2.04–4.40) 83% <0.001
Quality 0.036
?≥15 2 391 13.2 (6.06–27.99) 0% 0.96
?<15 10 1336 2.32 (1.65–3.02) 64% 0.003
Area 0.988
?Asia 2 84 4.26 (1.65–10.99) 45% 0.17
?Europe/Oceania 10 1643 2.72 (2.03–3.64) 77% <0.001
Age 0.140
?≥60 8 1327 3.27 (2.39–4.48) 71% 0.001
?<60 4 400 1.59 (0.85–2.95) 79% 0.002
Center 0.947
?Multi-center 4 822 2.60 (1.84–3.69) 77% 0.005
?Single-center 8 905 3.27 (2.05–5.22) 76% <0.001
Method 0.021
?PCR 4 877 1.70 (1.20–2.42) 72% 0.014
?Non-PCR 8 850 6.63 (4.20–10.49) 36% 0.14
Tab.3  Meta-regression analysis of studies that reported the association of peripheral blood telomere length and overall survival of hematology malignancy patients
Fig.2  Forest plot of hazard ratios of patient survival in all studies focusing on telomere length in peripheral blood. (A) Overall survival in patients with solid cancer. (B) Progression-free survival in patients with solid cancer. (C) Overall survival in patients with hematology malignancy. (D) Progression-free survival in patients with hematology malignancy. HR>1 implies a survival disadvantage for the group with a short telomere length.
Fig.3  Forest plots of hazard ratios of patient survival in all studies focusing on telomere length in tumor tissue or telomere length ratios of tumor tissue to adjacent normal mucosa. (A) Overall survival of patients with telomere length evaluated in tumor tissue. (B) Progression-free survival of patients with telomere length evaluated in tumor tissue. (C) Overall survival of patients evaluating telomere length ratios of tumor tissue to adjacent normal mucosa. (D) Progression-free survival of patients evaluating telomere length ratios of tumor tissue to adjacent normal mucosa. HR>1 implies a survival disadvantage for the group with a short telomere length.
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