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Cited by 484Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsGenetic Associations and Epidemiology

Telomere length and risk of incident cancer and cancer mortality

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Willeit, Peter, Willeit, Johann, Mayr, Agnes, Weger, Siegfried, Oberhollenzer, Friedrich, Brandstätter, Anita, Kronenberg, Florian, Kiechl, Stefan·2010·JAMA
DOI 10.1001/jama.2010.897
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Abstract

CONTEXT: Telomeres are essential to preserve the integrity of the genome. Critically short telomeres lead to replicative cell senescence and chromosomal instability and may thereby increase cancer risk. OBJECTIVE: To determine the association between baseline telomere length and incident cancer and cancer mortality. DESIGN, SETTING, AND PARTICIPANTS: Leukocyte telomere length was measured by quantitative polymerase chain reaction in 787 participants free of cancer at baseline in 1995 from the prospective, population-based Bruneck Study in Italy. MAIN OUTCOME MEASURES: Incident cancer and cancer mortality over a follow-up period of 10 years (1995-2005 with a follow-up rate of 100%). RESULTS: A total of 92 of 787 participants (11.7%) developed cancer (incidence rate, 13.3 per 1000 person-years). Short telomere length at baseline was associated with incident cancer independently of standard cancer risk factors (multivariable hazard ratio [HR] per 1-SD decrease in log(e)-transformed telomere length, 1.60; 95% confidence interval [CI], 1.30-1.98; P < .001). Compared with participants in the longest telomere length group, the multivariable HR for incident cancer was 2.15 (95% CI, 1.12-4.14) in the middle length group and 3.11 (95% CI, 1.65-5.84) in the shortest length group (P < .001). Incidence rates were 5.1 (95% CI, 2.9-8.7) per 1000 person-years in the longest telomere length group, 14.2 (95% CI, 10.0-20.1) per 1000 person-years in the middle length group, and 22.5 (95% CI, 16.9-29.9) per 1000 person-years in the shortest length group. The association equally applied to men and women and emerged as robust under a variety of circumstances. Furthermore, short telomere length was associated with cancer mortality (multivariable HR per 1-SD decrease in log(e)-transformed telomere length, 2.13; 95% CI, 1.58-2.86; P < .001) and individual cancer subtypes with a high fatality rate. CONCLUSION: In this study population, there was a statistically significant inverse relationship between telomere length and both cancer incidence and mortality.

AI snapshot

Written from the paper’s full text.

TL;DR

In the prospective, population-based Bruneck Study, shorter baseline leukocyte telomere length was associated with higher incident cancer and cancer mortality over 10 years. The association was independent of standard cancer risk factors and appeared stronger for fatal cancers.

Key findings

  • Among 787 cancer-free participants at baseline, 92 (11.7%) developed cancer over 10 years (incidence rate, 13.3 per 1000 person-years); 44 cancer deaths occurred (mortality rate, 6.2 per 1000 person-years).
  • Each 1-SD decrease in log e-transformed telomere length was associated with incident cancer (multivariable HR, 1.60; 95% CI, 1.30-1.98; P<.001) and cancer mortality (multivariable HR, 2.13; 95% CI, 1.58-2.86; P<.001).
  • Compared with the longest telomere length tertile, incident cancer HRs were 2.15 (95% CI, 1.12-4.14) in the middle tertile and 3.11 (95% CI, 1.65-5.84) in the shortest tertile; cancer mortality HRs were 5.63 (95% CI, 1.27-24.98) and 11.11 (95% CI, 2.61-47.36), respectively.
  • Incidence rates were 5.1, 14.2, and 22.5 per 1000 person-years across longest, middle, and shortest telomere tertiles; cancer mortality rates were 0.8, 6.0, and 12.9 per 1000 person-years, respectively.

Methods

  • Prospective, population-based cohort: the Bruneck Study in Italy; 787 participants free of cancer at the 1995 baseline, followed for 10 years (1995-2005) with 100% follow-up.
  • Leukocyte telomere length was measured by quantitative polymerase chain reaction and expressed as relative T/S ratio; analyses used log e-transformed T/S ratios and tertile groups.
  • Cox proportional hazard models estimated associations with incident cancer and cancer mortality, adjusted for age, sex, social class, smoking, alcohol, diabetes, physical activity, BMI, high-sensitivity C-reactive protein, vitamin D, LDL cholesterol, and in a second model interleukin 6 and chronic infection.

Limitations

  • The paper states the study population was entirely white, so findings cannot necessarily be extrapolated to other races and ethnicities.
  • The paper states the number of cases was limited to 92 incident cancers and 44 cancer deaths, and the sample was too small to precisely assess associations for each specific cancer type.
  • The paper states telomere length was measured in circulating blood leukocytes rather than distinct tissues, and fatal/nonfatal tumor classification was based on data through 2005 and subject to further refinement; the observational design also cannot by itself establish causality.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1001/jama.2010.897

Cites

37 of 37 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 19 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Baseline telomere length was associated with cancer mortality (multivariable HR per 1-SD decrease in log e-transformed telomere length, 2.13; 95% CI, 1.58-2.86; P<.001).

    “Furthermore, short telomere length was associated with cancer mortality (multivariable HR per 1-SD decrease in log e -transformed telomere length, 2.13; 95% CI, 1.58-2.86;PϽ.001)”
    • Also stated in: § RESULTS · plain
      “An association was seen between baseline telomere length and cancer mortality (multivariable HR per 1-SD decrease in log e -transformed telomere length, 2.13 [95% CI, 1.58-2.86];P Ͻ .001)”
    Quote in the paperSubstantial claim
  • Findingown data

    Compared with participants with the longest telomere lengths, the multivariable HR for cancer mortality was 11.11 (95% CI, 2.61-47.36) in the shortest length group.

    “Compared with participants with the longest telomere lengths, the multivariable HR for cancer mortality was 5.63 (95% CI, 1.27-24.98) in the middle length group and 11.11 (95% CI, 2.61-47.36) in the shortest length group (PϽ.001).”
    Quote in the paperSubstantial claim
  • Findingown data

    Compared with participants in the longest telomere length group, the multivariable HR for incident cancer was 3.11 (95% CI, 1.65-5.84) in the shortest length group.

    “Compared with participants in the longest telomere length group, the multivariable HR for incident cancer was 2.15 (95% CI, 1.12-4.14) in the middle length group and 3.11 (95% CI, 1.65-5.84) in the shortest length group (PϽ.001).”
    • Also stated in: § RESULTS · plain
      “Compared with participants in the longest telomere length group, the multivariable HR for incident cancer was 2.15 (95% CI, 1.12-4.14) in the middle length group and 3.11 (95% CI, 1.65-5.84) in the shortest length group (P Ͻ.001).”
    Quote in the paperSubstantial claim
  • Findingown data

    The association between baseline telomere length and cancer mortality surpassed the association for cardiovascular mortality (HR, 1.41; 95% CI, 1.01-1.96; P=.05).

    “that surpassed the associations obtained for cardiovascular mortality (HR, 1.41 [95% CI, 1.01-1.96];P = .05)and mortality from other causes (HR, 1.57 [95% CI, 1.17-2.10];P = .003).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Compared with participants with the longest telomere lengths, the multivariable HR for cancer mortality was 5.63 (95% CI, 1.27-24.98) in the middle length group.

    “Compared with participants with the longest telomere lengths, the multivariable HR for cancer mortality was 5.63 (95% CI, 1.27-24.98) in the middle length group and 11.11 (95% CI, 2.61-47.36) in the shortest length group (PϽ.001).”
    Quote in the paperSubstantial claim
  • May combine two claims. 15
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 9

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    During the 10-year follow-up, 92 of 787 participants (11.7%) developed cancer, corresponding to an incidence rate of 13.3 per 1000 person-years (95% CI, 10.8-16.3).

    “A total of 92 of 787 participants (11.7%) developed cancer (incidence rate, 13.3 per 1000 person-years).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Of the 92 incident cancer cases, 44 were fatal, corresponding to a mortality rate of 6.2 per 1000 person-years (95% CI, 4.6-8.3).

    “in 44 of whom it was fatal (mortality rate, 6.2 per 1000 person-years; 95% CI, 4.6-8.3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In absolute terms, 2, 14, and 28 individuals in the longest, middle, and shortest telomere length groups, respectively, died of cancer, corresponding to mortality rates of 0.8, 6.0, and 12.9 per 1000 person-years.

    “In absolute terms 2, 14, and 28 of individuals in the longest, middle, and short-est telomere length groups, respectively, died of cancer, corresponding to mortality rates of 0.8, 6.0, and 12.9 per 1000 person-years, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Telomere length had a similar predictive value for cancer in both men and women and in various age groups.

    “Furthermore, an analysis revealed telomere length to have a similar predictive value for cancer in both men and women and in various age groups (FIGURE 3).”
    • Also stated in: § Abstract · boosted
      “The association equally applied to men and women and emerged as robust under a variety of circumstances.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The overall number of incident cancer cases was 92 and cancer mortality cases was 44.

    “the overall number of cases is limited to 92 and 44, respectively”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Sensitivity analyses excluding participants with prior cancer or extending the list of covariates yielded similar results.

    “Sensitivity analyses excluding participants with prior cancer or extending the list of covariates yielded similar results (Figure 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    In this study population, there was a statistically significant inverse relationship between telomere length and both cancer incidence and mortality.

    “ConclusionIn this study population, there was a statistically significant inverse relationship between telomere length and both cancer incidence and mortality.”
    • Also stated in: § COMMENT · boosted
      “We demonstrated significant inverse correlations between baseline leukocyte telomerelengthandbothcancerincidenceand mortality,whichemergedasindependent of standard cancer risk factors (Figure 1).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In fibroblast cultures, accruing senescent cells were shown to produce and release high amounts of growth factors, causing an overwhelming proliferation of the surrounding tissue, and to secrete metalloproteinase, diminishing intercellular adhesions and potentially favoring metastatic spread of tumors.

    “In fibroblast cultures, accruing senescent cells were shown to produce and release high amounts of growth factors, 27 causing an overwhelming proliferation of the surrounding tissue, and to secrete metalloproteinase, diminishing intercellular adhesions and potentially favoring metastatic spread of tumors.28”
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    • cites [27]

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    Premisecitation

    Current evidence on telomere length and cancer mainly derives from case-control studies and is inconsistent for various specific types of cancer.

    “Current evidence mainly derives from case-control studies and is inconsistent for various specific types of cancer.[7][8][9][10][11][12][13][14][15]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7][8][9][10][11][12][13][14][15]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In a mouse model, deficiency of the telomerase RNA component caused a markedly enhanced frequency of chromosomal abnormalities and sporadic cancer, particularly in the case of simultaneous inactivation of the tumor suppressor gene p53.

    “Inamousemodel,deficiencyofthetelom-eraseRNAcomponent(theRNAtemplate fortelomereprolongation)causedamarkedlyenhancedfrequencyofchromosomal abnormalities and sporadic cancer, 2 particularly in the case of simultaneous inactivation of the tumor suppressor gene p53. 1”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2]

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    Premisecitation

    Dyskeratosis congenita, a rare disorder of telomere maintenance, was associated with visceral malignancies and squamous cell carcinoma of the skin.

    “Dyskeratosis congenita, a rare disorder of telomere maintenance, was associated with visceral malignancies and squamous cell carcinoma of the skin. 32”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32]

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    Premisecitation

    A significantly higher production of vascular endothelial growth factor in senescent cells may stimulate tumor growth and dissemination by promoting neovascularization.

    “Moreover, a significantly higher productionofvascularendothelialgrowthfactor in senescent cells 29,30 may stimulate tumorgrowthanddisseminationbypromoting neovascularization.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29]

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  • May combine two claims.

    Premisecitation

    Short telomeres and concurrent chromosomal instability contribute to malignant cell transformation.

    “there are several lines of evidence from experimental animals, basic research, genome-wide association studies, and rare disorders of telomere maintenance [1][2][3][4][5] suggesting that short telomeres and concurrent chromosomal instability contribute to malignant cell transformation.3,6”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1][2][3][4][5]

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  • May combine two claims.

    Interpretationown data

    Short telomeres are associated with an enhanced risk of cancer and fatal cancer in particular.

    “In conclusion, our study shows that short telomeres are associated with an enhanced risk of cancer and fatal cancer in particular.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Complete follow-up data on clinical end points between 1995 and 2005 were available for 787 participants.

    “Complete follow-up data on clinical end points occurring between 1995 and 2005 were available for the remaining 787 participants.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Polymorphisms in the gene encoding TERT, the catalytic subunit of telomerase, were associated with an increased risk for cancer of the lung, urinary bladder, prostate, and cervix.

    “Rafnar et al 5 demonstrated that polymorphisms in the gene encoding TERT, the catalytic subunit of telomerase, were associated with an increased risk for cancer of the lung, urinary bladder, prostate, and cervix.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rafnar et al 5

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Population characteristics are comparable with those of other Western communities, but transferability of findings to geographical regions with a prominently distinct genetic background remains to be established.

    “Population characteristics are comparable with those of other Western communities, but transferability of our findings to geographical regions with a prominently distinct genetic background remains to be established.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Our results corroborate previous evaluations linking short telomere length to bladder cancer, renal cell carcinoma, non-Hodgkin lymphoma, lung cancer, and head and neck tumors, but failed to obtain significant correlations for colorectal and breast cancer.

    “Our results corroborate well with previous evaluations demonstrating a link between short telomere length and bladder cancer, 7,8,22 renal cell carcinoma, 8,9 non-Hodgkin lymphoma, 10 lung cancer, 11 and head and neck tumors, 8 but failed to obtain significant correlations between short telomere length and colorectal and breast cancer.[12][13][14]23”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [7]

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    Leukocyte telomere length measurement by quantitative PCR was highly reproducible and correlated with Southern Blot-based mean telomere length restriction fragments.

    “As shown previously, 21 telomere length measurement by quantitative PCR was highly reproducible and correlated with Southern Blot-based mean telomere length restriction fragments.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21]

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Telomere length measurement was performed in quadruplicate, showed a high level of reproducibility, and was corrected for quantitative PCR efficiency.

    “Telomere length measurement was performed in quadruplicate, showed a high level of reproducibility, and was corrected for quantitative PCR efficiency.”
    Quote in the paperNot a substantial claim
20 of 20

  • The authors state this as an assumption.

    This is the first prospective, population-based study to estimate the impact of telomere length on overall cancer manifestation and mortality.

    “Toourknowledge,thisisthefirstprospective, population-based study to estimate the impact of telomere length on overall cancer manifestation and mortality.”

  • The paper relies on this without support.

    There is a considerable paucity of data regarding cancer mortality.

    “Moreover, there is a considerable paucity of data regarding cancer mortality.”

  • The paper relies on this without support.

    Few evaluations have been prospective in design and measured telomere length well in advance of cancer manifestation; all studies to date were conducted in selected patient groups or healthy volunteers recruited among health professionals.

    “Few evaluations have been prospective in design and have measured telomere length well in advance of cancer manifestation; all of the studies, to date, were conducted in selected patient groups or healthy volunteers re-cruited among health professionals.”

  • The paper relies on this without support.

    A variety of experimental and genetic studies support the hypothesis that telomere attrition contributes to the manifestation and dissemination of malignancies.

    “A variety of experimental and genetic studies support the hypothesis that telomere attrition contributes to the manifestation and dissemination of malignancies.”
4 of 4

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Authors
Willeit, P., Willeit, J., Mayr, A., Weger, S., Oberhollenzer, F., Brandstätter, A., Kronenberg, F., & Kiechl, S.
Affiliations
Innsbruck Medical University (AT)
Corresponding author
Kiechl, Stefan
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2010-07-07
Volume
304
Issue
1
Pages
69
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2010.897
OpenAlex
W2035720189
Cited by
484
References
37
Citations by year
2026: 9 · 2025: 8 · 2024: 31 · 2023: 10 · 2022: 13 · 2021: 26 · 2020: 36 · 2019: 26 · 2018: 42 · 2017: 37 · 2016: 33 · 2015: 38 · 2014: 56 · 2013: 32 · 2012: 49
FWCI
25.78
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
telomere length, leukocyte telomeres, cancer incidence, cancer mortality, short telomeres, chromosomal instability, Bruneck Study, cancer risk biomarkers, aging and cancer risk, sex differences in cancer risk, genetic susceptibility to cancer, cancer risk factors, cancer screening, early cancer detection
MeSH terms
Adult, Aged, Female, Humans, Italy, Leukocytes, Male, Middle Aged, Neoplasms, Prospective Studies, Risk, Polymerase Chain Reaction, Telomere

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