Shortened Telomere Length Is Associated with Increased Risk of Cancer: A Meta-Analysis

“The inverted funnel plots and Egger’s test (linear regression analysis) were used to investigate publication bias [49].”

“The fixedeffects model and the random-effects model, based on the MantelHaenszel method [47] and the DerSimonian and Laird method [48], respectively, were used to combine values from different studies.”

“Heterogeneity was also quantified with the I(2) statistic, a value that indicates what proportion of the total variation across studies is beyond chance, where 0% indicates no observed heterogeneity and larger values show increasing heterogeneity [46].”

“The fixedeffects model and the random-effects model, based on the MantelHaenszel method [47] and the DerSimonian and Laird method [48], respectively, were used to combine values from different studies.”

“Firstly, several variables may affect the length of telomeres, such as age, sex, obesity, smoking, oxidative stress and chronic inflammation [12,64,65,66].”

“05 [45].”

“Thus, telomere length has been suggested as a ‘‘cellular mitotic clock’’ that defines the number of cell divisions and cellular life span [1,5].”

“Thus, telomere length has been suggested as a ‘‘cellular mitotic clock’’ that defines the number of cell divisions and cellular life span [1,5].”

“For example, short telomeres cause an increased risk of developing epithelial cancers by the formation of complex non-reciprocal translocations [15,16], and telomeres in tumor cells and their precursor lesions are significantly shorter than that in surrounding non-tumor cells [17,18].”

“Studies have showed that telomeres are critical for maintaining genomic integrity and that telomere dysfunction or shortening is an early, common genetic alteration acquired in the multistep process of malignant transformation [12,50].”

“Firstly, several variables may affect the length of telomeres, such as age, sex, obesity, smoking, oxidative stress and chronic inflammation [12,64,65,66].”

“In addition, it has been reported that short telomeres on specific chromosome arms may be more important for cancer risk than the overall telomere length in a cell, and chromosome arms with the shortest telomeres were more often found in the telomere fusions, leading to chromosome instability [58,59].”

“For example, short telomeres cause an increased risk of developing epithelial cancers by the formation of complex non-reciprocal translocations [15,16], and telomeres in tumor cells and their precursor lesions are significantly shorter than that in surrounding non-tumor cells [17,18].”

“The possible explanation may be that the difference in hormones, particularly estrogen, may affect telomere dynamics through its antioxidant attributes and its ability to stimulate telomerase, which can elongate telomere ends [57].”

“Additionally, telomere shortening is involved in initiation and progression of malignancies in mouse models and functional studies [13,14].”

“Several studies have documented correlations between shortened telomeres and multiple human diseases associated with age, such as Alzheimer’s disease [6], myocardial infarction [7], vascular dementia [8], liver cirrhosis [9], atherosclerosis [10], ulcerative colitis [11] and premature aging syndromes [12].”

“Additionally, telomere shortening is involved in initiation and progression of malignancies in mouse models and functional studies [13,14].”

“Wu [19] 2003 USA Caucasian Lung cancer 54/54 Retrospective Hospital-based Lymphocytes Q-FISHLSC”

“Several studies have documented correlations between shortened telomeres and multiple human diseases associated with age, such as Alzheimer’s disease [6], myocardial infarction [7], vascular dementia [8], liver cirrhosis [9], atherosclerosis [10], ulcerative colitis [11] and premature aging syndromes [12].”

“In addition, telomere dysfunction has been found to be associated with decreased DNA repair capacity and complex cytogenetic abnormalities [51].”

“For example, the progressive loss of telomeric repeats with each cell division can induce replicative senescence and limit the proliferative potential of a cell, thus functioning as a tumor suppressor [12,55].”

“McGrath [23] 2007 USA Not defined Bladder cancer (HPFS) 123/125 Prospective Population-based Buffy coat Quantitative PCR”

“length may be genetically determined [69], and cells with different origins show a good intra-individual correlation for telomere length in healthy subjects and case subjects [70,71], it may be disputable for the use of hematopoietic cells to be a proxy of average individual telomere length, because the variation in t…”

“Both of animal studies and clinical observations have shown that shorter telomeres were associated with increased risk of cancers, such as epithelial cancers [52,53,54].”

“Several studies have documented correlations between shortened telomeres and multiple human diseases associated with age, such as Alzheimer’s disease [6], myocardial infarction [7], vascular dementia [8], liver cirrhosis [9], atherosclerosis [10], ulcerative colitis [11] and premature aging syndromes [12].”

“break, causing genome instability and enhancing potential for malignant transformation via fusion-bridge-breakage cycles [56].”

“Our meta-analysis included nine breast cancer studies [21,29,31,35,36,38], four bladder studies [19,20,23], three lung cancer studies [19,24,34], two renal cancer studies [19,22], two gastric cancers [27,30], two colorectal cancers [38] and seven studies of other cancers [19,26,28,32,33,37] (Table 1).”

“In fact, we did try to calculate the summary ORs using adjusted ORs available from only nine original papers [21,24,26,27,28, 29,31,36,39], and we found that there were no substantial changes in the pooled, adjusted ORs (OR = 1.”

“In fact, we did try to calculate the summary ORs using adjusted ORs available from only nine original papers [21,24,26,27,28, 29,31,36,39], and we found that there were no substantial changes in the pooled, adjusted ORs (OR = 1.”

“Recently, a study by Nordfjäll et al [63] evaluated the blood telomere length in 959 individuals at baseline and after 10 years of follows-up, and they found no differences in telomere length (at baseline or at follow up) between controls and those who later were diagnosed with cancer, which may challenge the hypothes…”

“Most of studies provided matching information by age and/or other variables except for three studies [21,25,35].”

“Our meta-analysis included nine breast cancer studies [21,29,31,35,36,38], four bladder studies [19,20,23], three lung cancer studies [19,24,34], two renal cancer studies [19,22], two gastric cancers [27,30], two colorectal cancers [38] and seven studies of other cancers [19,26,28,32,33,37] (Table 1).”

“Our meta-analysis included nine breast cancer studies [21,29,31,35,36,38], four bladder studies [19,20,23], three lung cancer studies [19,24,34], two renal cancer studies [19,22], two gastric cancers [27,30], two colorectal cancers [38] and seven studies of other cancers [19,26,28,32,33,37] (Table 1).”

“Our meta-analysis included nine breast cancer studies [21,29,31,35,36,38], four bladder studies [19,20,23], three lung cancer studies [19,24,34], two renal cancer studies [19,22], two gastric cancers [27,30], two colorectal cancers [38] and seven studies of other cancers [19,26,28,32,33,37] (Table 1).”

“Among those 26 publications, five were excluded either because they did not provide available data to extract the ORs and 95% CI [40,41,43,44] or the subjects were of cancer-prone predisposition [42].”

“frequent chromosomal abnormalities mainly occur on certain chromosome arms, such as gains of 1q, 8q, 17q, and 20q, and losses of 8p, 9p, 16q, and 17p [60,61,62].”

“length may be genetically determined [69], and cells with different origins show a good intra-individual correlation for telomere length in healthy subjects and case subjects [70,71], it may be disputable for the use of hematopoietic cells to be a proxy of average individual telomere length, because the variation in t…”

“Our meta-analysis included nine breast cancer studies [21,29,31,35,36,38], four bladder studies [19,20,23], three lung cancer studies [19,24,34], two renal cancer studies [19,22], two gastric cancers [27,30], two colorectal cancers [38] and seven studies of other cancers [19,26,28,32,33,37] (Table 1).”

“Hou [30] 2009 Poland Caucasian Gastric cancer 300/416 Retrospective Population-based Lymphocytes Quantitative PCR”

“Lan [32] 2009 Finland Caucasian Non-Hodgkin Lymphoma 107/107 Prospective Population-based Whole blood Quantitative PCR”

“Our meta-analysis included nine breast cancer studies [21,29,31,35,36,38], four bladder studies [19,20,23], three lung cancer studies [19,24,34], two renal cancer studies [19,22], two gastric cancers [27,30], two colorectal cancers [38] and seven studies of other cancers [19,26,28,32,33,37] (Table 1).”

“In addition, it has been reported that short telomeres on specific chromosome arms may be more important for cancer risk than the overall telomere length in a cell, and chromosome arms with the shortest telomeres were more often found in the telomere fusions, leading to chromosome instability [58,59].”

“Studies have showed that telomeres are critical for maintaining genomic integrity and that telomere dysfunction or shortening is an early, common genetic alteration acquired in the multistep process of malignant transformation [12,50].”

“Hosgood [34] 2009 China Asian Lung cancer 109/97 Retrospective Population-based Sputum Quantitative PCR”

“Shao [22] 2007 USA Mixed Renal Cancer 65/65 Retrospective Hospital-based Lymphocytes Q-FISHLSC”

“In fact, we did try to calculate the summary ORs using adjusted ORs available from only nine original papers [21,24,26,27,28, 29,31,36,39], and we found that there were no substantial changes in the pooled, adjusted ORs (OR = 1.”

“Several studies have documented correlations between shortened telomeres and multiple human diseases associated with age, such as Alzheimer’s disease [6], myocardial infarction [7], vascular dementia [8], liver cirrhosis [9], atherosclerosis [10], ulcerative colitis [11] and premature aging syndromes [12].”

“Human telomeres are approximately 10–15 kb in somatic cells and progressively shortened by ,30 to 200 bp after each cycle of mitotic division, due to incomplete replication of linear DNA molecules and the absence of a mechanism for elongation of telomeres [3].”

“Our meta-analysis included nine breast cancer studies [21,29,31,35,36,38], four bladder studies [19,20,23], three lung cancer studies [19,24,34], two renal cancer studies [19,22], two gastric cancers [27,30], two colorectal cancers [38] and seven studies of other cancers [19,26,28,32,33,37] (Table 1).”

“Among those 26 publications, five were excluded either because they did not provide available data to extract the ORs and 95% CI [40,41,43,44] or the subjects were of cancer-prone predisposition [42].”

“Our meta-analysis included nine breast cancer studies [21,29,31,35,36,38], four bladder studies [19,20,23], three lung cancer studies [19,24,34], two renal cancer studies [19,22], two gastric cancers [27,30], two colorectal cancers [38] and seven studies of other cancers [19,26,28,32,33,37] (Table 1).”

“For example, short telomeres cause an increased risk of developing epithelial cancers by the formation of complex non-reciprocal translocations [15,16], and telomeres in tumor cells and their precursor lesions are significantly shorter than that in surrounding non-tumor cells [17,18].”

“Further, there is some evidence that treatment status (chemotherapy or radiation) can alter telomere length [67,68], and we cannot rule out the possibility of such an effect because of unavailable information about the disease treatment status from the studies used in the analysis.”

“For example, short telomeres cause an increased risk of developing epithelial cancers by the formation of complex non-reciprocal translocations [15,16], and telomeres in tumor cells and their precursor lesions are significantly shorter than that in surrounding non-tumor cells [17,18].”

“In fact, we did try to calculate the summary ORs using adjusted ORs available from only nine original papers [21,24,26,27,28, 29,31,36,39], and we found that there were no substantial changes in the pooled, adjusted ORs (OR = 1.”

“Among those 26 publications, five were excluded either because they did not provide available data to extract the ORs and 95% CI [40,41,43,44] or the subjects were of cancer-prone predisposition [42].”

“Further, there is some evidence that treatment status (chemotherapy or radiation) can alter telomere length [67,68], and we cannot rule out the possibility of such an effect because of unavailable information about the disease treatment status from the studies used in the analysis.”

“Among those 26 publications, five were excluded either because they did not provide available data to extract the ORs and 95% CI [40,41,43,44] or the subjects were of cancer-prone predisposition [42].”

“Both of animal studies and clinical observations have shown that shorter telomeres were associated with increased risk of cancers, such as epithelial cancers [52,53,54].”

“Among those 26 publications, five were excluded either because they did not provide available data to extract the ORs and 95% CI [40,41,43,44] or the subjects were of cancer-prone predisposition [42].”

“Mechanisms of Association Our cancer findings are compatible with known biology.(127) By limiting the proliferative potential of cells, telomere shorteningmay serve as a tumor suppressor, and individualswith longer telomeres may be more likely to acquire somatic mutationsowing to increasedproliferativepotential.”

“…been linked to mortality, several diseases and ageing related pathologies, including some cancers, cardiovascular diseases, obesity, Alzheimer’s disease, diabetes mellitus and osteoporosis in recent years (Jeyapalan and Sedivy, 2008; Aviv, 2002; Blasco, 2005; Ma et al., 2011; Valdes et al., 2007).”