Constitutive Telomere Length Research Articles

Genetic Variants of the TERT Gene, Telomere Length, and Circulating TERT as Prognostic Markers in Rectal Cancer Patients.

Simple SummarySingle nucleotide polymorphisms (SNPs) in the TERT gene, which encode the catalytic component of telomerase, can affect TERT expression and constitutive telomere length and have been associated with risk and/or outcome for several human cancers, but very few data are available about their impact on rectal cancer. The aim of our study was to comprehensively investigate the associations of eight common TERT SNPs with telomere length, circulating TERT mRNA in plasma, response to neoadjuvant therapy (CRT) and disease outcome in rectal cancer patients. Our findings indicate that the TERT variants can differently contribute to telomere erosion during CRT, circulating TERT levels and response to CRT. Thus, they could be a useful tool for improving the selection of patients who might benefit from CRT. Furthermore, circulating TERT variation during CRT and its level post-CRT are independent markers of response to CRT and disease progression.Single-nucleotide polymorphisms (SNPs) in the TERT gene can affect telomere length and TERT expression and have been associated with risk and/or outcome for several tumors, but very few data are available about their impact on rectal cancer. Eight SNPs (rs2736108, rs2735940, rs2736098, rs2736100, rs35241335, rs11742908, rs2736122 and rs2853690), mapping in regulatory and coding regions of the TERT gene, were studied in 194 rectal cancer patients to evaluate their association with constitutive telomere length, circulating TERT mRNA levels, response to neoadjuvant chemoradiotherapy (CRT) and disease outcome. At diagnosis, the rs2736100CC genotype was associated with longer telomeres measured pre-CRT, while the rs2736100CC, rs2736108TT and rs2735940AA were associated with greater telomere erosion evaluated post-CRT. The rs2736108CC and rs2853690AA/GG genotypes, respectively associated with lower telomere erosion and lower levels of circulating TERT post-CRT, were also independently associated with a better response to therapy [OR 4.6(1.1–19.1) and 3.0(1.3–6.9)]. Overall, post-CRT, low levels (≤ median value) of circulating TERT and its stable/decreasing levels compared to those pre-CRT, were independently associated with a better response to therapy [OR 5.8(1.9–17.8) and 5.3(1.4–19.4), respectively]. Furthermore, post-CRT, patients with long telomeres (>median value) and low levels of circulating TERT had a significantly lower risk of disease progression [HR 0.4(0.1–0.9) and 0.3(0.1–0.8), respectively]. These findings suggest that TERT SNPs could be a useful tool for improving the selection of patients who could benefit from CRT and support the role of telomere length and circulating TERT mRNA levels as useful markers for monitoring the response to therapy and disease outcome in rectal cancer patients.

Telomeres and Telomere Length: A General Overview.

Telomeres are highly conserved tandem nucleotide repeats that include proximal double-stranded and distal single-stranded regions that in complex with shelterin proteins afford protection at chromosomal ends to maintain genomic integrity. Due to the inherent limitations of DNA replication and telomerase suppression in most somatic cells, telomeres undergo age-dependent incremental attrition. Short or dysfunctional telomeres are recognized as DNA double-stranded breaks, triggering cells to undergo replicative senescence. Telomere shortening, therefore, acts as a counting mechanism that drives replicative senescence by limiting the mitotic potential of cells. Telomere length, a complex hereditary trait, is associated with aging and age-related diseases. Epidemiological data, in general, support an association with varying magnitudes between constitutive telomere length and several disorders, including cancers. Telomere attrition is also influenced by oxidative damage and replicative stress caused by genetic, epigenetic, and environmental factors. Several single nucleotide polymorphisms at different loci, identified through genome-wide association studies, influence inter-individual variation in telomere length. In addition to genetic factors, environmental factors also influence telomere length during growth and development. Telomeres hold potential as biomarkers that reflect the genetic predisposition together with the impact of environmental conditions and as targets for anti-cancer therapies.

Telomeres and Telomerase in Cutaneous Squamous Cell Carcinoma.

The role of telomere biology and telomerase activation in skin cancers has been investigated in melanoma and basal cell carcinoma but limited evidence is available for cutaneous squamous cell carcinoma (cSCC). We will review the current knowledge on the role of telomere and telomerase pathway in cSCC pathogenesis. At the somatic level, both long and short telomere lengths have been described in cSCC. This telomere dichotomy is probably related to two different mechanisms of tumour initiation which determines two tumour subtypes. Telomere shortening is observed during the invasive progression from in situ forms of cSCC, such as Bowen’s disease (BD) and actinic keratosis (AK), to invasive cSCC. At the germline level, controversial results have been reported on the association between constitutive telomere length and risk of cSCC. Approximately 75–85% of cSCC tumours are characterized by a high level of telomerase activity. Telomerase activation has been also reported in AKs and BD and in sun-damaged skin, thus supporting the hypothesis that UV modulates telomerase activity in the skin. Activating TERT promoter mutations have been identified in 32–70% of cSCCs, with the majority showing the UV-signature. No significant correlation was observed between TERT promoter mutations and cSCC clinico-pathological features. However, TERT promoter mutations have been recently suggested to be independent predictors of an adverse outcome. The attention on telomere biology and telomerase activity in cSCC is increasing for the potential implications in the development of effective tools for prognostic assessment and of therapeutic strategies in patients with cutaneous cSCC.

Telomere length, ATM mutation status and cancer risk in Ataxia-Telangiectasia families.

Recent studies have linked constitutive telomere length (TL) to aging-related diseases including cancer at different sites. ATM participates in the signaling of telomere erosion, and inherited mutations in ATM have been associated with increased risk of cancer, particularly breast cancer. The goal of this study was to investigate whether carriage of an ATM mutation and TL interplay to modify cancer risk in ataxia-telangiectasia (A-T) families.The study population consisted of 284 heterozygous ATM mutation carriers (HetAT) and 174 non-carriers (non-HetAT) from 103 A-T families. Forty-eight HetAT and 14 non-HetAT individuals had cancer, among them 25 HetAT and 6 non-HetAT were diagnosed after blood sample collection. We measured mean TL using a quantitative PCR assay and genotyped seven single-nucleotide polymorphisms (SNPs) recurrently associated with TL in large population-based studies.HetAT individuals were at increased risk of cancer (OR = 2.3, 95%CI = 1.2-4.4, P = 0.01), and particularly of breast cancer for women (OR = 2.9, 95%CI = 1.2-7.1, P = 0.02), in comparison to their non-HetAT relatives. HetAT individuals had longer telomeres than non-HetAT individuals (P = 0.0008) but TL was not associated with cancer risk, and no significant interaction was observed between ATM mutation status and TL. Furthermore, rs9257445 (ZNF311) was associated with TL in HetAT subjects and rs6060627 (BCL2L1) modified cancer risk in HetAT and non-HetAT women.Our findings suggest that carriage of an ATM mutation impacts on the age-related TL shortening and that TL per se is not related to cancer risk in ATM carriers. TL measurement alone is not a good marker for predicting cancer risk in A-T families.

Differences in telomere length between sporadic and familial cutaneous melanoma.

Several pieces of evidence indicate that a complex relationship exists between constitutional telomere length (TL) and the risk of cutaneous melanoma. Although the general perception is that longer telomeres increase melanoma risk, some studies do not support this association. We hypothesize that discordant data are due to the characteristics of the studied populations. To evaluate the association of TL with familial and sporadic melanoma. TL was measured by multiplex quantitative polymerase chain reaction in leukocytes from 310 patients with melanoma according to familial/sporadic and single/multiple cancers and 216 age-matched controls. Patients with sporadic melanoma were found to have shorter telomeres compared with those with familial melanoma. In addition, shorter telomeres, while tending to reduce the risk of familial melanoma regardless of single or multiple tumours, nearly trebled the risk of single sporadic melanoma. This is the first time that TL has been correlated to opposite effects on melanoma risk according to the presence or absence of familial predisposition. Individual susceptibility to melanoma should be taken into account when assessing the role of TL as a risk factor.

Highlights of This Issue

The epidermal growth factor receptor (EGFR) is a validated therapeutic target in many human cancers. In spite of the frequent EGFR overexpression in squamous cell carcinoma (SCC), the anti-EGFR antibody, cetuximab, as a single agent exhibits marginal efficacy. Our study shows an impressive efficacy of cetuximab/namitecan combination, which reflects a complete abrogation of EGFR expression, in SCC preclinical models characterized by high EGFR gene copy number. The study provides a molecular basis for a rational combination to be exploited for possible therapeutic applications in the clinical setting and suggests EGFR gene copy number as a possible marker for patient selection.Shortened constitutional telomere length is a well-established risk factor for the development of primary malignancies, related to genomic instability that may result from excessive telomere shortening. However, the relationship between telomere length and risk for second malignancies has not been explored. Gramatges and colleagues performed a matched case-control analysis of telomere length between survivors with and without second malignancies within the Childhood Cancer Survivor Study. A relationship was observed with shortened telomeres, driven by a highly significant association with thyroid second cancers. These results suggest cancer predisposition related to genetic or therapy-related telomere shortening, or other factors affecting telomere homeostasis.Both protein kinase C (PKC) and Twist1 play an important role in cancer pathology, including epithelial-mesenchymal transition as well as treatment resistance. Shiota and colleagues have explored the signaling pathway evoked by androgen-deprivation therapy (ADT) for prostate cancer. ADT induced PKC activation and Twist1 induction. On the other hand, an inhibition of PKC, especially PKCβ and PKCϵ, suppressed Twist1 expression, indicating the novel relationship between PKC and Twist1. Accordingly, PKC inhibition combined with ADT such as novel antiandrogen enzalutamide exerted excellent synergistic anticancer effects, suggesting that PKC inhibition as an alternative of Twist1 inhibition might be a promising therapeutic strategy.The uptake transporter SLC22A1 (OCT1) has been suggested to contribute to imatinib resistance; however, its role for imatinib transport into cells is controversial. Nies and colleagues applied an array of in vitro and in vivo model systems to systematically elucidate the contribution of OCT1 to imatinib transport. Using various OCT1-overexpressing cells, leukemic cells being devoid of OCT1 mRNA and protein, and Oct1-deficient mice the authors demonstrate that cellular uptake of imatinib is independent of OCT1. Therefore, OCT1 is apparently not a valid biomarker for imatinib resistance.

Telomere Content and Risk of Second Malignant Neoplasm in Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study

Shorter constitutional telomere length has been associated with increased cancer incidence. Furthermore, telomere shortening is observed in response to intensive chemotherapy and/or ionizing radiation exposure. We aimed to determine whether less telomere content was associated with treatment-related second malignant neoplasms (SMN) in childhood cancer survivors. Using a nested case-control design, 147 cancer survivors with breast cancer, thyroid cancer, or sarcoma developing after treatment for childhood cancer (cases) were matched (1:1) with childhood cancer survivors without a SMN (controls). Cases and controls were matched by primary cancer diagnosis, years since diagnosis, age at the time of sample collection, years of follow-up from childhood cancer diagnosis, exposure to specific chemotherapy agents, and to specific radiation fields. We performed conditional logistic regression using telomere content as a continuous variable to estimate ORs with corresponding 95% confidence intervals (CI) for development of SMN. ORs were also estimated for specific SMN types, i.e., breast cancer, thyroid cancer, and sarcoma. There was an inverse relationship between telomere content and SMN, with an adjusted OR of 0.3 per unit change in telomere length to single-copy gene ratio (95% CI, 0.09-1.02; P = 0.05). Patients with thyroid cancer SMN were less likely to have more telomere content (OR, 0.04; 95% CI, 0.00-0.55; P = 0.01), but statistically significant associations could not be demonstrated for breast cancer or sarcoma. A relation between less telomere content and treatment-related thyroid cancer was observed, suggesting that shorter telomeres may contribute to certain SMNs in childhood cancer survivors.

Full-Intensity Transplantation and Short Telomeres Increase The Risk Of Cognitive Impairment After Allogeneic Hematopoietic Cell Transplantation (HCT) – Results Of a Prospective Longitudinal Study

▪ BackgroundImpaired cognition – an increasingly recognized concern after HCT – has significant potential to impact societal reintegration. Previous studies have focused on recipients of full-intensity allogeneic HCT; the trajectory of cognitive function after reduced-intensity HCT is unclear. Furthermore, the pathogenesis of cognitive impairment after HCT is unknown. Telomeres are repetitive DNA-protein structures localized to chromosome ends that protect chromosome integrity. Telomeric shortening occurs with each cell division; chemo/radiation hastens telomeric attrition. Glial cells are mitotic and susceptible to telomeric shortening. Constitutional telomere length using blood DNA is representative of the whole organism. Telomeric shortening (measured in blood) is associated with Alzheimer's disease severity. Shorter telomeres could play a role in cognitive impairment after HCT. MethodsThe longitudinal trajectory of cognitive function was assessed from pre-HCT (n=194), to 6m (n=165), 1y (n=155), 2y (n=125) post-HCT using standardized neuropsychological tests (14 tests assessing 8 domains: executive function, processing speed, verbal speed, verbal fluency, working memory, auditory memory, visual memory, fine motor dexterity). IQ was assessed to estimate cognitive reserve. Cognitive function was also assessed in age-, gender-matched healthy controls (HC: n=98) at corresponding time points. Generalized estimating equations (GEE) were fitted to transformed HC scores using time, IQ and sex as covariates; these were then used to compute fitted scores and residuals (fitted – observed scores) in HCT recipients, thus ensuring that HCT residuals were devoid of practice effects. Standardized HCT residuals were transformed to T-scores (mean=50 and SD=10) for GEE analysis. Blood germline DNA was procured pre-HCT (n=142) to assess relative telomere length (RTL: ratio of telomeres to single genes) using qPCR-based telomere assay. RTL was dichotomized as short vs. long (< vs. ≥ median). p≤0.01 was used as critical value to account for multiple comparisons. ResultsMedian age at study was 49y for HCT recipients (range: 19-71) and 51y for HCs; primary diagnoses included acute leukemia (69%), lymphoma (14%) and others (17%). Reduced-intensity conditioning was used in 53% of HCT recipients. Myeloablative total body irradiation was used in 72% of full-intensity HCT recipients. Fifty-one percent of all HCT recipients developed chronic graft-versus-host disease. Compared with HCs, HCT recipients as a whole demonstrated lower cognitive function post-HCT in executive function, p=0.0008; processing speed, p=0.003; verbal fluency, p=0.003; motor dexterity, p=0.001. Multivariable longitudinal analysis of HCT recipients identified older age, male gender, Hispanic ethnicity, low education, income and cognitive reserve, high risk of relapse and high fatigue as significant contributors to cognitive impairment after HCT. After adjusting for these variables, cognitive function was worse in patients who received full-intensity HCT (compared with reduced-intensity) conditioning in executive functioning, p=0.01; processing speed, p=0.0005; verbal speed, p<0.0001; visual memory, p=0.002 (Fig 1). Importantly, there were no significant differences in cognitive functioning between reduced-intensity HCT recipients and HCs (p>0.1; Fig 1). Longitudinal multivariable analysis showed a significant association between short telomeres measured prior to HCT and post-HCT cognitive reduction in female HCT recipients for executive function, p=0.004; processing speed, p=0.009; verbal speed, p=0.009; and working memory, p=0.003 (Fig 2). ConclusionsWe demonstrate several new findings in this study: patients receiving full-intensity HCT are at risk for cognitive impairment in executive functioning, processing speed, verbal speed and visual memory; those receiving reduced-intensity HCT are generally spared. In addition, telomeric shortening prior to HCT is associated with poorer executive function, processing speed, verbal speed and working memory in females after HCT, and not males. Identifying vulnerable subpopulations will facilitate implementation of prevention strategies. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Telomere Length and the Risk of Cutaneous Malignant Melanoma in Melanoma-Prone Families with and without CDKN2A Mutations

IntroductionRecent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations.Materials and MethodsWe measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM) cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT.ResultsWe found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02–7.72, P = 0.04). The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002). One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002) after Bonferroni correction.DiscussionOur findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk.

Abstract 2554: Constitutive short telomere length and lung cancer risk: a large case- control study.

Abstract Background: Telomeres plays a key role in the maintenance of chromosomal stability and integrity. Telomere dysfunction is a common crucial event in malignant transformation and tumorigenesis. Short telomere length in surrogate tissues (peripheral blood leukocytes, or PBLs) has been associated with increased risks of several cancers. In this study, we used a large case control study to evaluate the association of overall telomere length in PBLs with the risk of lung cancer. Methods: We measured the overall telomere lengths in PBLs using real-time quantitative PCR method in a large case-control study with 769 Caucasian lung cancer cases and 769 age, gender, and ethnicity matched healthy controls Wilcoxon rank sum test was used to compare the differences between case patients and control subjects. Unconditional multivariate logistic regression analysis was used to assess the association between telomere length and lung cancer risk. In addition, the effect of age, gender and smoking status was evaluated and correlation analyses between variables were performed. Results: As expected, telomere length was inversely correlated with age in both cases and controls. Lung cancer patients had significantly shorter overall telomere lengths (mean ± standard deviation: 1.20 ±0.37 versus 1.25 ±0.35 p =0.002) than controls, which was only evident in men (1.15 ±0.36 versus 1.24 ±0.36 p &amp;lt;0.001) but not in women. Multivariate logistic regression analysis showed that short overall telomere length was associated with a dose-dependent increase in lung cancer risk. Compared to the individuals within the highest quartile of telomere length, the OR for those within the 3rd, 2nd and 1st quartiles was 0.88 (95% CI 0.65-1.18), 1.08 (95% CI 0.80-1.44) and 1.49 (95% CI 1.12-1.99), respectively (p for trend &amp;lt; 0.001). This effect was more pronounced in current and former smokers (p for trend &amp;lt; 0.001) than in nonsmokers. There was a significant interaction between smoking and overall telomere length in elevating lung cancer risk (p for interaction &amp;lt;0.001). Conclusions: This is the largest epidemiological study to evaluate constitutive telomere length and lung cancer risk. Our data strongly support the role of telomere dysfunction in lung carcinogenesis, highlighting its specific interaction with smoking. Citation Format: Beatriz Sanchez-Espiridion, Jian Gu, David W. Chang, Joe Y. Chang, Charles Lu, Jack A. Roth, Xifeng Wu. Constitutive short telomere length and lung cancer risk: a large case- control study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2554. doi:10.1158/1538-7445.AM2013-2554

Abstract A82: Can telomere length be modified in healthy people?

Abstract Short constitutional telomere length has been associated with aging and cancer, but how telomere length is affected by other epidemiologic or environmental variables in health has not been thoroughly studied. Understanding these associations with telomere length in health is important for studies to evaluate the relationship of telomere length and diseases such as cancer. We measured peripheral blood leukocyte DNA telomere length with quantitative PCR in 1977 non-related healthy controls collected through the Colon Cancer Family Registry (an NCI cooperative group) and through the Mayo Biobank and Biobank for Gastrointestinal Health Research, two IRB approved prospective biospecimen collections based at Mayo Clinic, Rochester, MN. The controls were a median age of 50.6 years old, and 49.6% of the controls were male. Ninety-six percent of the controls were white; 1.8% were Asian, and &amp;lt;1% were either black, Pacific Islander, or Native American. Less than 1% of controls were Hispanic. On univariate analysis, as age increased, telomere length decreased (Pearson correlation coefficient = −0.07, 95% CI: −0.11, −0.03). Telomeres were longer in people who consumed more fruits (p&amp;lt;0.01) and vegetables (p&amp;lt;0.01); took aspirin on a regular basis (p&amp;lt;0.01); or had a family history of cancers of any type (p=0.05). Women had longer telomeres than men (p=0.03). Telomeres were shorter in people who consumed alcohol (p&amp;lt;0.01), took folate on a regular basis (p=0.01), or who consumed red meat (p&amp;lt;0.01). Statistical significance was not found in the following variables: tobacco use, diagnosis of diabetes, intake of calcium, use of hormone replacement therapy in women, or body mass index. On multivariate analysis, age, vegetable consumption, family history of colorectal cancer or any type of cancer, and folate intake were identified as being significantly associated with telomere length. Telomere length may be associated with multiple environmental and demographic variables in healthy individuals, and adjusting for these may be important for studies that test for an association between telomere length and diseases such as cancer. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A82.

Abstract 2994: Constitutional telomere length correlates with colorectal cancer (CRC), but varies by age of cancer onset

Abstract Introduction: Short constitutional telomere length is associated with aging and cancer, but the correlation of telomere length and age at diagnosis of CRC has not been evaluated. Methods: We measured telomere length using quantitative PCR of peripheral blood leukocyte DNA in 1026 individuals diagnosed with MSS CRC who were ≤60 years of age and were chemo-radiotherapy naïve at the time of blood draw. We compared telomere length with 1972 unrelated healthy controls who were frequency matched for gender and age at time of blood collection. We used constructed percentiles of telomere length using the data from the controls. Results: Overall, regardless of cancer status, there was a weak negative correlation of telomere length with age such that as age increased telomere length decreased (Pearson correlation coefficient =−0.1, p&amp;lt; 0.0001); and men had shorter telomeres than women (p=0.0002). The odds ratio (OR) for MSS CRC increased with longer telomere length (OR 1.62 [CI: 1.31-1.99] for those with telomere lengths in the 90th percentile compared to those with telomere lengths in the 50th percentile. In multivariate analysis with adjustment for gender, BMI, smoking, alcohol, and diabetes, telomere length remained an independent risk factor for CRC (p&amp;lt; 0.001), with interaction between telomere length and age (≤50, longer telomeres increased CRC risk; &amp;gt; 50 years old, increasing telomere length associated with decreased CRC risk). Risk was higher for MSS CRC ≤50 years for patients with telomere lengths in the 90th percentile compared to those in the 50th percentile (OR 2.31; CI:1.65-3.23). For subjects diagnosed 50-60 yrs, longer telomere length was associated with lower risk of CRC, and shorter telomere length was associated with the development of CRC (OR 1.22 for telomere lengths in the 10th percentile compared to those in the 50th percentile (OR 1.22:CI; 1.05-1.43). Conclusion: Telomere dynamics appear to influence MSS CRC risk and may differ on the basis of age of cancer diagnosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2994. doi:10.1158/1538-7445.AM2011-2994

Constitutive telomere length and gastric cancer risk: Case‐control analysis in Chinese Han population

The shortening of telomeres may result in chromosome instability and thus promote tumorigenesis. Previous studies have demonstrated clear involvement of telomere shortening in the carcinogenesis of several malignancies. However, the association between constitutive telomere shortening and gastric cancer development has yet to be established. Therefore, in the present study, we measured average telomere length using quantitative real-time PCR in peripheral blood lymphocytes from a gastric cancer (GC) case-control study consisting of 396 cases and 378 controls. The results showed that GC patients had significantly shorter average telomere length than matched controls (mean +/- SD 0.89 +/- 0.19 vs 1.06 +/- 0.25, P < 0.001). We further categorized telomere length using the 50% value in the controls as a cut-off point and assessed the association between telomere length and GC risk using multivariate logistic regression analysis. We found that short telomere length was associated with a significantly increased GC risk (adjusted odds ratio = 2.14, 95% confidence interval = 1.52-2.93). Quartile stratification revealed a dose-response relationship between telomere shortening and GC risk (P for trend < 0.001). Stratified analysis showed that sex, age, and alcohol drinking, but not smoking and Helicobacter pylori infection, seem to have a modulating effect on the average telomere length in both cases and controls. We also found that telomere shortening and smoking had a significant joint effect on GC risk. Collectively, our findings provide the first evidence linking the short telomere length in peripheral blood lymphocytes to elevated GC risk, which warrants further investigation in other populations.